23935931	Auditory sensory modulation difficulties and problems with automatic re-orienting to sound are well documented in autism spectrum disorders (ASD). Abnormal preattentive arousal processes may contribute to these deficits. In this study, we investigated components of the cortical auditory evoked potential (CAEP) reflecting preattentive arousal in children with ASD and typically developing (TD) children aged 3-8 years. Pairs of clicks ('S1' and 'S2') separated by a 1 sec S1-S2 interstimulus interval (ISI) and much longer (8-10 sec) S1-S1 ISIs were presented monaurally to either the left or right ear. In TD children, the P50, P100 and N1c CAEP components were strongly influenced by temporal novelty of clicks and were much greater in response to the S1 than the S2 click. Irrespective of the stimulation side, the 'tangential' P100 component was rightward lateralized in TD children, whereas the 'radial' N1c component had higher amplitude contralaterally to the stimulated ear. Compared to the TD children, children with ASD demonstrated 1) reduced amplitude of the P100 component under the condition of temporal novelty (S1) and 2) an attenuated P100 repetition suppression effect. The abnormalities were lateralized and depended on the presentation side. They were evident in the case of the left but not the right ear stimulation. The P100 abnormalities in ASD correlated with the degree of developmental delay and with the severity of auditory sensory modulation difficulties observed in early life. The results suggest that some rightward-lateralized brain networks that are crucially important for arousal and attention re-orienting are compromised in children with ASD and that this deficit contributes to sensory modulation difficulties and possibly even other behavioral deficits in ASD.	t	\N
21823798	In older adults, difficulties processing complex auditory scenes, such as speech comprehension in noisy environments, might be due to a specific impairment of temporal processing at early, automatic processing stages involving auditory sensory memory (ASM). Even though age effects on auditory temporal processing have been well-documented, there is a paucity of research on how ASM processing of more complex tone-patterns is altered by age. In the current study, age effects on ASM processing of temporal and frequency aspects of two-tone patterns were investigated using a passive listening protocol. The P1 component, the mismatch negativity (MMN) and the P3a component of event-related brain potentials (ERPs) to tone frequency and temporal pattern deviants were recorded in younger and older adults as a measure of auditory event detection, ASM processing, and attention switching, respectively. MMN was elicited with smaller amplitude to both frequency and temporal deviants in older adults. Furthermore, P3a was elicited only in the younger adults. In conclusion, the smaller MMN amplitude indicates that automatic processing of both frequency and temporal aspects of two-tone patterns is impaired in older adults. The failure to initiate an attention switch, suggested by the absence of P3a, indicates that impaired ASM processing of patterns may lead to less distractibility in older adults. Our results suggest age-related changes in ASM processing of patterns that cannot be explained by an inhibitory deficit.	t	\N
19929331	Native language experience plays a critical role in shaping speech categorization, but the exact mechanisms by which it does so are not well understood. Investigating category learning of nonspeech sounds with which listeners have no prior experience allows their experience to be systematically controlled in a way that is impossible to achieve by studying natural speech acquisition, and it provides a means of probing the boundaries and constraints that general auditory perception and cognition bring to the task of speech category learning. In this study, we used a multimodal, video-game-based implicit learning paradigm to train participants to categorize acoustically complex, nonlinguistic sounds. MMN responses to the nonspeech stimuli were collected before and after training, and changes in MMN resulting from the nonspeech category learning closely resemble patterns of change typically observed during speech category learning. Results indicate that changes in mismatch negativity resulting from the nonspeech category learning closely resemble patterns of change typically observed during speech category learning. This suggests that the often-observed "specialized" neural responses to speech sounds may result, at least in part, from the expertise we develop with speech categories through experience rather than from properties unique to speech (e.g., linguistic or vocal tract gestural information). Furthermore, particular characteristics of the training paradigm may inform our understanding of mechanisms that support natural speech acquisition.	t	\N
20578033	Understanding the basic neural processes that underlie complex higher-order cognitive operations and functional domains is a fundamental goal of cognitive neuroscience. Electroencephalography (EEG) is a non-invasive and relatively inexpensive method for assessing neurophysiological function that can be used to achieve this goal. EEG measures the electrical activity of large, synchronously firing populations of neurons in the brain with electrodes placed on the scalp. This unit outlines the basics of setting up an EEG experiment with human participants, including equipment, and a step-by-step guide to applying and preparing an electrode cap. Also included are support protocols for two event-related potential (ERP) paradigms, P50 suppression, and mismatch negativity (MMN), which are measures of early sensory processing. These paradigms can be used to assess the integrity of early sensory processing in normal individuals and clinical populations, such as individuals with schizophrenia.	t	\N
20665718	Subjects detected rarely occurring shifts between two simple tone-patterns, in a paradigm that dissociated the effects of rarity from those of pitch, habituation, and attention. Whole-head magnetoencephalography suggested that rare attended pattern-shifts evoked activity first in the superior temporal plane (sTp, peak ~100 ms), then superior temporal sulcus (sTs, peak ~130 ms), then posteroventral prefrontal (pvpF, peak ~230 ms), and anterior temporal cortices (aT, peak ~370 ms). Activity was more prominent in the right hemisphere. After subtracting the effects of nonshift tones (balanced for pitch and habituation status), weak but consistent differential effects of pattern-shifts began in aT at 90-130 ms, spread to sTs and sTp at ∼130 ms, then pvpF, and finally returned to aT. Cingulate activity resembled prefrontal. Responses to pattern shifts were greatly attenuated when the same stimuli were ignored, suggesting that the initial superior temporal activity reflected an attention-related mismatch negativity. The prefrontal activity at ~230 ms corresponded in latency and task correlates with simultaneously recorded event-related potential components N2b and P3a; the subsequent temporal activity corresponded to the P3b. These results were confirmed in sensors specific for frontal or temporal cortex, and thus are independent of the inverse method used. Overall, these results suggest that auditory working memory for temporal patterns begins with detection of the pattern change by an interaction of anterior and superior temporal structures, followed by identification of the event and its consequences led by posteroventral prefrontal and cingulate cortices, and finally, definitive encoding of the event in anterior temporal areas.	t	\N
20929535	We investigated the processing of task-irrelevant and unexpected novel sounds and its modulation by working-memory load in children aged 9-10 and in adults. Environmental sounds (novels) were embedded amongst frequently presented standard sounds in an auditory-visual distraction paradigm. Each sound was followed by a visual target. In two conditions, participants evaluated the position of a visual stimulus (0-back, low load) or compared the position of the current stimulus with the one two trials before (2-back, high load). Processing of novel sounds were measured with reaction times, hit rates and the auditory event-related brain potentials (ERPs) Mismatch Negativity (MMN), P3a, Reorienting Negativity (RON) and visual P3b. In both memory load conditions novels impaired task performance in adults whereas they improved performance in children. Auditory ERPs reflect age-related differences in the time-window of the MMN as children showed a positive ERP deflection to novels whereas adults lack an MMN. The attention switch towards the task irrelevant novel (reflected by P3a) was comparable between the age groups. Adults showed more efficient reallocation of attention (reflected by RON) under load condition than children. Finally, the P3b elicited by the visual target stimuli was reduced in both age groups when the preceding sound was a novel. Our results give new insights in the development of novelty processing as they (1) reveal that task-irrelevant novel sounds can result in contrary effects on the performance in a visual primary task in children and adults, (2) show a positive ERP deflection to novels rather than an MMN in children, and (3) reveal effects of auditory novels on visual target processing.	t	\N
21368051	Certain features of objects or events can be represented by more than a single sensory system, such as roughness of a surface (sight, sound, and touch), the location of a speaker (audition and sight), and the rhythm or duration of an event (by all three major sensory systems). Thus, these properties can be said to be sensory-independent or amodal. A key question is whether common multisensory cortical regions process these amodal features, or does each sensory system contain its own specialized region(s) for processing common features? We tackled this issue by investigating simple duration-detection mechanisms across audition and touch; these systems were chosen because fine duration discriminations are possible in both. The mismatch negativity (MMN) component of the human event-related potential provides a sensitive metric of duration processing and has been elicited independently during both auditory and somatosensory investigations. Employing high-density electroencephalographic recordings in conjunction with intracranial subdural recordings, we asked whether fine duration discriminations, represented by the MMN, were generated in the same cortical regions regardless of the sensory modality being probed. Scalp recordings pointed to statistically distinct MMN topographies across senses, implying differential underlying cortical generator configurations. Intracranial recordings confirmed these noninvasive findings, showing generators of the auditory MMN along the superior temporal gyrus with no evidence of a somatosensory MMN in this region, whereas a robust somatosensory MMN was recorded from postcentral gyrus in the absence of an auditory MMN. The current data clearly argue against a common circuitry account for amodal duration processing.	t	\N
21483666	Acute stress is a stereotypical, but multimodal response to a present or imminent challenge overcharging an organism. Among the different branches of this multimodal response, the consequences of glucocorticoid secretion have been extensively investigated, mostly in connection with long-term memory (LTM). However, stress responses comprise other endocrine signaling and altered neuronal activity wholly independent of pituitary regulation. To date, knowledge of the impact of such "paracorticoidal" stress responses on higher cognitive functions is scarce. We investigated the impact of an ecological stressor on the ability to direct selective attention using event-related potentials in humans. Based on research in rodents, we assumed that a stress-induced imbalance of catecholaminergic transmission would impair this ability. The stressor consisted of a single cold pressor test. Auditory negative difference (Nd) and mismatch negativity (MMN) were recorded in a tonal dichotic listening task. A time series of such tasks confirmed an increased distractibility occurring 4-7 minutes after onset of the stressor as reflected by an attenuated Nd. Salivary cortisol began to rise 8-11 minutes after onset when no further modulations in the event-related potentials (ERP) occurred, thus precluding a causal relationship. This effect may be attributed to a stress-induced activation of mesofrontal dopaminergic projections. It may also be attributed to an activation of noradrenergic projections. Known characteristics of the modulation of ERP by different stress-related ligands were used for further disambiguation of causality. The conjuncture of an attenuated Nd and an increased MMN might be interpreted as indicating a dopaminergic influence. The selective effect on the late portion of the Nd provides another tentative clue for this. Prior studies have deliberately tracked the adrenocortical influence on cognition, as it has proven most influential with respect to LTM. However, current cortisol-optimized study designs would have failed to detect the present findings regarding attention.	t	\N
21750713	In the present study we investigated the capacity of the memory store underlying the mismatch negativity (MMN) response in musicians and nonmusicians for complex tone patterns. While previous studies have focused either on the kind of information that can be encoded or on the decay of the memory trace over time, we studied capacity in terms of the length of tone sequences, i.e., the number of individual tones that can be fully encoded and maintained. By means of magnetoencephalography (MEG) we recorded MMN responses to deviant tones that could occur at any position of standard tone patterns composed of four, six or eight tones during passive, distracted listening. Whereas there was a reliable MMN response to deviant tones in the four-tone pattern in both musicians and nonmusicians, only some individuals showed MMN responses to the longer patterns. This finding of a reliable capacity of the short-term auditory store underlying the MMN response is in line with estimates of a three to five item capacity of the short-term memory trace from behavioural studies, although pitch and contour complexity covaried with sequence length, which might have led to an understatement of the reported capacity. Whereas there was a tendency for an enhancement of the pattern MMN in musicians compared to nonmusicians, a strong advantage for musicians could be shown in an accompanying behavioural task of detecting the deviants while attending to the stimuli for all pattern lengths, indicating that long-term musical training differentially affects the memory capacity of auditory short-term memory for complex tone patterns with and without attention. Also, a left-hemispheric lateralization of MMN responses in the six-tone pattern suggests that additional networks that help structuring the patterns in the temporal domain might be recruited for demanding auditory processing in the pitch domain.	t	\N
21808660	Have you ever shouted your child's name from the kitchen while they were watching television in the living room to no avail, so you shout their name again, only louder? Yet, still no response. The current study provides evidence that young children process loudness changes differently than pitch changes when they are engaged in another task such as watching a video. Intensity level changes were physiologically detected only when they were behaviorally relevant, but frequency level changes were physiologically detected without task relevance in younger children. This suggests that changes in pitch rather than changes in volume may be more effective in evoking a response when sounds are unexpected. Further, even though behavioral ability may appear to be similar in younger and older children, attention-based physiologic responses differ from automatic physiologic processes in children. Results indicate that 1) the automatic auditory processes leading to more efficient higher-level skills continue to become refined through childhood; and 2) there are different time courses for the maturation of physiological processes encoding the distinct acoustic attributes of sound pitch and sound intensity. The relevance of these findings to sound perception in real-world environments is discussed.	t	\N
22163029	The detection of deviant sounds is a crucial function of the auditory system and is reflected by the automatically elicited mismatch negativity (MMN), an auditory evoked potential at 100 to 250 ms from stimulus onset. It has recently been shown that rarely occurring frequency and location deviants in an oddball paradigm trigger a more negative response than standard sounds at very early latencies in the middle latency response of the human auditory evoked potential. This fast and early ability of the auditory system is corroborated by the finding of neurons in the animal auditory cortex and subcortical structures, which restore their adapted responsiveness to standard sounds, when a rare change in a sound feature occurs. In this study, we investigated whether the detection of intensity deviants is also reflected at shorter latencies than those of the MMN. Auditory evoked potentials in response to click sounds were analyzed regarding the auditory brain stem response, the middle latency response (MLR) and the MMN. Rare stimuli with a lower intensity level than standard stimuli elicited (in addition to an MMN) a more negative potential in the MLR at the transition from the Na to the Pa component at circa 24 ms from stimulus onset. This finding, together with the studies about frequency and location changes, suggests that the early automatic detection of deviant sounds in an oddball paradigm is a general property of the auditory system.	t	\N
22213909	Behavioural and electrophysiological studies give differing impressions of when auditory discrimination is mature. Ability to discriminate frequency and speech contrasts reaches adult levels only around 12 years of age, yet an electrophysiological index of auditory discrimination, the mismatch negativity (MMN), is reported to be as large in children as in adults. Auditory ERPs were measured in 30 children (7 to 12 years), 23 teenagers (13 to 16 years) and 32 adults (35 to 56 years) in an oddball paradigm with tone or syllable stimuli. For each stimulus type, a standard stimulus (1000 Hz tone or syllable [ba]) occurred on 70% of trials, and one of two deviants (1030 or 1200 Hz tone, or syllables [da] or [bi]) equiprobably on the remaining trials. For the traditional MMN interval of 100–250 ms post-onset, size of mismatch responses increased with age, whereas the opposite trend was seen for an interval from 300 to 550 ms post-onset, corresponding to the late discriminative negativity (LDN). Time-frequency analysis of single trials revealed that the MMN resulted from phase-synchronization of oscillations in the theta (4–7 Hz) range, with greater synchronization in adults than children. Furthermore, the amount of synchronization was significantly correlated with frequency discrimination threshold. These results show that neurophysiological processes underlying auditory discrimination continue to develop through childhood and adolescence. Previous reports of adult-like MMN amplitudes in children may be artefactual results of using peak measurements when comparing groups that differ in variance.	t	\N
22221004	Deviations from repetitive auditory stimuli evoke a mismatch negativity (MMN). Counterintuitively, omissions of repetitive stimuli do not. Violations of patterns reflecting complex rules also evoke MMN. To detect a MMN to missing stimuli, we developed an auditory gestalt task using one stimulus. Groups of six pips (50 ms duration, 330 ms stimulus onset asynchrony [SOA], 400 trials), were presented with an intertrial interval (ITI) of 750 ms while subjects (n=16) watched a silent video. Occasional deviant groups had missing 4th or 6th tones (50 trials each). Missing stimuli evoked a MMN (p<.05). The missing 4th (-0.8 µV, p<.01) and the missing 6th stimuli (-1.1 µV, p<.05) were more negative than standard 6th stimuli (0.3 µV). MMN can be elicited by a missing stimulus at long SOAs by violation of a gestalt grouping rule. Patterned stimuli appear more sensitive to omissions and ITI than homogenous streams.	t	\N
22551948	Recent studies show that electrophysiological markers of auditory processing such as the cortical 100 ms response (M100) and the mismatch field, derived from magnetoencephalography, might be used to identify children with autism spectrum disorders--M100 peak latency--and to stratify children with autism according to the degree of language impairment--mismatch field peak latency. The present study examined the latency of right superior temporal gyrus M100 and mismatch field in a cohort of children and young adolescents with specific language impairment (n=17), in comparison with age-matched and nonverbal intelligence quotient-matched typically developing controls (n=21). Neither group showed symptoms associated with autism. Although M100 latency (reflecting early auditory processing) did not distinguish controls from children with specific language impairment, the later 'change detection' mismatch field response was significantly delayed (by >50 ms) in the specific language impairment group. Linear discriminant analysis confirmed the role of mismatch field latency (92%) but not M100 latency (8%) in distinguishing groups. The present results lend support to the claim that a delayed M100 is specific to autism spectrum disorders (with relative independence of degree of language impairment) and that a delayed mismatch field reflects an abnormality more generally associated with language impairment, suggesting that mismatch field delay in the present specific language impairment group and previously reported in autistic children with language impairment may be indicative of a common neural system dysfunction.	t	\N
22570723	Multisensory learning and resulting neural brain plasticity have recently become a topic of renewed interest in human cognitive neuroscience. Music notation reading is an ideal stimulus to study multisensory learning, as it allows studying the integration of visual, auditory and sensorimotor information processing. The present study aimed at answering whether multisensory learning alters uni-sensory structures, interconnections of uni-sensory structures or specific multisensory areas. In a short-term piano training procedure musically naive subjects were trained to play tone sequences from visually presented patterns in a music notation-like system [Auditory-Visual-Somatosensory group (AVS)], while another group received audio-visual training only that involved viewing the patterns and attentively listening to the recordings of the AVS training sessions [Auditory-Visual group (AV)]. Training-related changes in cortical networks were assessed by pre- and post-training magnetoencephalographic (MEG) recordings of an auditory, a visual and an integrated audio-visual mismatch negativity (MMN). The two groups (AVS and AV) were differently affected by the training. The results suggest that multisensory training alters the function of multisensory structures, and not the uni-sensory ones along with their interconnections, and thus provide an answer to an important question presented by cognitive models of multisensory training.	t	\N
22815876	The precise neural mechanisms underlying speech sound representations are still a matter of debate. Proponents of 'sparse representations' assume that on the level of speech sounds, only contrastive or otherwise not predictable information is stored in long-term memory. Here, in a passive oddball paradigm, we challenge the neural foundations of such a 'sparse' representation; we use words that differ only in their penultimate consonant ("coronal" [t] vs. "dorsal" [k] place of articulation) and for example distinguish between the German nouns Latz ([lats]; bib) and Lachs ([laks]; salmon). Changes from standard [t] to deviant [k] and vice versa elicited a discernible Mismatch Negativity (MMN) response. Crucially, however, the MMN for the deviant [lats] was stronger than the MMN for the deviant [laks]. Source localization showed this difference to be due to enhanced brain activity in right superior temporal cortex. These findings reflect a difference in phonological 'sparsity': Coronal [t] segments, but not dorsal [k] segments, are based on more sparse representations and elicit less specific neural predictions; sensory deviations from this prediction are more readily 'tolerated' and accordingly trigger weaker MMNs. The results foster the neurocomputational reality of 'representationally sparse' models of speech perception that are compatible with more general predictive mechanisms in auditory perception.	t	\N
22916282	Auditory deviance detection in humans is indexed by the mismatch negativity (MMN), a component of the auditory evoked potential (AEP) of the electroencephalogram (EEG) occurring at a latency of 100-250 ms after stimulus onset. However, by using classic oddball paradigms, differential responses to regularity violations of simple auditory features have been found at the level of the middle latency response (MLR) of the AEP occurring within the first 50 ms after stimulus (deviation) onset. These findings suggest the existence of fast deviance detection mechanisms for simple feature changes, but it is not clear whether deviance detection among more complex acoustic regularities could be observed at such early latencies. To test this, we examined the pre-attentive processing of rare stimulus repetitions in a sequence of tones alternating in frequency in both long and middle latency ranges. Additionally, we introduced occasional changes in the interaural time difference (ITD), so that a simple-feature regularity could be examined in the same paradigm. MMN was obtained for both repetition and ITD deviants, occurring at 150 ms and 100 ms after stimulus onset respectively. At the level of the MLR, a difference was observed between standards and ITD deviants at the Na component (20-30 ms after stimulus onset), for 800 Hz tones, but not for repetition deviants. These findings suggest that detection mechanisms for deviants to simple regularities, but not to more complex regularities, are already activated in the MLR range, supporting the view that the auditory deviance detection system is organized in a hierarchical manner.	t	\N
23028971	For the perception of timbre of a musical instrument, the attack time is known to hold crucial information. The first 50 to 150 ms of sound onset reflect the excitation mechanism, which generates the sound. Since auditory processing and music perception in particular are known to be hampered in cochlear implant (CI) users, we conducted an electroencephalography (EEG) study with an oddball paradigm to evaluate the processing of small differences in musical sound onset. The first 60 ms of a cornet sound were manipulated in order to examine whether these differences are detected by CI users and normal-hearing controls (NH controls), as revealed by auditory evoked potentials (AEPs). Our analysis focused on the N1 as an exogenous component known to reflect physical stimuli properties as well as on the P2 and the Mismatch Negativity (MMN). Our results revealed different N1 latencies as well as P2 amplitudes and latencies for the onset manipulations in both groups. An MMN could be elicited only in the NH control group. Together with additional findings that suggest an impact of musical training on CI users' AEPs, our findings support the view that impaired timbre perception in CI users is at partly due to altered sound onset feature detection.	t	\N
23131615	This study investigated whether the mismatch negativity (MMN) event-related brain potential (ERP) could be evoked by purely top-down, attentional control. An infrequently occurring tone was designated as a target prior to presenting a randomized sequence of five equi-probably occurring tones. MMN elicitation to the tones categorized as "high", "medium", or "low" frequency, and designated as the target, would indicate that the change detection process can be driven solely by top-down control. However, MMNs were not elicited by the categorized tones. Only the N2b and P3b attention-driven target detection components were elicited. These results suggest that top-down factors alone cannot generate mismatch negativity. Standard formation by stimulus-driven factors is required.	t	\N
23241212	Coloured-hearing (CH) synesthesia is a perceptual phenomenon in which an acoustic stimulus (the inducer) initiates a concurrent colour perception (the concurrent). Individuals with CH synesthesia "see" colours when hearing tones, words, or music; this specific phenomenon suggesting a close relationship between auditory and visual representations. To date, it is still unknown whether the perception of colours is associated with a modulation of brain functions in the inducing brain area, namely in the auditory-related cortex and associated brain areas. In addition, there is an on-going debate as to whether attention to the inducer is necessarily required for eliciting a visual concurrent, or whether the latter can emerge in a pre-attentive fashion. By using the EEG technique in the context of a pre-attentive mismatch negativity (MMN) paradigm, we show that the binding of tones and colours in CH synesthetes is associated with increased MMN amplitudes in response to deviant tones supposed to induce novel concurrent colour perceptions. Most notably, the increased MMN amplitudes we revealed in the CH synesthetes were associated with stronger intracerebral current densities originating from the auditory cortex, parietal cortex, and ventral visual areas. The automatic binding of tones and colours in CH synesthetes is accompanied by an early pre-attentive process recruiting the auditory cortex, inferior and superior parietal lobules, as well as ventral occipital areas.	t	\N
23308266	Computational and experimental research has revealed that auditory sensory predictions are derived from regularities of the current environment by using internal generative models. However, so far, what has not been addressed is how the auditory system handles situations giving rise to redundant or even contradictory predictions derived from different sources of information. To this end, we measured error signals in the event-related brain potentials (ERPs) in response to violations of auditory predictions. Sounds could be predicted on the basis of overall probability, i.e., one sound was presented frequently and another sound rarely. Furthermore, each sound was predicted by an informative visual cue. Participants' task was to use the cue and to discriminate the two sounds as fast as possible. Violations of the probability based prediction (i.e., a rare sound) as well as violations of the visual-auditory prediction (i.e., an incongruent sound) elicited error signals in the ERPs (Mismatch Negativity [MMN] and Incongruency Response [IR]). Particular error signals were observed even in case the overall probability and the visual symbol predicted different sounds. That is, the auditory system concurrently maintains and tests contradictory predictions. Moreover, if the same sound was predicted, we observed an additive error signal (scalp potential and primary current density) equaling the sum of the specific error signals. Thus, the auditory system maintains and tolerates functionally independently represented redundant and contradictory predictions. We argue that the auditory system exploits all currently active regularities in order to optimally prepare for future events.	t	\N
23585888	To localize the neural generators of the musically elicited mismatch negativity with high temporal resolution we conducted a beamformer analysis (Synthetic Aperture Magnetometry, SAM) on magnetoencephalography (MEG) data from a previous musical mismatch study. The stimuli consisted of a six-tone melodic sequence comprising broken chords in C- and G-major. The musical sequence was presented within an oddball paradigm in which the last tone was lowered occasionally (20%) by a minor third. The beamforming analysis revealed significant right hemispheric neural activation in the superior temporal (STC), inferior frontal (IFC), superior frontal (SFC) and orbitofrontal (OFC) cortices within a time window of 100-200 ms after the occurrence of a deviant tone. IFC and SFC activation was also observed in the left hemisphere. The pronounced early right inferior frontal activation of the auditory mismatch negativity has not been shown in MEG studies so far. The activation in STC and IFC is consistent with earlier electroencephalography (EEG), optical imaging and functional magnetic resonance imaging (fMRI) studies that reveal the auditory and inferior frontal cortices as main generators of the auditory MMN. The observed right hemispheric IFC is also in line with some previous music studies showing similar activation patterns after harmonic syntactic violations. The results demonstrate that a deviant tone within a musical sequence recruits immediately a distributed neural network in frontal and prefrontal areas suggesting that top-down processes are involved when expectation violation occurs within well-known stimuli.	t	\N
23617597	The human auditory cortex automatically encodes acoustic input from the environment and differentiates regular sound patterns from deviant ones in order to identify important, irregular events. The Mismatch Negativity (MMN) response is a neuronal marker for the detection of sounds that are unexpected, based on the encoded regularities. It is also elicited by violations of more complex regularities and musical expertise has been shown to have an effect on the processing of complex regularities. Using magnetoencephalography (MEG), we investigated the MMN response to salient or less salient deviants by varying the standard probability (70%, 50% and 35%) of a pattern oddball paradigm. To study the effects of musical expertise in the encoding of the patterns, we compared the responses of a group of non-musicians to those of musicians. We observed significant MMN in all conditions, including the least salient condition (35% standards), in response to violations of the predominant tone pattern for both groups. The amplitude of MMN from the right hemisphere was influenced by the standard probability. This effect was modulated by long-term musical training: standard probability changes influenced MMN amplitude in the group of non-musicians only. This study indicates that pattern violations are detected automatically, even if they are of very low salience, both in non-musicians and musicians, with salience having a stronger impact on processing in the right hemisphere of non-musicians. Long-term musical training influences this encoding, in that non-musicians benefit to a greater extent from a good signal-to-noise ratio (i.e. high probability of the standard pattern), while musicians are less dependent on the salience of an acoustic environment.	t	\N
23708059	The auditory system is organized such that progressively more complex features are represented across successive cortical hierarchical stages. Just when and where the processing of phonemes, fundamental elements of the speech signal, is achieved in this hierarchy remains a matter of vigorous debate. Non-invasive measures of phonemic representation have been somewhat equivocal. While some studies point to a primary role for middle/anterior regions of the superior temporal gyrus (STG), others implicate the posterior STG. Differences in stimulation, task and inter-individual anatomical/functional variability may account for these discrepant findings. Here, we sought to clarify this issue by mapping phonemic representation across left perisylvian cortex, taking advantage of the excellent sampling density afforded by intracranial recordings in humans. We asked whether one or both major divisions of the STG were sensitive to phonemic transitions. The high signal-to-noise characteristics of direct intracranial recordings allowed for analysis at the individual participant level, circumventing issues of inter-individual anatomic and functional variability that may have obscured previous findings at the group level of analysis. The mismatch negativity (MMN), an electrophysiological response elicited by changes in repetitive streams of stimulation, served as our primary dependent measure. Oddball configurations of pairs of phonemes, spectro-temporally matched non-phonemes, and simple tones were presented. The loci of the MMN clearly differed as a function of stimulus type. Phoneme representation was most robust over middle/anterior STG/STS, but was also observed over posterior STG/SMG. These data point to multiple phonemic processing zones along perisylvian cortex, both anterior and posterior to primary auditory cortex. This finding is considered within the context of a dual stream model of auditory processing in which functionally distinct ventral and dorsal auditory processing pathways may be engaged by speech stimuli.	t	\N
23715097	In this study, we used magnetoencephalography and a mismatch paradigm to investigate speech processing in stroke patients with auditory comprehension deficits and age-matched control subjects. We probed connectivity within and between the two temporal lobes in response to phonemic (different word) and acoustic (same word) oddballs using dynamic causal modelling. We found stronger modulation of self-connections as a function of phonemic differences for control subjects versus aphasics in left primary auditory cortex and bilateral superior temporal gyrus. The patients showed stronger modulation of connections from right primary auditory cortex to right superior temporal gyrus (feed-forward) and from left primary auditory cortex to right primary auditory cortex (interhemispheric). This differential connectivity can be explained on the basis of a predictive coding theory which suggests increased prediction error and decreased sensitivity to phonemic boundaries in the aphasics' speech network in both hemispheres. Within the aphasics, we also found behavioural correlates with connection strengths: a negative correlation between phonemic perception and an inter-hemispheric connection (left superior temporal gyrus to right superior temporal gyrus), and positive correlation between semantic performance and a feedback connection (right superior temporal gyrus to right primary auditory cortex). Our results suggest that aphasics with impaired speech comprehension have less veridical speech representations in both temporal lobes, and rely more on the right hemisphere auditory regions, particularly right superior temporal gyrus, for processing speech. Despite this presumed compensatory shift in network connectivity, the patients remain significantly impaired.	t	\N
23825422	Hierarchical predictive coding suggests that attention in humans emerges from increased precision in probabilistic inference, whereas expectation biases attention in favor of contextually anticipated stimuli. We test these notions within auditory perception by independently manipulating top-down expectation and attentional precision alongside bottom-up stimulus predictability. Our findings support an integrative interpretation of commonly observed electrophysiological signatures of neurodynamics, namely mismatch negativity (MMN), P300, and contingent negative variation (CNV), as manifestations along successive levels of predictive complexity. Early first-level processing indexed by the MMN was sensitive to stimulus predictability: here, attentional precision enhanced early responses, but explicit top-down expectation diminished it. This pattern was in contrast to later, second-level processing indexed by the P300: although sensitive to the degree of predictability, responses at this level were contingent on attentional engagement and in fact sharpened by top-down expectation. At the highest level, the drift of the CNV was a fine-grained marker of top-down expectation itself. Source reconstruction of high-density EEG, supported by intracranial recordings, implicated temporal and frontal regions differentially active at early and late levels. The cortical generators of the CNV suggested that it might be involved in facilitating the consolidation of context-salient stimuli into conscious perception. These results provide convergent empirical support to promising recent accounts of attention and expectation in predictive coding.	t	\N
23850664	Over the last four decades, a range of different neuroimaging tools have been used to study human auditory attention, spanning from classic event-related potential studies using electroencephalography to modern multimodal imaging approaches (e.g., combining anatomical information based on magnetic resonance imaging with magneto- and electroencephalography). This review begins by exploring the different strengths and limitations inherent to different neuroimaging methods, and then outlines some common behavioral paradigms that have been adopted to study auditory attention. We argue that in order to design a neuroimaging experiment that produces interpretable, unambiguous results, the experimenter must not only have a deep appreciation of the imaging technique employed, but also a sophisticated understanding of perception and behavior. Only with the proper caveats in mind can one begin to infer how the cortex supports a human in solving the "cocktail party" problem. This article is part of a Special Issue entitled Human Auditory Neuroimaging.	t	\N
23886958	The purpose of the study was to test the hypothesis that sound context modulates the magnitude of auditory distraction, indexed by behavioral and electrophysiological measures. Participants were asked to identify tone duration, while irrelevant changes occurred in tone frequency, tone intensity, and harmonic structure. Frequency deviants were randomly intermixed with standards (Uni-Condition), with intensity deviants (Bi-Condition), and with both intensity and complex deviants (Tri-Condition). Only in the Tri-Condition did the auditory distraction effect reflect the magnitude difference among the frequency and intensity deviants. The mixture of the different types of deviants in the Tri-Condition modulated the perceived level of distraction, demonstrating that the sound context can modulate the effect of deviance level on processing irrelevant acoustic changes in the environment. These findings thus indicate that perceptual contrast plays a role in change detection processes that leads to auditory distraction.	t	\N
23920129	A better understanding of melodic pitch perception in cochlear implants (CIs) may guide signal processing and/or rehabilitation techniques to improve music perception and appreciation in CI patients. In this study, the mismatch negativity (MMN) in response to infrequent changes in 5-tone pitch contours was obtained in CI users and normal-hearing (NH) listeners. Melodic contour identification (MCI) was also measured. Results showed that MCI performance was poorer in CI than in NH subjects; the MMNs were missing in all CI subjects for the 1-semitone contours. The MMNs with the 5-semitone contours were observed in a smaller proportion of CI than NH subjects. Results suggest that encoding of pitch contour changes in CI users appears to be degraded, most likely due to the limited pitch cues provided by the CI and deafness-related compromise of brain substrates.	t	\N
24143195	Unexpected physical increases in the intensity of a frequently occurring "standard" auditory stimulus are experienced as obtrusive. This could either be because of a physical change, the increase in intensity of the "deviant" stimulus, or a psychological change, the violation of the expectancy for the occurrence of the lower intensity standard stimulus. Two experiments were run in which event-related potentials (ERPs) were recorded to determine whether "psychological" increments (violation of an expectancy for a lower intensity) would be processed differently than psychological decrements (violation of an expectancy for a higher intensity). Event-related potentials (ERPs) were recorded while subjects were presented with auditory tones that alternated between low and high intensity. The subjects ignored the auditory stimuli while watching a video. Deviants were created by repeating the same stimulus. In the first experiment, pairs of stimuli alternating in intensity, were presented in separate increment (H-L...H-L...H-H...H-L, in which H = 80 dB SPL and L = 60 dB SPL) and decrement conditions (L-H...L-H...L-L... L-H, in which H = 90 dB SPL and L = 80 dB SPL). The paradigm employed in the second experiment consisted of an alternating intensity pattern (H-L-H-L-H-H-H-L) or (H-L-H-L-L-L-H-L). Importantly, the stimulus prior to the deviant (the standard) and the actual deviants in both increment and decrement conditions in both experiments were physically identical (80 dB SPL tones). The repetition of the lower intensity tone therefore acted as a psychological rather than a physical decrement (a higher intensity tone was expected) while the repetition of the higher intensity tone acted as a psychological increment (a lower intensity tone was expected). The psychological increments in both experiments elicited a larger amplitude mismatch negativity (MMN) than the decrements. Thus, regardless of whether an acoustic change signals a physical increase in intensity or violates an expected decrease in intensity, a large MMN will be elicited.	t	\N
24158725	The goal of this review article is to redefine what the mismatch negativity (MMN) component of event-related potentials reflects in auditory scene analysis, and to provide an overview of how the MMN serves as a valuable tool in Cognitive Neuroscience research. In doing so, some of the old beliefs (five common 'myths') about MMN will be dispelled, such as the notion that MMN is a simple feature discriminator and that attention itself modulates MMN elicitation. A revised description of what MMN truly reflects will be provided, which includes a principal focus onto the highly context-dependent nature of MMN elicitation and new terminology to discuss MMN and attention. This revised framework will help clarify what has been a long line of seemingly contradictory results from studies in which behavioral ability to hear differences between sounds and passive elicitation of MMN have been inconsistent. Understanding what MMN is will also benefit clinical research efforts by providing a new picture of how to design appropriate paradigms suited to various clinical populations.	t	\N
24366694	One of the major challenges in human brain science is the functional hemispheric asymmetry of auditory processing. Behavioral and neurophysiological studies have demonstrated that speech processing is dominantly handled in the left hemisphere, whereas music processing dominantly occurs in the right. Using magnetoencephalography, we measured the auditory mismatch negativity elicited by band-pass filtered click-trains, which deviated from frequently presented standard sound signals in a spectral or temporal domain. The results showed that spectral and temporal deviants were dominantly processed in the right and left hemispheres, respectively. Hemispheric asymmetry was not limited to high-level cognitive processes, but also originated from the pre-attentive neural processing stage represented by mismatch negativity.	t	\N
24475052	The brain response to auditory novelty comprises two main eeg components: an early mismatch negativity and a late P300. Whereas the former has been proposed to reflect a prediction error, the latter is often associated with working memory updating. Interestingly, these two proposals predict fundamentally different dynamics: prediction errors are thought to propagate serially through several distinct brain areas, while working memory supposes that activity is sustained over time within a stable set of brain areas. Here we test this temporal dissociation by showing how the generalization of brain activity patterns across time can characterize the dynamics of the underlying neural processes. This method is applied to magnetoencephalography (MEG) recordings acquired from healthy participants who were presented with two types of auditory novelty. Following our predictions, the results show that the mismatch evoked by a local novelty leads to the sequential recruitment of distinct and short-lived patterns of brain activity. In sharp contrast, the global novelty evoked by an unexpected sequence of five sounds elicits a sustained state of brain activity that lasts for several hundreds of milliseconds. The present results highlight how MEG combined with multivariate pattern analyses can characterize the dynamics of human cortical processes.	t	\N
24548430	Natural sound environments are dynamic, with overlapping acoustic input originating from simultaneously active sources. A key function of the auditory system is to integrate sensory inputs that belong together and segregate those that come from different sources. We hypothesized that this skill is impaired in individuals with phonological processing difficulties. There is considerable disagreement about whether phonological impairments observed in children with developmental language disorders can be attributed to specific linguistic deficits or to more general acoustic processing deficits. However, most tests of general auditory abilities have been conducted with a single set of sounds. We assessed the ability of school-aged children (7-15 years) to parse complex auditory non-speech input, and determined whether the presence of phonological processing impairments was associated with stream perception performance. A key finding was that children with language impairments did not show the same developmental trajectory for stream perception as typically developing children. In addition, children with language impairments required larger frequency separations between sounds to hear distinct streams compared to age-matched peers. Furthermore, phonological processing ability was a significant predictor of stream perception measures, but only in the older age groups. No such association was found in the youngest children. These results indicate that children with language impairments have difficulty parsing speech streams, or identifying individual sound events when there are competing sound sources. We conclude that language group differences may in part reflect fundamental maturational disparities in the analysis of complex auditory scenes.	t	\N
24771006	Detecting regularity and change in the environment is crucial for survival, as it enables making predictions about the world and informing goal-directed behavior. In the auditory modality, the detection of regularity involves segregating incoming sounds into distinct perceptual objects (stream segregation). The detection of change from this within-stream regularity is associated with the mismatch negativity, a component of auditory event-related brain potentials (ERPs). A central unanswered question is how the detection of regularity and the detection of change are interrelated, and whether attention affects the former, the latter, or both. Here we show that the detection of regularity and the detection of change can be empirically dissociated, and that attention modulates the detection of change without precluding the detection of regularity, and the perceptual organization of the auditory background into distinct streams. By applying frequency spectra analysis on the EEG of subjects engaged in a selective listening task, we found distinct peaks of ERP synchronization, corresponding to the rhythm of the frequency streams, independently of whether the stream was attended or ignored. Our results provide direct neurophysiological evidence of regularity detection in the auditory background, and show that it can occur independently of change detection and in the absence of attention.	t	\N
25178752	The ability to read passages of information fluently and with comprehension is a basic component of socioeconomic success. Reading ability depends on the integrity of underlying visual and auditory (phonological) systems. This study investigated the integrity of reading ability in schizophrenia relative to the integrity of underlying visual and auditory function. The participants were 45 schizophrenia patients, 19 clinical high-risk patients, and 65 comparison subjects. Reading was assessed using tests sensitive to visual or phonological reading dysfunction. Sensory, neuropsychological, and functional outcome measures were also obtained. Schizophrenia patients displayed reading deficits that were far more severe (effect size >2.0) than would be predicted based on general neurocognitive impairments (effect size 1.0-1.4). The deficits correlated highly with both visual and auditory sensory measures, including impaired mismatch negativity generation (r=0.62, N=51, p=0.0002). Patients with established schizophrenia displayed both visual and phonological impairments, whereas high-risk patients showed isolated visual impairments. More than 70% of schizophrenia patients met criteria for acquired dyslexia, with 50% reading below eighth grade level despite intact premorbid reading ability. Reading deficits also correlated significantly (rp=0.4, N=30, p=0.03) with failure to match parental socioeconomic achievement, over and above contributions of more general cognitive impairment. Patients with schizophrenia display severe deficits in reading ability that represent a potentially remediable cause of impaired socioeconomic function. Such deficits are not presently captured during routine clinical assessment. Deficits most likely develop during the years immediately surrounding illness onset and may contribute to the reduced educational and occupational achievement associated with schizophrenia.	t	\N
25231619	In animal models, single-neuron response properties such as stimulus-specific adaptation have been described as possible precursors to mismatch negativity, a human brain response to stimulus change. In the present study, we attempted to bridge the gap between human and animal studies by characterising responses to changes in the frequency of repeated tone series in the anesthetised guinea pig using small-animal magnetoencephalography (MEG). We showed that 1) auditory evoked fields (AEFs) qualitatively similar to those observed in human MEG studies can be detected noninvasively in rodents using small-animal MEG; 2) guinea pig AEF amplitudes reduce rapidly with tone repetition, and this AEF reduction is largely complete by the second tone in a repeated series; and 3) differences between responses to the first (deviant) and later (standard) tones after a frequency transition resemble those previously observed in awake humans using a similar stimulus paradigm.	t	\N
25342520	Neurofeedback is a strong direct training method for brain function, wherein brain activity patterns are measured and displayed as feedback, and trainees try to stabilize the feedback signal onto certain desirable states to regulate their own mental states. Here, we introduce a novel neurofeedback method, using the mismatch negativity (MMN) responses elicited by similar sounds that cannot be consciously discriminated. Through neurofeedback training, without participants' attention to the auditory stimuli or awareness of what was to be learned, we found that the participants could unconsciously achieve a significant improvement in the auditory discrimination of the applied stimuli. Our method has great potential to provide effortless auditory perceptual training. Based on this method, participants do not need to make an effort to discriminate auditory stimuli, and can choose tasks of interest without boredom due to training. In particular, it could be used to train people to recognize speech sounds that do not exist in their native language and thereby facilitate foreign language learning.	t	\N
25379456	Although sensory processing abnormalities contribute to widespread cognitive and psychosocial impairments in schizophrenia (SZ) patients, scalp-channel measures of averaged event-related potentials (ERPs) mix contributions from distinct cortical source-area generators, diluting the functional relevance of channel-based ERP measures. SZ patients (n = 42) and non-psychiatric comparison subjects (n = 47) participated in a passive auditory duration oddball paradigm, eliciting a triphasic (Deviant-Standard) tone ERP difference complex, here termed the auditory deviance response (ADR), comprised of a mid-frontal mismatch negativity (MMN), P3a positivity, and re-orienting negativity (RON) peak sequence. To identify its cortical sources and to assess possible relationships between their response contributions and clinical SZ measures, we applied independent component analysis to the continuous 68-channel EEG data and clustered the resulting independent components (ICs) across subjects on spectral, ERP, and topographic similarities. Six IC clusters centered in right superior temporal, right inferior frontal, ventral mid-cingulate, anterior cingulate, medial orbitofrontal, and dorsal mid-cingulate cortex each made triphasic response contributions. Although correlations between measures of SZ clinical, cognitive, and psychosocial functioning and standard (Fz) scalp-channel ADR peak measures were weak or absent, for at least four IC clusters one or more significant correlations emerged. In particular, differences in MMN peak amplitude in the right superior temporal IC cluster accounted for 48% of the variance in SZ-subject performance on tasks necessary for real-world functioning and medial orbitofrontal cluster P3a amplitude accounted for 40%/54% of SZ-subject variance in positive/negative symptoms. Thus, source-resolved auditory deviance response measures including MMN may be highly sensitive to SZ clinical, cognitive, and functional characteristics.	t	\N
21159322	Phonology is a lower-level structural aspect of language involving the sounds of a language and their organization in that language. Numerous behavioral studies utilizing priming, which refers to an increased sensitivity to a stimulus following prior experience with that or a related stimulus, have provided evidence for the role of phonology in visual word recognition. However, most language studies utilizing priming in conjunction with functional magnetic resonance imaging (fMRI) have focused on lexical-semantic aspects of language processing. The aim of the present study was to investigate the neurobiological substrates of the automatic, implicit stages of phonological processing. While undergoing fMRI, eighteen individuals performed a lexical decision task (LDT) on prime-target pairs including word-word homophone and pseudoword-word pseudohomophone pairs with a prime presentation below perceptual threshold. Whole-brain analyses revealed several cortical regions exhibiting hemodynamic response suppression due to phonological priming including bilateral superior temporal gyri (STG), middle temporal gyri (MTG), and angular gyri (AG) with additional region of interest (ROI) analyses revealing response suppression in the left lateralized supramarginal gyrus (SMG). Homophone and pseudohomophone priming also resulted in different patterns of hemodynamic responses relative to one another. These results suggest that phonological processing plays a key role in visual word recognition. Furthermore, enhanced hemodynamic responses for unrelated stimuli relative to primed stimuli were observed in midline cortical regions corresponding to the default-mode network (DMN) suggesting that DMN activity can be modulated by task requirements within the context of an implicit task.	t	\N
21500313	The effects of neural activity on cerebral hemodynamics underlie human brain imaging with functional magnetic resonance imaging and positron emission tomography. However, the threshold and characteristics of the converse effects, wherein the cerebral hemodynamic and metabolic milieu influence neural activity, remain unclear. We tested whether mild hypercapnia (5% CO2 ) decreases the magnetoencephalogram response to auditory pattern recognition and visual semantic tasks. Hypercapnia induced statistically significant decreases in event-related fields without affecting behavioral performance. Decreases were observed in early sensory components in both auditory and visual modalities as well as later cognitive components related to memory and language. Effects were distributed across cortical regions. Decreases were comparable in evoked versus spontaneous spectral power. Hypercapnia is commonly used with hemodynamic models to calibrate the blood oxygenation level-dependent response. Modifying model assumptions to incorporate the current findings produce a modest but measurable decrease in the estimated cerebral metabolic rate for oxygen change with activation. Because under normal conditions, low cerebral pH would arise when bloodflow is unable to keep pace with neuronal activity, the cortical depression observed here may reflect a homeostatic mechanism by which neuronal activity is adjusted to a level that can be sustained by available bloodflow. Animal studies suggest that these effects may be mediated by pH-modulating presynaptic adenosine receptors. Although the data is not clear, comparable changes in cortical pH to those induced here may occur during sleep apnea, sleep, and exercise. If so, these results suggest that such activities may in turn have generalized depressive effects on cortical activity.	t	\N
22496909	Understanding how the brain processes stimuli in a rich natural environment is a fundamental goal of neuroscience. Here, we showed a feature film to 10 healthy volunteers during functional magnetic resonance imaging (fMRI) of hemodynamic brain activity. We then annotated auditory and visual features of the motion picture to inform analysis of the hemodynamic data. The annotations were fitted to both voxel-wise data and brain network time courses extracted by independent component analysis (ICA). Auditory annotations correlated with two independent components (IC) disclosing two functional networks, one responding to variety of auditory stimulation and another responding preferentially to speech but parts of the network also responding to non-verbal communication. Visual feature annotations correlated with four ICs delineating visual areas according to their sensitivity to different visual stimulus features. In comparison, a separate voxel-wise general linear model based analysis disclosed brain areas preferentially responding to sound energy, speech, music, visual contrast edges, body motion and hand motion which largely overlapped the results revealed by ICA. Differences between the results of IC- and voxel-based analyses demonstrate that thorough analysis of voxel time courses is important for understanding the activity of specific sub-areas of the functional networks, while ICA is a valuable tool for revealing novel information about functional connectivity which need not be explained by the predefined model. Our results encourage the use of naturalistic stimuli and tasks in cognitive neuroimaging to study how the brain processes stimuli in rich natural environments.	t	\N
23777481	Numerous studies have provided clues about the ontogeny of lateralization of auditory processing in humans, but most have employed specific subtypes of stimuli and/or have assessed responses in discrete temporal windows. The present study used near-infrared spectroscopy (NIRS) to establish changes in hemodynamic activity in the neocortex of preverbal infants (aged 4-11 months) while they were exposed to two distinct types of complex auditory stimuli (full sentences and musical phrases). Measurements were taken from bilateral temporal regions, including both anterior and posterior superior temporal gyri. When the infant sample was treated as a homogenous group, no significant effects emerged for stimulus type. However, when infants' hemodynamic responses were categorized according to their overall changes in volume, two very clear neurophysiological patterns emerged. A high-responder group showed a pattern of early and increasing activation, primarily in the left hemisphere, similar to that observed in comparable studies with adults. In contrast, a low-responder group showed a pattern of gradual decreases in activation over time. Although age did track with responder type, no significant differences between these groups emerged for stimulus type, suggesting that the high- versus low-responder characterization generalizes across classes of auditory stimuli. These results highlight a new way to conceptualize the variable cortical blood flow patterns that are frequently observed across infants and stimuli, with hemodynamic response volumes potentially serving as an early indicator of developmental changes in auditory-processing sensitivity.	t	\N
22786953	Auditory spatial perception plays a critical role in day-to-day communication. For instance, listeners utilize acoustic spatial information to segregate individual talkers into distinct auditory "streams" to improve speech intelligibility. However, spatial localization is an exceedingly difficult task in everyday listening environments with numerous distracting echoes from nearby surfaces, such as walls. Listeners' brains overcome this unique challenge by relying on acoustic timing and, quite surprisingly, visual spatial information to suppress short-latency (1-10 ms) echoes through a process known as "the precedence effect" or "echo suppression." In the present study, we employed electroencephalography (EEG) to investigate the neural time course of echo suppression both with and without the aid of coincident visual stimulation in human listeners. We find that echo suppression is a multistage process initialized during the auditory N1 (70-100 ms) and followed by space-specific suppression mechanisms from 150 to 250 ms. Additionally, we find a robust correlate of listeners' spatial perception (i.e., suppressing or not suppressing the echo) over central electrode sites from 300 to 500 ms. Contrary to our hypothesis, vision's powerful contribution to echo suppression occurs late in processing (250-400 ms), suggesting that vision contributes primarily during late sensory or decision making processes. Together, our findings support growing evidence that echo suppression is a slow, progressive mechanism modifiable by visual influences during late sensory and decision making stages. Furthermore, our findings suggest that audiovisual interactions are not limited to early, sensory-level modulations but extend well into late stages of cortical processing.	t	\N
25710328	To form a veridical percept of the environment, the brain needs to integrate sensory signals from a common source but segregate those from independent sources. Thus, perception inherently relies on solving the "causal inference problem." Behaviorally, humans solve this problem optimally as predicted by Bayesian Causal Inference; yet, the underlying neural mechanisms are unexplored. Combining psychophysics, Bayesian modeling, functional magnetic resonance imaging (fMRI), and multivariate decoding in an audiovisual spatial localization task, we demonstrate that Bayesian Causal Inference is performed by a hierarchy of multisensory processes in the human brain. At the bottom of the hierarchy, in auditory and visual areas, location is represented on the basis that the two signals are generated by independent sources (= segregation). At the next stage, in posterior intraparietal sulcus, location is estimated under the assumption that the two signals are from a common source (= forced fusion). Only at the top of the hierarchy, in anterior intraparietal sulcus, the uncertainty about the causal structure of the world is taken into account and sensory signals are combined as predicted by Bayesian Causal Inference. Characterizing the computational operations of signal interactions reveals the hierarchical nature of multisensory perception in human neocortex. It unravels how the brain accomplishes Bayesian Causal Inference, a statistical computation fundamental for perception and cognition. Our results demonstrate how the brain combines information in the face of uncertainty about the underlying causal structure of the world.	t	\N
20146608	The neural responses to sensory consequences of a self-produced motor act are suppressed compared with those in response to a similar but externally generated stimulus. Previous studies in the somatosensory and auditory systems have shown that the motor-induced suppression of the sensory mechanisms is sensitive to delays between the motor act and the onset of the stimulus. The present study investigated time-dependent neural processing of auditory feedback in response to self-produced vocalizations. ERPs were recorded in response to normal and pitch-shifted voice auditory feedback during active vocalization and passive listening to the playback of the same vocalizations. The pitch-shifted stimulus was delivered to the subjects' auditory feedback after a randomly chosen time delay between the vocal onset and the stimulus presentation. Results showed that the neural responses to delayed feedback perturbations were significantly larger than those in response to the pitch-shifted stimulus occurring at vocal onset. Active vocalization was shown to enhance neural responsiveness to feedback alterations only for nonzero delays compared with passive listening to the playback. These findings indicated that the neural mechanisms of auditory feedback processing are sensitive to timing between the vocal motor commands and the incoming auditory feedback. Time-dependent neural processing of auditory feedback may be an important feature of the audio-vocal integration system that helps to improve the feedback-based monitoring and control of voice structure through vocal error detection and correction.	t	\N
20493828	Magnetoencephalography (MEG) is an increasingly popular non-invasive tool used to record, on a millisecond timescale, the magnetic field changes generated by cortical neural activity. MEG has the advantage, over fMRI for example, that it is a direct measure of neural activity. In the current investigation we used MEG to measure cortical responses to tactile and auditory stimuli in the macaque monkey. We had two aims. First, we sought to determine whether MEG, a technique that may have low spatial accuracy, could be used to distinguish the location and organization of sensory cortical fields in macaque monkeys, a species with a relatively small brain compared to that of the human. Second, we wanted to examine the temporal dynamics of cortical responses in the macaque monkey relative to the human. We recorded MEG data from anesthetized monkeys and, for comparison, from awake humans that were presented with simple tactile and auditory stimuli. Neural source reconstruction of MEG data showed that primary somatosensory and auditory cortex could be differentiated and, further, that separate representations of the digit and lip within somatosensory cortex could be identified in macaque monkeys as well as humans. We compared the latencies of activity from monkey and human data for the three stimulation types and proposed a correspondence between the neural responses of the two species. We thus demonstrate the feasibility of using MEG in the macaque monkey and provide a non-human primate model for examining the relationship between external evoked magnetic fields and their underlying neural sources.	t	\N
20598152	The detection of any abrupt change in the environment is important to survival. Since memory of preceding sensory conditions is necessary for detecting changes, such a change-detection system relates closely to the memory system. Here we used an auditory change-related N1 subcomponent (change-N1) of event-related brain potentials to investigate cortical mechanisms underlying change detection and echoic memory. Change-N1 was elicited by a simple paradigm with two tones, a standard followed by a deviant, while subjects watched a silent movie. The amplitude of change-N1 elicited by a fixed sound pressure deviance (70 dB vs. 75 dB) was negatively correlated with the logarithm of the interval between the standard sound and deviant sound (1, 10, 100, or 1000 ms), while positively correlated with the logarithm of the duration of the standard sound (25, 100, 500, or 1000 ms). The amplitude of change-N1 elicited by a deviance in sound pressure, sound frequency, and sound location was correlated with the logarithm of the magnitude of physical differences between the standard and deviant sounds. The present findings suggest that temporal representation of echoic memory is non-linear and Weber-Fechner law holds for the automatic cortical response to sound changes within a suprathreshold range. Since the present results show that the behavior of echoic memory can be understood through change-N1, change-N1 would be a useful tool to investigate memory systems.	t	\N
20633569	Studies in all sensory modalities have demonstrated amplification of early brain responses to attended signals, but less is known about the processes by which listeners selectively ignore stimuli. Here we use MEG and a new paradigm to dissociate the effects of selectively attending, and ignoring in time. Two different tasks were performed successively on the same acoustic stimuli: triplets of tones (A, B, C) with noise-bursts interspersed between the triplets. In the COMPARE task subjects were instructed to respond when tones A and C were of same frequency. In the PASSIVE task they were instructed to respond as fast as possible to noise-bursts. COMPARE requires attending to A and C and actively ignoring tone B, but PASSIVE involves neither attending to nor ignoring the tones. The data were analyzed separately for frontal and auditory-cortical channels to independently address attentional effects on low-level sensory versus putative control processing. We observe the earliest attend/ignore effects as early as 100 ms post-stimulus onset in auditory cortex. These appear to be generated by modulation of exogenous (stimulus-driven) sensory evoked activity. Specifically related to ignoring, we demonstrate that active-ignoring-induced input inhibition involves early selection. We identified a sequence of early (<200 ms post-onset) auditory cortical effects, comprised of onset response attenuation and the emergence of an inhibitory response, and provide new, direct evidence that listeners actively ignoring a sound can reduce their stimulus related activity in auditory cortex by 100 ms after onset when this is required to execute specific behavioral objectives.	t	\N
21233780	The neural origins of the cortical response to rare sensory events remain poorly understood. Using simultaneous event-related potentials and magnetic resonance imaging, we investigated the anatomical profile of regional activity at various processing stages during performance of auditory and visual variants of an oddball paradigm. The earliest rarity-detection response was found in sensory-specific cortices, rapidly spreading to tertiary association areas, mesial temporal and frontal cortices by 150-200 ms. P3m-related activity was not found in sensory-specific cortices. On the basis of the anatomic distribution of P3m-related activity, this component is likely to reflect more generalized cognitive abilities hosted by association cortical regions.	t	\N
21261633	Humans must often focus attention onto relevant sensory signals in the presence of simultaneous irrelevant signals. This type of attention has been explored in vision with the N2pc component, and the present study sought to find an analogous auditory effect. In Experiment 1, two 750-ms sounds were presented simultaneously, one from each of two lateral speakers. On each trial, participants indicated whether one of the two sounds was a pre-defined target. We found that targets elicited an N2ac component: a negativity in the N2 latency range at anterior contralateral electrodes. We also observed a later and more posterior contralateral positivity. Experiment 2 replicated these effects and demonstrated that they arose from competition between attended and unattended tones rather than reflecting lateralized effects of attention for individual tones. The N2ac component may provide a useful tool for studying selective attention within auditory scenes.	t	\N
21305666	Both sighted and blind individuals can readily interpret meaning behind everyday real-world sounds. In sighted listeners, we previously reported that regions along the bilateral posterior superior temporal sulci (pSTS) and middle temporal gyri (pMTG) are preferentially activated when presented with recognizable action sounds. These regions have generally been hypothesized to represent primary loci for complex motion processing, including visual biological motion processing and audio-visual integration. However, it remained unclear whether, or to what degree, life-long visual experience might impact functions related to hearing perception or memory of sound-source actions. Using functional magnetic resonance imaging (fMRI), we compared brain regions activated in congenitally blind versus sighted listeners in response to hearing a wide range of recognizable human-produced action sounds (excluding vocalizations) versus unrecognized, backward-played versions of those sounds. Here, we show that recognized human action sounds commonly evoked activity in both groups along most of the left pSTS/pMTG complex, though with relatively greater activity in the right pSTS/pMTG by the blind group. These results indicate that portions of the postero-lateral temporal cortices contain domain-specific hubs for biological and/or complex motion processing independent of sensory-modality experience. Contrasting the two groups, the sighted listeners preferentially activated bilateral parietal plus medial and lateral frontal networks, whereas the blind listeners preferentially activated left anterior insula plus bilateral anterior calcarine and medial occipital regions, including what would otherwise have been visual-related cortex. These global-level network differences suggest that blind and sighted listeners may preferentially use different memory retrieval strategies when hearing and attempting to recognize action sounds.	t	\N
21380858	Most ecologically natural sensory inputs are not limited to a single modality. While it is possible to use real ecological materials as experimental stimuli to investigate the neural basis of multi-sensory experience, parametric control of such tokens is limited. By using artificial bimodal stimuli composed of approximations to ecological signals, we aim to observe the interactions between putatively relevant stimulus attributes. Here we use MEG as an electrophysiological tool and employ as a measure the steady-state response (SSR), an experimental paradigm typically applied to unimodal signals. In this experiment we quantify the responses to a bimodal audio-visual signal with different degrees of temporal (phase) congruity, focusing on stimulus properties critical to audiovisual speech. An amplitude modulated auditory signal ('pseudo-speech') is paired with a radius-modulated ellipse ('pseudo-mouth'), with the envelope of low-frequency modulations occurring in phase or at offset phase values across modalities. We observe (i) that it is possible to elicit an SSR to bimodal signals; (ii) that bimodal signals exhibit greater response power than unimodal signals; and (iii) that the SSR power at specific harmonics and sensors differentially reflects the congruity between signal components. Importantly, we argue that effects found at the modulation frequency and second harmonic reflect differential aspects of neural coding of multisensory signals. The experimental paradigm facilitates a quantitative characterization of properties of multi-sensory speech and other bimodal computations.	t	\N
21807011	In real-world settings, information from multiple sensory modalities is combined to form a complete, behaviorally salient percept - a process known as multisensory integration. While deficits in auditory and visual processing are often observed in schizophrenia, little is known about how multisensory integration is affected by the disorder. The present study examined auditory, visual, and combined audio-visual processing in schizophrenia patients using high-density electrical mapping. An ecologically relevant task was used to compare unisensory and multisensory evoked potentials from schizophrenia patients to potentials from healthy normal volunteers. Analysis of unisensory responses revealed a large decrease in the N100 component of the auditory-evoked potential, as well as early differences in the visual-evoked components in the schizophrenia group. Differences in early evoked responses to multisensory stimuli were also detected. Multisensory facilitation was assessed by comparing the sum of auditory and visual evoked responses to the audio-visual evoked response. Schizophrenia patients showed a significantly greater absolute magnitude response to audio-visual stimuli than to summed unisensory stimuli when compared to healthy volunteers, indicating significantly greater multisensory facilitation in the patient group. Behavioral responses also indicated increased facilitation from multisensory stimuli. The results represent the first report of increased multisensory facilitation in schizophrenia and suggest that, although unisensory deficits are present, compensatory mechanisms may exist under certain conditions that permit improved multisensory integration in individuals afflicted with the disorder.	t	\N
21958655	Perceptual sensitivities are malleable via learning, even in adults. We trained adults to discriminate complex sounds (periodic, frequency-modulated sweep trains) using two different training procedures, and used psychoacoustic tests and evoked potential measures (the N1-P2 complex) to assess changes in both perceptual and neural sensitivities. Training took place either on a single day, or daily across eight days, and involved discrimination of pairs of stimuli using a single-interval, forced-choice task. In some participants, training started with dissimilar pairs that became progressively more similar across sessions, whereas in others training was constant, involving only one, highly similar, stimulus pair. Participants were better able to discriminate the complex sounds after training, particularly after progressive training, and the evoked potentials elicited by some of the sounds increased in amplitude following training. Significant amplitude changes were restricted to the P2 peak. Our findings indicate that changes in perceptual sensitivities parallel enhanced neural processing. These results are consistent with the proposal that changes in perceptual abilities arise from the brain's capacity to adaptively modify cortical representations of sensory stimuli, and that different training regimens can lead to differences in cortical sensitivities, even after relatively short periods of training.	t	\N
22367585	In recent years, it has become evident that neural responses previously considered to be unisensory can be modulated by sensory input from other modalities. In this regard, visual neural activity elicited to viewing a face is strongly influenced by concurrent incoming auditory information, particularly speech. Here, we applied an additive-factors paradigm aimed at quantifying the impact that auditory speech has on visual event-related potentials (ERPs) elicited to visual speech. These multisensory interactions were measured across parametrically varied stimulus salience, quantified in terms of signal to noise, to provide novel insights into the neural mechanisms of audiovisual speech perception. First, we measured a monotonic increase of the amplitude of the visual P1-N1-P2 ERP complex during a spoken-word recognition task with increases in stimulus salience. ERP component amplitudes varied directly with stimulus salience for visual, audiovisual, and summed unisensory recordings. Second, we measured changes in multisensory gain across salience levels. During audiovisual speech, the P1 and P1-N1 components exhibited less multisensory gain relative to the summed unisensory components with reduced salience, while N1-P2 amplitude exhibited greater multisensory gain as salience was reduced, consistent with the principle of inverse effectiveness. The amplitude interactions were correlated with behavioral measures of multisensory gain across salience levels as measured by response times, suggesting that change in multisensory gain associated with unisensory salience modulations reflects an increased efficiency of visual speech processing.	t	\N
22464943	Limited information is available on the relationship between antisocial personality disorder (ASPD) and early filtering, or gating, of information, even though this could contribute to the repeatedly reported impairment in ASPD of higher-order information processing. In order to investigate early filtering in ASPD, we compared electrophysiological measures of auditory sensory gating assessed by the paired-click paradigm in males with ASPD (n = 37) to healthy controls (n = 28). Stimulus encoding was measured by P50, N100, and P200 auditory evoked potentials; auditory sensory gating (ASG) was measured by a reduction in amplitude of evoked potentials following click repetition. Effects were studied of co-existing past alcohol or drug use disorders, ASPD symptom counts, and trait impulsivity. Controls and ASPD did not differ in P50, N100, or P200 amplitude or ASG. Past alcohol or drug use disorders had no effect. In controls, impulsivity related to improved P50 and P200 gating. In ASPD, P50 or N100 gating was impaired with more symptoms or increased impulsivity, respectively, suggesting impaired early filtering of irrelevant information. In controls the relationship between P50 and P200 gating and impulsivity was reversed, suggesting better gating with higher impulsivity scores. This could reflect different roles of ASG in behavioral regulation in controls versus ASPD.	t	\N
22547804	Bilingualism profoundly affects the brain, yielding functional and structural changes in cortical regions dedicated to language processing and executive function [Crinion J, et al. (2006) Science 312:1537-1540; Kim KHS, et al. (1997) Nature 388:171-174]. Comparatively, musical training, another type of sensory enrichment, translates to expertise in cognitive processing and refined biological processing of sound in both cortical and subcortical structures. Therefore, we asked whether bilingualism can also promote experience-dependent plasticity in subcortical auditory processing. We found that adolescent bilinguals, listening to the speech syllable [da], encoded the stimulus more robustly than age-matched monolinguals. Specifically, bilinguals showed enhanced encoding of the fundamental frequency, a feature known to underlie pitch perception and grouping of auditory objects. This enhancement was associated with executive function advantages. Thus, through experience-related tuning of attention, the bilingual auditory system becomes highly efficient in automatically processing sound. This study provides biological evidence for system-wide neural plasticity in auditory experts that facilitates a tight coupling of sensory and cognitive functions.	t	\N
22592306	Poor sensitivity to the interaural time difference (ITD) constrains the ability of human bilateral cochlear implant users to listen in everyday noisy acoustic environments. ITD sensitivity to periodic pulse trains degrades sharply with increasing pulse rate but can be restored at high pulse rates by jittering the interpulse intervals in a binaurally coherent manner (Laback and Majdak. Binaural jitter improves interaural time-difference sensitivity of cochlear implantees at high pulse rates. Proc Natl Acad Sci USA 105: 814-817, 2008). We investigated the neural basis of the jitter effect by recording from single inferior colliculus (IC) neurons in bilaterally implanted, anesthetized cats. Neural responses to trains of biphasic pulses were measured as a function of pulse rate, jitter, and ITD. An effect of jitter on neural responses was most prominent for pulse rates above 300 pulses/s. High-rate periodic trains evoked only an onset response in most IC neurons, but introducing jitter increased ongoing firing rates in about half of these neurons. Neurons that had sustained responses to jittered high-rate pulse trains showed ITD tuning comparable with that produced by low-rate periodic pulse trains. Thus, jitter appears to improve neural ITD sensitivity by restoring sustained firing in many IC neurons. The effect of jitter on IC responses is qualitatively consistent with human psychophysics. Action potentials tended to occur reproducibly at sparse, preferred times across repeated presentations of high-rate jittered pulse trains. Spike triggered averaging of responses to jittered pulse trains revealed that firing was triggered by very short interpulse intervals. This suggests it may be possible to restore ITD sensitivity to periodic carriers by simply inserting short interpulse intervals at select times.	t	\N
22628458	Successful integration of auditory and visual inputs is crucial for both basic perceptual functions and for higher-order processes related to social cognition. Autism spectrum disorders (ASD) are characterized by impairments in social cognition and are associated with abnormalities in sensory and perceptual processes. Several groups have reported that individuals with ASD are impaired in their ability to integrate socially relevant audiovisual (AV) information, and it has been suggested that this contributes to the higher-order social and cognitive deficits observed in ASD. However, successful integration of auditory and visual inputs also influences detection and perception of nonsocial stimuli, and integration deficits may impair earlier stages of information processing, with cascading downstream effects. To assess the integrity of basic AV integration, we recorded high-density electrophysiology from a cohort of high-functioning children with ASD (7-16 years) while they performed a simple AV reaction time task. Children with ASD showed considerably less behavioral facilitation to multisensory inputs, deficits that were paralleled by less effective neural integration. Evidence for processing differences relative to typically developing children was seen as early as 100 ms poststimulation, and topographic analysis suggested that children with ASD relied on different cortical networks during this early multisensory processing stage.	t	\N
22735387	Decreased blood hemoglobin (HbB) levels and anemia have been associated with abnormal brainstem auditory evoked responses (BAER). Lead (Pb) exposure has also been associated with anemia and aberrant BAER. This study investigated the relationship between HbB level and BAER wave latency and amplitude in Pb-exposed Andean children. Sixty-six children aged 2 to 15 years (mean age: 9.1; SD: 3.3) living in Pb-contaminated villages were screened for HbB levels, blood Pb (PbB) levels and BAER latencies and amplitudes. The mean HbB level observed in the study group was 11.9 g/dL (SD: 1.4; range: 8.6-14.8 g/dL). The mean HbB level corrected for altitude was 10.3g/dL (SD: 1.4; range: 6.9-13.1 g/dL), and suggestive of anemia. The mean PbB level was 49.3 μg/dL (SD: 30.1; range: 4.4-119.1 μg/dL) and indicative of Pb poisoning. Spearman rho correlation analyses revealed significant associations between the BAER absolute latencies and HbB level, indicating that as the HbB level decreased, the BAER wave latency increased. Children with low HbB levels (≤11 g/dL) showed significantly prolonged absolute latencies of waves I, II, III, IV and V compared to the children with normal HbB levels. Although a significant relationship between HbB and BAER waves was observed, no significant associations between PbB level and BAER parameters were found. Low hemoglobin levels may diminish auditory sensory-neural function, and is therefore an important variable to consider when assessing BAER in children with anemia and/or Pb exposure.	t	\N
22773777	Many neurons adapt their spike output to accommodate the prevailing sensory environment. Although such adaptation is thought to improve coding of relevant stimulus features, the relationship between adaptation at the neural and behavioral levels remains to be established. Here we describe improved discrimination performance for an auditory spatial cue (interaural time differences, ITDs) following adaptation to stimulus statistics. Physiological recordings in the midbrain of anesthetized guinea pigs and measurement of discrimination performance in humans both demonstrate improved coding of the most prevalent ITDs in a distribution, but with highest accuracy maintained for ITDs corresponding to frontal locations, suggesting the existence of a fovea for auditory space. A biologically plausible model accounting for the physiological data suggests that neural tuning is stabilized by inhibition to maintain high discriminability for frontal locations. The data support the notion that adaptive coding in the midbrain is a key element of behaviorally efficient sound localization in dynamic acoustic environments.	t	\N
22885999	Event-related potentials (ERPs) to tones that are self-initiated are reduced in their magnitude in comparison with ERPs to tones that are externally generated. This phenomenon has been taken as evidence for an efference copy of the motor command acting to suppress the sensory response. However, self-initiation provides a strong temporal cue for the stimulus which might also contribute to the ERP suppression for self-initiated tones. The current experiment sought to investigate the suppression of monaural tones by temporal cueing and also whether the addition of self-initiation enhanced this suppression. Lastly, the experiment sought to investigate the lateralisation of the ERP suppression via presenting these monaural tones to each ear respectively. We examined source waveforms extracted from the lateralised auditory cortices and measured the modulation of the N1 and P2 components by cueing and self-initiation. Self-initiation significantly reduced the amplitude of the N1 component. Temporal cueing without self-initiation significantly reduced the P2 component. There were no significant differences in the amplitude of either the N1 or the P2 between self-initiation and temporal cuing. There was a significant lateralisation effect on the N1-it being significantly larger contralateral to the ear of stimulation. There was no interaction between lateralisation and side of the temporal cue or side of self-initiation suggesting that the effects of self-initiation and temporal cuing are equal bilaterally. We conclude that a significant proportion of ERP suppression by self-initiation is a result of inherent temporal cueing.	t	\N
23071654	Selectively attending to task-relevant sounds whilst ignoring background noise is one of the most amazing feats performed by the human brain. Here, we studied the underlying neural mechanisms by recording magnetoencephalographic (MEG) responses of 14 healthy human subjects while they performed a near-threshold auditory discrimination task vs. a visual control task of similar difficulty. The auditory stimuli consisted of notch-filtered continuous noise masker sounds, and of 1020-Hz target tones occasionally (p = 0.1) replacing 1000-Hz standard tones of 300-ms duration that were embedded at the center of the notches, the widths of which were parametrically varied. As a control for masker effects, tone-evoked responses were additionally recorded without masker sound. Selective attention to tones significantly increased the amplitude of the onset M100 response at ~100 ms to the standard tones during presence of the masker sounds especially with notches narrower than the critical band. Further, attention modulated sustained response most clearly at 300-400 ms time range from sound onset, with narrower notches than in case of the M100, thus selectively reducing the masker-induced suppression of the tone-evoked response. Our results show evidence of a multiple-stage filtering mechanism of sensory input in the human auditory cortex: 1) one at early (~100 ms) latencies bilaterally in posterior parts of the secondary auditory areas, and 2) adaptive filtering of attended sounds from task-irrelevant background masker at longer latency (~300 ms) in more medial auditory cortical regions, predominantly in the left hemisphere, enhancing processing of near-threshold sounds.	t	\N
23145143	It has been previously demonstrated by our group that a visual stimulus made of dynamically changing luminance evokes an echo or reverberation at ~10 Hz, lasting up to a second. In this study we aimed to reveal whether similar echoes also exist in the auditory modality. A dynamically changing auditory stimulus equivalent to the visual stimulus was designed and employed in two separate series of experiments, and the presence of reverberations was analyzed based on reverse correlations between stimulus sequences and EEG epochs. The first experiment directly compared visual and auditory stimuli: while previous findings of ~10 Hz visual echoes were verified, no similar echo was found in the auditory modality regardless of frequency. In the second experiment, we tested if auditory sequences would influence the visual echoes when they were congruent or incongruent with the visual sequences. However, the results in that case similarly did not reveal any auditory echoes, nor any change in the characteristics of visual echoes as a function of audio-visual congruence. The negative findings from these experiments suggest that brain oscillations do not equivalently affect early sensory processes in the visual and auditory modalities, and that alpha (8-13 Hz) oscillations play a special role in vision.	t	\N
23251704	Cognitive task demands in one sensory modality (T1) can have beneficial effects on a secondary task (T2) in a different modality, due to reduced top-down control needed to inhibit the secondary task, as well as crossmodal spread of attention. This contrasts findings of cognitive load compromising a secondary modality's processing. We manipulated cognitive load within one modality (visual) and studied the consequences of cognitive demands on secondary (auditory) processing. 15 healthy participants underwent a simultaneous EEG-fMRI experiment. Data from 8 participants were obtained outside the scanner for validation purposes. The primary task (T1) was to respond to a visual working memory (WM) task with four conditions, while the secondary task (T2) consisted of an auditory oddball stream, which participants were asked to ignore. The fMRI results revealed fronto-parietal WM network activations in response to T1 task manipulation. This was accompanied by significantly higher reaction times and lower hit rates with increasing task difficulty which confirmed successful manipulation of WM load. Amplitudes of auditory evoked potentials, representing fundamental auditory processing showed a continuous augmentation which demonstrated a systematic relation to cross-modal cognitive load. With increasing WM load, primary auditory cortices were increasingly deactivated while psychophysiological interaction results suggested the emergence of auditory cortices connectivity with visual WM regions. These results suggest differential effects of crossmodal attention on fundamental auditory processing. We suggest a continuous allocation of resources to brain regions processing primary tasks when challenging the central executive under high cognitive load.	t	\N
23281832	If we initiate a sound by our own motor behavior, the N1 component of the auditory event-related brain potential (ERP) that the sound elicits is attenuated compared to the N1 elicited by the same sound when it is initiated externally. It has been suggested that this N1 suppression results from an internal predictive mechanism that is in the service of discriminating the sensory consequences of one's own actions from other sensory input. As the N1-suppression effect is becoming a popular approach to investigate predictive processing in cognitive and social neuroscience, it is important to exclude an alternative interpretation not related to prediction. According to the attentional account, the N1 suppression is due to a difference in the allocation of attention between self- and externally-initiated sounds. To test this hypothesis, we manipulated the allocation of attention to the sounds in different blocks: Attention was directed either to the sounds, to the own motor acts or to visual stimuli. If attention causes the N1-suppression effect, then manipulating attention should affect the effect for self-initiated sounds. We found N1 suppression in all conditions. The N1 per se was affected by attention, but there was no interaction between attention and self-initiation effects. This implies that self-initiation N1 effects are not caused by attention. The present results support the assumption that the N1-suppression effect for self-initiated sounds indicates the operation of an internal predictive mechanism. Furthermore, while attention had an influence on the N1a, N1b, and N1c components, the N1-suppression effect was confined to the N1b and N1c subcomponents suggesting that the major contribution to the auditory N1-suppression effect is circumscribed to late N1 components.	t	\N
23301775	Using electrophysiology, we have examined two questions in relation to musical training - namely, whether it enhances sensory encoding of the human voice and whether it improves the ability to ignore irrelevant auditory change. Participants performed an auditory distraction task, in which they identified each sound as either short (350 ms) or long (550 ms) and ignored a change in timbre of the sounds. Sounds consisted of a male and a female voice saying a neutral sound [a], and of a cello and a French Horn playing an F3 note. In some blocks, musical sounds occurred on 80% of trials, while voice sounds on 20% of trials. In other blocks, the reverse was true. Participants heard naturally recorded sounds in half of experimental blocks and their spectrally-rotated versions in the other half. Regarding voice perception, we found that musicians had a larger N1 event-related potential component not only to vocal sounds but also to their never before heard spectrally-rotated versions. We therefore conclude that musical training is associated with a general improvement in the early neural encoding of complex sounds. Regarding the ability to ignore irrelevant auditory change, musicians' accuracy tended to suffer less from the change in timbre of the sounds, especially when deviants were musical notes. This behavioral finding was accompanied by a marginally larger re-orienting negativity in musicians, suggesting that their advantage may lie in a more efficient disengagement of attention from the distracting auditory dimension.	t	\N
23316957	There is an accumulating body of evidence indicating that neuronal functional specificity to basic sensory stimulation is mutable and subject to experience. Although fMRI experiments have investigated changes in brain activity after relative to before perceptual learning, brain activity during perceptual learning has not been explored. This work investigated brain activity related to auditory frequency discrimination learning using a variational Bayesian approach for source localization, during simultaneous EEG and fMRI recording. We investigated whether the practice effects are determined solely by activity in stimulus-driven mechanisms or whether high-level attentional mechanisms, which are linked to the perceptual task, control the learning process. The results of fMRI analyses revealed significant attention and learning related activity in left and right superior temporal gyrus STG as well as the left inferior frontal gyrus IFG. Current source localization of simultaneously recorded EEG data was estimated using a variational Bayesian method. Analysis of current localized to the left inferior frontal gyrus and the right superior temporal gyrus revealed gamma band activity correlated with behavioral performance. Rapid improvement in task performance is accompanied by plastic changes in the sensory cortex as well as superior areas gated by selective attention. Together the fMRI and EEG results suggest that gamma band activity in the right STG and left IFG plays an important role during perceptual learning.	t	\N
23326548	Auditory distraction is a failure to maintain focus on a stream of sounds. We investigated the neural correlates of distraction in a selective-listening pitch-discrimination task with high (competing speech) or low (white noise) distraction. High-distraction impaired performance and reduced the N1 peak of the auditory Event-Related Potential evoked by probe tones. In a series of simulations, we explored two theories to account for this effect: disruption of sensory gain or a disruption of inter-trial phase consistency. When compared to these simulations, our data were consistent with both effects of distraction. Distraction reduced the gain of the auditory evoked potential and disrupted the inter-trial phase consistency with which the brain responds to stimulus events. Tones at a non-target, unattended frequency were more susceptible to the effects of distraction than tones within an attended frequency band.	t	\N
23616340	Previous studies on crossmodal spatial orienting typically used simple and stereotyped stimuli in the absence of any meaningful context. This study combined computational models, behavioural measures and functional magnetic resonance imaging to investigate audiovisual spatial interactions in naturalistic settings. We created short videos portraying everyday life situations that included a lateralised visual event and a co-occurring sound, either on the same or on the opposite side of space. Subjects viewed the videos with or without eye-movements allowed (overt or covert orienting). For each video, visual and auditory saliency maps were used to index the strength of stimulus-driven signals, and eye-movements were used as a measure of the efficacy of the audiovisual events for spatial orienting. Results showed that visual salience modulated activity in higher-order visual areas, whereas auditory salience modulated activity in the superior temporal cortex. Auditory salience modulated activity also in the posterior parietal cortex, but only when audiovisual stimuli occurred on the same side of space (multisensory spatial congruence). Orienting efficacy affected activity in the visual cortex, within the same regions modulated by visual salience. These patterns of activation were comparable in overt and covert orienting conditions. Our results demonstrate that, during viewing of complex multisensory stimuli, activity in sensory areas reflects both stimulus-driven signals and their efficacy for spatial orienting; and that the posterior parietal cortex combines spatial information about the visual and the auditory modality.	t	\N
23624493	Findings in animal models demonstrate that activity within hierarchically early sensory cortical regions can be modulated by cross-sensory inputs through resetting of the phase of ongoing intrinsic neural oscillations. Here, subdural recordings evaluated whether phase resetting by auditory inputs would impact multisensory integration processes in human visual cortex. Results clearly showed auditory-driven phase reset in visual cortices and, in some cases, frank auditory event-related potentials (ERP) were also observed over these regions. Further, when audiovisual bisensory stimuli were presented, this led to robust multisensory integration effects which were observed in both the ERP and in measures of phase concentration. These results extend findings from animal models to human visual cortices, and highlight the impact of cross-sensory phase resetting by a non-primary stimulus on multisensory integration in ostensibly unisensory cortices.	t	\N
23647558	In the visual modality, perceptual demand on a goal-directed task has been shown to modulate the extent to which irrelevant information can be disregarded at a sensory-perceptual stage of processing. In the auditory modality, the effect of perceptual demand on neural representations of task-irrelevant sounds is unclear. We compared simultaneous ERPs and fMRI responses associated with task-irrelevant sounds across parametrically modulated perceptual task demands in a dichotic-listening paradigm. Participants performed a signal detection task in one ear (Attend ear) while ignoring task-irrelevant syllable sounds in the other ear (Ignore ear). Results revealed modulation of syllable processing by auditory perceptual demand in an ROI in middle left superior temporal gyrus and in negative ERP activity 130-230 msec post stimulus onset. Increasing the perceptual demand in the Attend ear was associated with a reduced neural response in both fMRI and ERP to task-irrelevant sounds. These findings are in support of a selection model whereby ongoing perceptual demands modulate task-irrelevant sound processing in auditory cortex.	t	\N
23664703	Both faces and voices are rich in socially-relevant information, which humans are remarkably adept at extracting, including a person's identity, age, gender, affective state, personality, etc. Here, we review accumulating evidence from behavioral, neuropsychological, electrophysiological, and neuroimaging studies which suggest that the cognitive and neural processing mechanisms engaged by perceiving faces or voices are highly similar, despite the very different nature of their sensory input. The similarity between the two mechanisms likely facilitates the multi-modal integration of facial and vocal information during everyday social interactions. These findings emphasize a parsimonious principle of cerebral organization, where similar computational problems in different modalities are solved using similar solutions.	t	\N
23827717	Learning and maintaining the sounds we use in vocal communication require accurate perception of the sounds we hear performed by others and feedback-dependent imitation of those sounds to produce our own vocalizations. Understanding how the central nervous system integrates auditory and vocal-motor information to enable communication is a fundamental goal of systems neuroscience, and insights into the mechanisms of those processes will profoundly enhance clinical therapies for communication disorders. Gaining the high-resolution insight necessary to define the circuits and cellular mechanisms underlying human vocal communication is presently impractical. Songbirds are the best animal model of human speech, and this review highlights recent insights into the neural basis of auditory perception and feedback-dependent imitation in those animals. Neural correlates of song perception are present in auditory areas, and those correlates are preserved in the auditory responses of downstream neurons that are also active when the bird sings. Initial tests indicate that singing-related activity in those downstream neurons is associated with vocal-motor performance as opposed to the bird simply hearing itself sing. Therefore, action potentials related to auditory perception and action potentials related to vocal performance are co-localized in individual neurons. Conceptual models of song learning involve comparison of vocal commands and the associated auditory feedback to compute an error signal that is used to guide refinement of subsequent song performances, yet the sites of that comparison remain unknown. Convergence of sensory and motor activity onto individual neurons points to a possible mechanism through which auditory and vocal-motor signals may be linked to enable learning and maintenance of the sounds used in vocal communication. This article is part of a Special Issue entitled "Communication Sounds and the Brain: New Directions and Perspectives".	t	\N
23988583	Experience-dependent characteristics of auditory function, especially with regard to speech-evoked auditory neurophysiology, have garnered increasing attention in recent years. This interest stems from both pragmatic and theoretical concerns as it bears implications for the prevention and remediation of language-based learning impairment in addition to providing insight into mechanisms engendering experience-dependent changes in human sensory function. Musicians provide an attractive model for studying the experience-dependency of auditory processing in humans due to their distinctive neural enhancements compared to nonmusicians. We have only recently begun to address whether these enhancements are observable early in life, during the initial years of music training when the auditory system is under rapid development, as well as later in life, after the onset of the aging process. Here we review neural enhancements in musically trained individuals across the life span in the context of cellular mechanisms that underlie learning, identified in animal models. Musicians' subcortical physiologic enhancements are interpreted according to a cognitive framework for auditory learning, providing a model in which to study mechanisms of experience-dependent changes in human auditory function.	t	\N
24072639	Neurobiological underpinnings of unusual sensory features in individuals with autism are unknown. Event-related potentials elicited by task-irrelevant sounds were used to elucidate neural correlates of auditory processing and associations with three common sensory response patterns (hyperresponsiveness; hyporesponsiveness; sensory seeking). Twenty-eight children with autism and 39 typically developing children (4-12 year-olds) completed an auditory oddball paradigm. Results revealed marginally attenuated P1 and N2 to standard tones and attenuated P3a to novel sounds in autism versus controls. Exploratory analyses suggested that within the autism group, attenuated N2 and P3a amplitudes were associated with greater sensory seeking behaviors for specific ranges of P1 responses. Findings suggest that attenuated early sensory as well as later attention-orienting neural responses to stimuli may underlie selective sensory features via complex mechanisms.	t	\N
24119225	Humans are able to extract regularities from complex auditory scenes in order to form perceptually meaningful elements. It has been shown previously that this process depends critically on both the temporal integration of the sensory input over time and the degree of frequency separation between concurrent sound sources. Our goal was to examine the relationship between these two aspects by means of magnetoencephalography (MEG). To achieve this aim, we combined time-frequency analysis on a sensor space level with source analysis. Our paradigm consisted of asymmetric ABA-tone triplets wherein the B-tones were presented temporally closer to the first A-tones, providing different tempi within the same sequence. Participants attended to the slowest B-rhythm whilst the frequency separation between tones was manipulated (0-, 2-, 4- and 10-semitones). The results revealed that the asymmetric ABA-triplets spontaneously elicited periodic-sustained responses corresponding to the temporal distribution of the A-B and B-A tone intervals in all conditions. Moreover, when attending to the B-tones, the neural representations of the A- and B-streams were both detectable in the scenarios which allow perceptual streaming (2-, 4- and 10-semitones). Alongside this, the steady-state responses tuned to the presentation of the B-tones enhanced significantly with increase of the frequency separation between tones. However, the strength of the B-tones related steady-state responses dominated the strength of the A-tones responses in the 10-semitones condition. Conversely, the representation of the A-tones dominated the B-tones in the cases of 2- and 4-semitones conditions, in which a greater effort was required for completing the task. Additionally, the P1 evoked fields' component following the B-tones increased in magnitude with the increase of inter-tonal frequency difference. The enhancement of the evoked fields in the source space, along with the B-tones related activity of the time-frequency results, likely reflect the selective enhancement of the attended B-stream. The results also suggested a dissimilar efficiency of the temporal integration of separate streams depending on the degree of frequency separation between the sounds. Overall, the present findings suggest that the neural effects of auditory streaming could be directly captured in the time-frequency spectrum at the sensor-space level.	t	\N
24314010	Auditory perceptual learning persistently modifies neural networks in the central nervous system. Central auditory processing comprises a hierarchy of sound analysis and integration, which transforms an acoustical signal into a meaningful object for perception. Based on latencies and source locations of auditory evoked responses, we investigated which stage of central processing undergoes neuroplastic changes when gaining auditory experience during passive listening and active perceptual training. Young healthy volunteers participated in a five-day training program to identify two pre-voiced versions of the stop-consonant syllable 'ba', which is an unusual speech sound to English listeners. Magnetoencephalographic (MEG) brain responses were recorded during two pre-training and one post-training sessions. Underlying cortical sources were localized, and the temporal dynamics of auditory evoked responses were analyzed. After both passive listening and active training, the amplitude of the P2m wave with latency of 200 ms increased considerably. By this latency, the integration of stimulus features into an auditory object for further conscious perception is considered to be complete. Therefore the P2m changes were discussed in the light of auditory object representation. Moreover, P2m sources were localized in anterior auditory association cortex, which is part of the antero-ventral pathway for object identification. The amplitude of the earlier N1m wave, which is related to processing of sensory information, did not change over the time course of the study. The P2m amplitude increase and its persistence over time constitute a neuroplastic change. The P2m gain likely reflects enhanced object representation after stimulus experience and training, which enables listeners to improve their ability for scrutinizing fine differences in pre-voicing time. Different trajectories of brain and behaviour changes suggest that the preceding effect of a P2m increase relates to brain processes, which are necessary precursors of perceptual learning. Cautious discussion is required when interpreting the finding of a P2 amplitude increase between recordings before and after training and learning.	t	\N
24423729	Across the animal kingdom, sensations resulting from an animal's own actions are processed differently from sensations resulting from external sources, with self-generated sensations being suppressed. A forward model has been proposed to explain this process across sensorimotor domains. During vocalization, reduced processing of one's own speech is believed to result from a comparison of speech sounds to corollary discharges of intended speech production generated from efference copies of commands to speak. Until now, anatomical and functional evidence validating this model in humans has been indirect. Using EEG with anatomical MRI to facilitate source localization, we demonstrate that inferior frontal gyrus activity during the 300ms before speaking was associated with suppressed processing of speech sounds in auditory cortex around 100ms after speech onset (N1). These findings indicate that an efference copy from speech areas in prefrontal cortex is transmitted to auditory cortex, where it is used to suppress processing of anticipated speech sounds. About 100ms after N1, a subsequent auditory cortical component (P2) was not suppressed during talking. The combined N1 and P2 effects suggest that although sensory processing is suppressed as reflected in N1, perceptual gaps may be filled as reflected in the lack of P2 suppression, explaining the discrepancy between sensory suppression and preserved sensory experiences. These findings, coupled with the coherence between relevant brain regions before and during speech, provide new mechanistic understanding of the complex interactions between action planning and sensory processing that provide for differentiated tagging and monitoring of one's own speech, processes disrupted in neuropsychiatric disorders.	t	\N
24695717	Detecting the location of salient sounds in the environment rests on the brain's ability to use differences in sounds arriving at both ears. Functional neuroimaging studies in humans indicate that the left and right auditory hemispaces are coded asymmetrically, with a rightward attentional bias that reflects spatial attention in vision. Neuropsychological observations in patients with spatial neglect have led to the formulation of two competing models: the orientation bias and right-hemisphere dominance models. The orientation bias model posits a symmetrical mapping between one side of the sensorium and the contralateral hemisphere, with mutual inhibition of the ipsilateral hemisphere. The right-hemisphere dominance model introduces a functional asymmetry in the brain's coding of space: the left hemisphere represents the right side, whereas the right hemisphere represents both sides of the sensorium. We used Dynamic Causal Modeling of effective connectivity and Bayesian model comparison to adjudicate between these alternative network architectures, based on human electroencephalographic data acquired during an auditory location oddball paradigm. Our results support a hemispheric asymmetry in a frontoparietal network that conforms to the right-hemisphere dominance model. We show that, within this frontoparietal network, forward connectivity increases selectively in the hemisphere contralateral to the side of sensory stimulation. We interpret this finding in light of hierarchical predictive coding as a selective increase in attentional gain, which is mediated by feedforward connections that carry precision-weighted prediction errors during perceptual inference. This finding supports the disconnection hypothesis of unilateral neglect and has implications for theories of its etiology.	t	\N
24956028	Listening situations with multiple talkers or background noise are common in everyday communication and are particularly demanding for older adults. Here we review current research on auditory perception in aging individuals in order to gain insights into the challenges of listening under noisy conditions. Informationally rich temporal structure in auditory signals--over a range of time scales from milliseconds to seconds--renders temporal processing central to perception in the auditory domain. We discuss the role of temporal structure in auditory processing, in particular from a perspective relevant for hearing in background noise, and focusing on sensory memory, auditory scene analysis, and speech perception. Interestingly, these auditory processes, usually studied in an independent manner, show considerable overlap of processing time scales, even though each has its own 'privileged' temporal regimes. By integrating perspectives on temporal structure processing in these three areas of investigation, we aim to highlight similarities typically not recognized.	t	\N
25245785	Atypical processing and integration of sensory inputs are hypothesized to play a role in unusual sensory reactions and social-cognitive deficits in autism spectrum disorder (ASD). Reports on the relationship between objective metrics of sensory processing and clinical symptoms, however, are surprisingly sparse. Here we examined the relationship between neurophysiological assays of sensory processing and (1) autism severity and (2) sensory sensitivities, in individuals with ASD aged 6-17. Multiple linear regression indicated significant associations between neural markers of auditory processing and multisensory integration, and autism severity. No such relationships were apparent for clinical measures of visual/auditory sensitivities. These data support that aberrant early sensory processing contributes to autism symptoms, and reveal the potential of electrophysiology to objectively subtype autism.	t	\N
25259525	Auditory selective attention plays an essential role for identifying sounds of interest in a scene, but the neural underpinnings are still incompletely understood. Recent findings demonstrate that neural activity that is time-locked to a particular amplitude-modulation (AM) is enhanced in the auditory cortex when the modulated stream of sounds is selectively attended to under sensory competition with other streams. However, the target sounds used in the previous studies differed not only in their AM, but also in other sound features, such as carrier frequency or location. Thus, it remains uncertain whether the observed enhancements reflect AM-selective attention. The present study aims at dissociating the effect of AM frequency on response enhancement in auditory cortex by using an ongoing auditory stimulus that contains two competing targets differing exclusively in their AM frequency. Electroencephalography results showed a sustained response enhancement for auditory attention compared to visual attention, but not for AM-selective attention (attended AM frequency vs. ignored AM frequency). In contrast, the response to the ignored AM frequency was enhanced, although a brief trend toward response enhancement occurred during the initial 15 s. Together with the previous findings, these observations indicate that selective enhancement of attended AMs in auditory cortex is adaptive under sustained AM-selective attention. This finding has implications for our understanding of cortical mechanisms for feature-based attentional gain control.	t	\N
25535356	When social animals communicate, the onset of informative content in one modality varies considerably relative to the other, such as when visual orofacial movements precede a vocalization. These naturally occurring asynchronies do not disrupt intelligibility or perceptual coherence. However, they occur on time scales where they likely affect integrative neuronal activity in ways that have remained unclear, especially for hierarchically downstream regions in which neurons exhibit temporally imprecise but highly selective responses to communication signals. To address this, we exploited naturally occurring face- and voice-onset asynchronies in primate vocalizations. Using these as stimuli we recorded cortical oscillations and neuronal spiking responses from functional MRI (fMRI)-localized voice-sensitive cortex in the anterior temporal lobe of macaques. We show that the onset of the visual face stimulus resets the phase of low-frequency oscillations, and that the face-voice asynchrony affects the prominence of two key types of neuronal multisensory responses: enhancement or suppression. Our findings show a three-way association between temporal delays in audiovisual communication signals, phase-resetting of ongoing oscillations, and the sign of multisensory responses. The results reveal how natural onset asynchronies in cross-sensory inputs regulate network oscillations and neuronal excitability in the voice-sensitive cortex of macaques, a suggested animal model for human voice areas. These findings also advance predictions on the impact of multisensory input on neuronal processes in face areas and other brain regions.	t	\N
25948269	Sensory processing involves identification of stimulus features, but also integration with the surrounding sensory and cognitive context. Previous work in animals and humans has shown fine-scale sensitivity to context in the form of learned knowledge about the statistics of the sensory environment, including relative probabilities of discrete units in a stream of sequential auditory input. These statistics are a defining characteristic of one of the most important sequential signals humans encounter: speech. For speech, extensive exposure to a language tunes listeners to the statistics of sound sequences. To address how speech sequence statistics are neurally encoded, we used high-resolution direct cortical recordings from human lateral superior temporal cortex as subjects listened to words and nonwords with varying transition probabilities between sound segments. In addition to their sensitivity to acoustic features (including contextual features, such as coarticulation), we found that neural responses dynamically encoded the language-level probability of both preceding and upcoming speech sounds. Transition probability first negatively modulated neural responses, followed by positive modulation of neural responses, consistent with coordinated predictive and retrospective recognition processes, respectively. Furthermore, transition probability encoding was different for real English words compared with nonwords, providing evidence for online interactions with high-order linguistic knowledge. These results demonstrate that sensory processing of deeply learned stimuli involves integrating physical stimulus features with their contextual sequential structure. Despite not being consciously aware of phoneme sequence statistics, listeners use this information to process spoken input and to link low-level acoustic representations with linguistic information about word identity and meaning.	t	\N
22803512	Existing 67-channel event-related potentials, obtained during recognition and working memory paradigms with words or faces, were used to examine early visual processing in schizophrenia patients prone to auditory hallucinations (AH, n = 26) or not (NH, n = 49) and healthy controls (HC, n = 46). Current source density (CSD) transforms revealed distinct, strongly left- (words) or right-lateralized (faces; N170) inferior-temporal N1 sinks (150 ms) in each group. N1 was quantified by temporal PCA of peak-adjusted CSDs. For words and faces in both paradigms, N1 was substantially reduced in AH compared with NH and HC, who did not differ from each other. The difference in N1 between AH and NH was not due to overall symptom severity or performance accuracy, with both groups showing comparable memory deficits. Our findings extend prior reports of reduced auditory N1 in AH, suggesting a broader early perceptual integration deficit that is not limited to the auditory modality.	t	\N
25231612	Atypical medial olivocochlear (MOC) feedback from brain stem to cochlea has been proposed to play a role in tinnitus, but even well-constructed tests of this idea have yielded inconsistent results. In the present study, it was hypothesized that low sound tolerance (mild to moderate hyperacusis), which can accompany tinnitus or occur on its own, might contribute to the inconsistency. Sound-level tolerance (SLT) was assessed in subjects (all men) with clinically normal or near-normal thresholds to form threshold-, age-, and sex-matched groups: 1) no tinnitus/high SLT, 2) no tinnitus/low SLT, 3) tinnitus/high SLT, and 4) tinnitus/low SLT. MOC function was measured from the ear canal as the change in magnitude of distortion-product otoacoustic emissions (DPOAE) elicited by broadband noise presented to the contralateral ear. The noise reduced DPOAE magnitude in all groups ("contralateral suppression"), but significantly more reduction occurred in groups with tinnitus and/or low SLT, indicating hyperresponsiveness of the MOC system compared with the group with no tinnitus/high SLT. The results suggest hyperresponsiveness of the interneurons of the MOC system residing in the cochlear nucleus and/or MOC neurons themselves. The present data, combined with previous human and animal data, indicate that neural pathways involving every major division of the cochlear nucleus manifest hyperactivity and/or hyperresponsiveness in tinnitus and/or low SLT. The overactivation may develop in each pathway separately. However, a more parsimonious hypothesis is that top-down neuromodulation is the driving force behind ubiquitous overactivation of the auditory brain stem and may correspond to attentional spotlighting on the auditory domain in tinnitus and hyperacusis.	t	\N
21909378	Speech is the most important form of human communication but ambient sounds and competing talkers often degrade its acoustics. Fortunately the brain can use visual information, especially its highly precise spatial information, to improve speech comprehension in noisy environments. Previous studies have demonstrated that audiovisual integration depends strongly on spatiotemporal factors. However, some integrative phenomena such as McGurk interference persist even with gross spatial disparities, suggesting that spatial alignment is not necessary for robust integration of audiovisual place-of-articulation cues. It is therefore unclear how speech-cues interact with audiovisual spatial integration mechanisms. Here, we combine two well established psychophysical phenomena, the McGurk effect and the ventriloquist's illusion, to explore this dependency. Our results demonstrate that conflicting spatial cues may not interfere with audiovisual integration of speech, but conflicting speech-cues can impede integration in space. This suggests a direct but asymmetrical influence between ventral 'what' and dorsal 'where' pathways.	t	\N
22390292	Human multisensory systems are known to bind inputs from the different sensory modalities into a unified percept, a process that leads to measurable behavioral benefits. This integrative process can be observed through multisensory illusions, including the McGurk effect and the sound-induced flash illusion, both of which demonstrate the ability of one sensory modality to modulate perception in a second modality. Such multisensory integration is highly dependent upon the temporal relationship of the different sensory inputs, with perceptual binding occurring within a limited range of asynchronies known as the temporal binding window (TBW). Previous studies have shown that this window is highly variable across individuals, but it is unclear how these variations in the TBW relate to an individual's ability to integrate multisensory cues. Here we provide evidence linking individual differences in multisensory temporal processes to differences in the individual's audiovisual integration of illusory stimuli. Our data provide strong evidence that the temporal processing of multiple sensory signals and the merging of multiple signals into a single, unified perception, are highly related. Specifically, the width of right side of an individuals' TBW, where the auditory stimulus follows the visual, is significantly correlated with the strength of illusory percepts, as indexed via both an increase in the strength of binding synchronous sensory signals and in an improvement in correctly dissociating asynchronous signals. These findings are discussed in terms of their possible neurobiological basis, relevance to the development of sensory integration, and possible importance for clinical conditions in which there is growing evidence that multisensory integration is compromised.	t	\N
23664001	The sight and sound of a person speaking or a ball bouncing may seem simultaneous, but their corresponding neural signals are spread out over time as they arrive at different multisensory brain sites. How subjective timing relates to such neural timing remains a fundamental neuroscientific and philosophical puzzle. A dominant assumption is that temporal coherence is achieved by sensory resynchronisation or recalibration across asynchronous brain events. This assumption is easily confirmed by estimating subjective audiovisual timing for groups of subjects, which is on average similar across different measures and stimuli, and approximately veridical. But few studies have examined normal and pathological individual differences in such measures. Case PH, with lesions in pons and basal ganglia, hears people speak before seeing their lips move. Temporal order judgements (TOJs) confirmed this: voices had to lag lip-movements (by ∼200 msec) to seem synchronous to PH. Curiously, voices had to lead lips (also by ∼200 msec) to maximise the McGurk illusion (a measure of audiovisual speech integration). On average across these measures, PH's timing was therefore still veridical. Age-matched control participants showed similar discrepancies. Indeed, normal individual differences in TOJ and McGurk timing correlated negatively: subjects needing an auditory lag for subjective simultaneity needed an auditory lead for maximal McGurk, and vice versa. This generalised to the Stream-Bounce illusion. Such surprising antagonism seems opposed to good sensory resynchronisation, yet average timing across tasks was still near-veridical. Our findings reveal remarkable disunity of audiovisual timing within and between subjects. To explain this we propose that the timing of audiovisual signals within different brain mechanisms is perceived relative to the average timing across mechanisms. Such renormalisation fully explains the curious antagonistic relationship between disparate timing estimates in PH and healthy participants, and how they can still perceive the timing of external events correctly, on average.	t	\N
24974346	We investigated whether visual speech fills in non-intact auditory speech (excised consonant onsets) in typically developing children from 4 to 14 years of age. Stimuli with the excised auditory onsets were presented in the audiovisual (AV) and auditory-only (AO) modes. A visual speech fill-in effect occurs when listeners experience hearing the same non-intact auditory stimulus (e.g., /-b/ag) as different depending on the presence/absence of visual speech such as hearing /bag/ in the AV mode but hearing /ag/ in the AO mode. We quantified the visual speech fill-in effect by the difference in the number of correct consonant onset responses between the modes. We found that easy visual speech cues /b/ provided greater filling in than difficult cues /g/. Only older children benefited from difficult visual speech cues, whereas all children benefited from easy visual speech cues, although 4- and 5-year-olds did not benefit as much as older children. To explore task demands, we compared results on our new task with those on the McGurk task. The influence of visual speech was uniquely associated with age and vocabulary abilities for the visual speech fill--in effect but was uniquely associated with speechreading skills for the McGurk effect. This dissociation implies that visual speech--as processed by children-is a complicated and multifaceted phenomenon underpinned by heterogeneous abilities. These results emphasize that children perceive a speaker's utterance rather than the auditory stimulus per se. In children, as in adults, there is more to speech perception than meets the ear.	t	\N
24996043	The brain improves speech processing through the integration of audiovisual (AV) signals. Situations involving AV speech integration may be crudely dichotomized into those where auditory and visual inputs contain (1) equivalent, complementary signals (validating AV speech) or (2) inconsistent, different signals (conflicting AV speech). This simple framework may allow the systematic examination of broad commonalities and differences between AV neural processes engaged by various experimental paradigms frequently used to study AV speech integration. We conducted an activation likelihood estimation metaanalysis of 22 functional imaging studies comprising 33 experiments, 311 subjects, and 347 foci examining "conflicting" versus "validating" AV speech. Experimental paradigms included content congruency, timing synchrony, and perceptual measures, such as the McGurk effect or synchrony judgments, across AV speech stimulus types (sublexical to sentence). Colocalization of conflicting AV speech experiments revealed consistency across at least two contrast types (e.g., synchrony and congruency) in a network of dorsal stream regions in the frontal, parietal, and temporal lobes. There was consistency across all contrast types (synchrony, congruency, and percept) in the bilateral posterior superior/middle temporal cortex. Although fewer studies were available, validating AV speech experiments were localized to other regions, such as ventral stream visual areas in the occipital and inferior temporal cortex. These results suggest that while equivalent, complementary AV speech signals may evoke activity in regions related to the corroboration of sensory input, conflicting AV speech signals recruit widespread dorsal stream areas likely involved in the resolution of conflicting sensory signals.	t	\N
20541597	Auditory perceptual 'restoration' occurs when the auditory system restores an occluded or masked sound of interest. Behavioral work on auditory restoration in humans began over 50 years ago using it to model a noisy environmental scene with competing sounds. It has become clear that not only humans experience auditory restoration: restoration has been broadly conserved in many species. Behavioral studies in humans and animals provide a necessary foundation to link the insights being obtained from human EEG and fMRI to those from animal neurophysiology. The aggregate of data resulting from multiple approaches across species has begun to clarify the neuronal bases of auditory restoration. Different types of neural responses supporting restoration have been found, supportive of multiple mechanisms working within a species. Yet a general principle has emerged that responses correlated with restoration mimic the response that would have been given to the uninterrupted sound of interest. Using the same technology to study different species will help us to better harness animal models of 'auditory scene analysis' to clarify the conserved neural mechanisms shaping the perceptual organization of sound and to advance strategies to improve hearing in natural environmental settings.	t	\N
20826671	Processing of complex acoustic scenes depends critically on the temporal integration of sensory information as sounds evolve naturally over time. It has been previously speculated that this process is guided by both innate mechanisms of temporal processing in the auditory system, as well as top-down mechanisms of attention and possibly other schema-based processes. In an effort to unravel the neural underpinnings of these processes and their role in scene analysis, we combine magnetoencephalography (MEG) with behavioral measures in humans in the context of polyrhythmic tone sequences. While maintaining unchanged sensory input, we manipulate subjects' attention to one of two competing rhythmic streams in the same sequence. The results reveal that the neural representation of the attended rhythm is significantly enhanced in both its steady-state power and spatial phase coherence relative to its unattended state, closely correlating with its perceptual detectability for each listener. Interestingly, the data reveal a differential efficiency of rhythmic rates of the order of few hertz during the streaming process, closely following known neural and behavioral measures of temporal modulation sensitivity in the auditory system. These findings establish a direct link between known temporal modulation tuning in the auditory system (particularly at the level of auditory cortex) and the temporal integration of perceptual features in a complex acoustic scene, while mediated by processes of attention.	t	\N
20844143	Segregation of concurrent sounds in complex acoustic environments is a fundamental feature of auditory scene analysis. A powerful cue used by the auditory system to segregate concurrent sounds, such as speakers' voices at a cocktail party, is inharmonicity. This can be demonstrated when a component of a harmonic complex tone is perceived as a separate tone "popping out" from the complex as a whole when it is sufficiently mistuned from its harmonic value. The neural bases of perceptual "pop out" of mistuned harmonics are unclear. We recorded multiunit activity from primary auditory cortex (A1) of behaving monkeys elicited by harmonic complex tones that were either "in tune" or that contained a mistuned third harmonic set at the best frequency of the neural populations. Responses to mistuned sounds were enhanced relative to responses to "in-tune" sounds, thus correlating with the enhanced perceptual salience of the mistuned component. Consistent with human psychophysics of "pop out," response enhancements increased with the degree of mistuning, were maximal for neural populations tuned to the frequency of the mistuned component, and were not observed under comparable stimulus conditions that do not elicit perceptual "pop out." Mistuning was also associated with changes in neuronal temporal response patterns phase locked to "beats" in the stimuli. Intracortical auditory evoked potentials paralleled noninvasive neurophysiological correlates of perceptual "pop out" in humans, further augmenting the translational relevance of the results. Findings suggest two complementary neural mechanisms for "pop out," based on the detection of local differences in activation level or coherence of temporal response patterns across A1.	t	\N
20975559	Analysis of the auditory environment, source identification and vocal communication all require efficient brain mechanisms for disambiguating, representing and understanding complex natural sounds as 'auditory objects'. Failure of these mechanisms leads to a diverse spectrum of clinical deficits. Here we review current evidence concerning the phenomenology, mechanisms and brain substrates of auditory agnosias and related disorders of auditory object processing. Analysis of lesions causing auditory object deficits has revealed certain broad anatomical correlations: deficient parsing of the auditory scene is associated with lesions involving the parieto-temporal junction, while selective disorders of sound recognition occur with more anterior temporal lobe or extra-temporal damage. Distributed neural networks have been increasingly implicated in the pathogenesis of such disorders as developmental dyslexia, congenital amusia and tinnitus. Auditory category deficits may arise from defective interaction of spectrotemporal encoding and executive and mnestic processes. Dedicated brain mechanisms are likely to process specialized sound objects such as voices and melodies. Emerging empirical evidence suggests a clinically relevant, hierarchical and modular neuropsychological model of auditory object processing that provides a framework for understanding auditory agnosias and makes specific predictions to direct future work.	t	\N
21196054	Humans and other animals can attend to one of multiple sounds and follow it selectively over time. The neural underpinnings of this perceptual feat remain mysterious. Some studies have concluded that sounds are heard as separate streams when they activate well-separated populations of central auditory neurons, and that this process is largely pre-attentive. Here, we argue instead that stream formation depends primarily on temporal coherence between responses that encode various features of a sound source. Furthermore, we postulate that only when attention is directed towards a particular feature (e.g. pitch) do all other temporally coherent features of that source (e.g. timbre and location) become bound together as a stream that is segregated from the incoherent features of other sources.	t	\N
21209201	Auditory figure-ground segregation, listeners' ability to selectively hear out a sound of interest from a background of competing sounds, is a fundamental aspect of scene analysis. In contrast to the disordered acoustic environment we experience during everyday listening, most studies of auditory segregation have used relatively simple, temporally regular signals. We developed a new figure-ground stimulus that incorporates stochastic variation of the figure and background that captures the rich spectrotemporal complexity of natural acoustic scenes. Figure and background signals overlap in spectrotemporal space, but vary in the statistics of fluctuation, such that the only way to extract the figure is by integrating the patterns over time and frequency. Our behavioral results demonstrate that human listeners are remarkably sensitive to the appearance of such figures. In a functional magnetic resonance imaging experiment, aimed at investigating preattentive, stimulus-driven, auditory segregation mechanisms, naive subjects listened to these stimuli while performing an irrelevant task. Results demonstrate significant activations in the intraparietal sulcus (IPS) and the superior temporal sulcus related to bottom-up, stimulus-driven figure-ground decomposition. We did not observe any significant activation in the primary auditory cortex. Our results support a role for automatic, bottom-up mechanisms in the IPS in mediating stimulus-driven, auditory figure-ground segregation, which is consistent with accumulating evidence implicating the IPS in structuring sensory input and perceptual organization.	t	\N
21355664	The effect of context on the identification of common environmental sounds (e.g., dogs barking or cars honking) was tested by embedding them in familiar auditory background scenes (street ambience, restaurants). Initial results with subjects trained on both the scenes and the sounds to be identified showed a significant advantage of about five percentage points better accuracy for sounds that were contextually incongruous with the background scene (e.g., a rooster crowing in a hospital). Further studies with naive (untrained) listeners showed that this incongruency advantage (IA) is level-dependent: there is no advantage for incongruent sounds lower than a Sound/Scene ratio (So/Sc) of -7.5 dB, but there is about five percentage points better accuracy for sounds with greater So/Sc. Testing a new group of trained listeners on a larger corpus of sounds and scenes showed that the effect is robust and not confined to a specific stimulus set. Modeling using spectral-temporal measures showed that neither analyses based on acoustic features, nor semantic assessments of sound-scene congruency can account for this difference, indicating the IA is a complex effect, possibly arising from the sensitivity of the auditory system to new and unexpected events, under particular listening conditions.	t	\N
21387016	Important sounds can be easily missed or misidentified in the presence of extraneous noise. We describe an auditory illusion in which a continuous ongoing tone becomes inaudible during a brief, non-masking noise burst more than one octave away, which is unexpected given the frequency resolution of human hearing. Participants strongly susceptible to this illusory discontinuity did not perceive illusory auditory continuity (in which a sound subjectively continues during a burst of masking noise) when the noises were short, yet did so at longer noise durations. Participants who were not prone to illusory discontinuity showed robust early electroencephalographic responses at 40-66 ms after noise burst onset, whereas those prone to the illusion lacked these early responses. These data suggest that short-latency neural responses to auditory scene components reflect subsequent individual differences in the parsing of auditory scenes.	t	\N
21428515	The precedence effect (PE) describes the ability to localize a direct, leading sound correctly when its delayed copy (lag) is present, though not separately audible. The relative contribution of binaural cues in the temporal fine structure (TFS) of lead-lag signals was compared to that of interaural level differences (ILDs) and interaural time differences (ITDs) carried in the envelope. In a localization dominance paradigm participants indicated the spatial location of lead-lag stimuli processed with a binaural noise-band vocoder whose noise carriers introduced random TFS. The PE appeared for noise bursts of 10 ms duration, indicating dominance of envelope information. However, for three test words the PE often failed even at short lead-lag delays, producing two images, one toward the lead and one toward the lag. When interaural correlation in the carrier was increased, the images appeared more centered, but often remained split. Although previous studies suggest dominance of TFS cues, no image is lateralized in accord with the ITD in the TFS. An interpretation in the context of auditory scene analysis is proposed: By replacing the TFS with that of noise the auditory system loses the ability to fuse lead and lag into one object, and thus to show the PE.	t	\N
21945789	This study investigates how acoustic change-events are represented in a listener's brain when attention is strongly focused elsewhere. Using magneto-encephalography (MEG) we examine whether cortical responses to different kinds of changes in stimulus statistics are similarly influenced by attentional load, and whether the processing of such acoustic changes in auditory cortex depends on modality-specific or general processing resources. We investigated these issues by examining cortical responses to two basic forms of acoustic transitions: (1) Violations of a simple acoustic pattern and (2) the emergence of a regular pattern from a random one. To simulate a complex sensory environment, these patterns were presented concurrently with streams of auditory and visual decoys. Listeners were required to perform tasks of high- and low-attentional-load in these domains. Results demonstrate that while auditory attentional-load does not influence the cortical representation of simple violations of regularity, it significantly reduces the magnitude of responses to the emergence of a regular acoustic pattern, suggesting a fundamentally skewed representation of the unattended auditory scene. In contrast, visual attentional-load had no effect on either transition response, consistent with the hypothesis that processing resources necessary for change detection are modality-specific.	t	\N
22036957	Parsing of sound sources in the auditory environment or 'auditory scene analysis' is a computationally demanding cognitive operation that is likely to be vulnerable to the neurodegenerative process in Alzheimer's disease. However, little information is available concerning auditory scene analysis in Alzheimer's disease. Here we undertook a detailed neuropsychological and neuroanatomical characterization of auditory scene analysis in a cohort of 21 patients with clinically typical Alzheimer's disease versus age-matched healthy control subjects. We designed a novel auditory dual stream paradigm based on synthetic sound sequences to assess two key generic operations in auditory scene analysis (object segregation and grouping) in relation to simpler auditory perceptual, task and general neuropsychological factors. In order to assess neuroanatomical associations of performance on auditory scene analysis tasks, structural brain magnetic resonance imaging data from the patient cohort were analysed using voxel-based morphometry. Compared with healthy controls, patients with Alzheimer's disease had impairments of auditory scene analysis, and segregation and grouping operations were comparably affected. Auditory scene analysis impairments in Alzheimer's disease were not wholly attributable to simple auditory perceptual or task factors; however, the between-group difference relative to healthy controls was attenuated after accounting for non-verbal (visuospatial) working memory capacity. These findings demonstrate that clinically typical Alzheimer's disease is associated with a generic deficit of auditory scene analysis. Neuroanatomical associations of auditory scene analysis performance were identified in posterior cortical areas including the posterior superior temporal lobes and posterior cingulate. This work suggests a basis for understanding a class of clinical symptoms in Alzheimer's disease and for delineating cognitive mechanisms that mediate auditory scene analysis both in health and in neurodegenerative disease.	t	\N
22280585	Despite many studies investigating auditory spatial impressions in rooms, few have addressed the impact of simultaneous visual cues on localization and the perception of spaciousness. The current research presents an immersive audiovisual environment in which participants were instructed to make auditory width judgments in dynamic bi-modal settings. The results of these psychophysical tests suggest the importance of congruent audio visual presentation to the ecological interpretation of an auditory scene. Supporting data were accumulated in five rooms of ascending volumes and varying reverberation times. Participants were given an audiovisual matching test in which they were instructed to pan the auditory width of a performing ensemble to a varying set of audio and visual cues in rooms. Results show that both auditory and visual factors affect the collected responses and that the two sensory modalities coincide in distinct interactions. The greatest differences between the panned audio stimuli given a fixed visual width were found in the physical space with the largest volume and the greatest source distance. These results suggest, in this specific instance, a predominance of auditory cues in the spatial analysis of the bi-modal scene.	t	\N
22371616	Auditory streaming and visual plaids have been used extensively to study perceptual organization in each modality. Both stimuli can produce bistable alternations between grouped (one object) and split (two objects) interpretations. They also share two peculiar features: (i) at the onset of stimulus presentation, organization starts with a systematic bias towards the grouped interpretation; (ii) this first percept has 'inertia'; it lasts longer than the subsequent ones. As a result, the probability of forming different objects builds up over time, a landmark of both behavioural and neurophysiological data on auditory streaming. Here we show that first percept bias and inertia are independent. In plaid perception, inertia is due to a depth ordering ambiguity in the transparent (split) interpretation that makes plaid perception tristable rather than bistable: experimental manipulations removing the depth ambiguity suppressed inertia. However, the first percept bias persisted. We attempted a similar manipulation for auditory streaming by introducing level differences between streams, to bias which stream would appear in the perceptual foreground. Here both inertia and first percept bias persisted. We thus argue that the critical common feature of the onset of perceptual organization is the grouping bias, which may be related to the transition from temporally/spatially local to temporally/spatially global computation.	t	\N
22371619	Recent studies have shown that auditory scene analysis involves distributed neural sites below, in, and beyond the auditory cortex (AC). However, it remains unclear what role each site plays and how they interact in the formation and selection of auditory percepts. We addressed this issue through perceptual multistability phenomena, namely, spontaneous perceptual switching in auditory streaming (AS) for a sequence of repeated triplet tones, and perceptual changes for a repeated word, known as verbal transformations (VTs). An event-related fMRI analysis revealed brain activity timelocked to perceptual switching in the cerebellum for AS, in frontal areas for VT, and the AC and thalamus for both. The results suggest that motor-based prediction, produced by neural networks outside the auditory system, plays essential roles in the segmentation of acoustic sequences both in AS and VT. The frequency of perceptual switching was determined by a balance between the activation of two sites, which are proposed to be involved in exploring novel perceptual organization and stabilizing current perceptual organization. The effect of the gene polymorphism of catechol-O-methyltransferase (COMT) on individual variations in switching frequency suggests that the balance of exploration and stabilization is modulated by catecholamines such as dopamine and noradrenalin. These mechanisms would support the noteworthy flexibility of auditory scene analysis.	t	\N
22371621	Auditory stream segregation involves linking temporally separate acoustic events into one or more coherent sequences. For any non-trivial sequence of sounds, many alternative descriptions can be formed, only one or very few of which emerge in awareness at any time. Evidence from studies showing bi-/multistability in auditory streaming suggest that some, perhaps many of the alternative descriptions are represented in the brain in parallel and that they continuously vie for conscious perception. Here, based on a predictive coding view, we consider the nature of these sound representations and how they compete with each other. Predictive processing helps to maintain perceptual stability by signalling the continuation of previously established patterns as well as the emergence of new sound sources. It also provides a measure of how well each of the competing representations describes the current acoustic scene. This account of auditory stream segregation has been tested on perceptual data obtained in the auditory streaming paradigm.	t	\N
22612172	Observers often remember a scene as containing information that was not presented but that would have likely been located just beyond the observed boundaries of the scene. This effect is called boundary extension (BE; e.g., Intraub & Richardson, 1989). Previous studies have observed BE in memory for visual and haptic stimuli, and the present experiments examined whether BE occurred in memory for auditory stimuli (prose, music). Experiments 1 and 2 varied the amount of auditory content to be remembered. BE was not observed, but when auditory targets contained more content, boundary restriction (BR) occurred. Experiment 3 presented auditory stimuli with less content and BR also occurred. In Experiment 4, white noise was added to stimuli with less content to equalize the durations of auditory stimuli, and BR still occurred. Experiments 5 and 6 presented trained stories and popular music, and BR still occurred. This latter finding ruled out the hypothesis that the lack of BE in Experiments 1-4 reflected a lack of familiarity with the stimuli. Overall, memory for auditory content exhibited BR rather than BE, and this pattern was stronger if auditory stimuli contained more content. Implications for the understanding of general perceptual processing and directions for future research are discussed.	t	\N
22753470	A visual scene is perceived in terms of visual objects. Similar ideas have been proposed for the analogous case of auditory scene analysis, although their hypothesized neural underpinnings have not yet been established. Here, we address this question by recording from subjects selectively listening to one of two competing speakers, either of different or the same sex, using magnetoencephalography. Individual neural representations are seen for the speech of the two speakers, with each being selectively phase locked to the rhythm of the corresponding speech stream and from which can be exclusively reconstructed the temporal envelope of that speech stream. The neural representation of the attended speech dominates responses (with latency near 100 ms) in posterior auditory cortex. Furthermore, when the intensity of the attended and background speakers is separately varied over an 8-dB range, the neural representation of the attended speech adapts only to the intensity of that speaker but not to the intensity of the background speaker, suggesting an object-level intensity gain control. In summary, these results indicate that concurrent auditory objects, even if spectrotemporally overlapping and not resolvable at the auditory periphery, are neurally encoded individually in auditory cortex and emerge as fundamental representational units for top-down attentional modulation and bottom-up neural adaptation.	t	\N
22829899	In natural environments, sensory information is embedded in temporally contiguous streams of events. This is typically the case when seeing and listening to a speaker or when engaged in scene analysis. In such contexts, two mechanisms are needed to single out and build a reliable representation of an event (or object): the temporal parsing of information and the selection of relevant information in the stream. It has previously been shown that rhythmic events naturally build temporal expectations that improve sensory processing at predictable points in time. Here, we asked to which extent temporal regularities can improve the detection and identification of events across sensory modalities. To do so, we used a dynamic visual conjunction search task accompanied by auditory cues synchronized or not with the color change of the target (horizontal or vertical bar). Sounds synchronized with the visual target improved search efficiency for temporal rates below 1.4 Hz but did not affect efficiency above that stimulation rate. Desynchronized auditory cues consistently impaired visual search below 3.3 Hz. Our results are interpreted in the context of the Dynamic Attending Theory: specifically, we suggest that a cognitive operation structures events in time irrespective of the sensory modality of input. Our results further support and specify recent neurophysiological findings by showing strong temporal selectivity for audiovisual integration in the auditory-driven improvement of visual search efficiency.	t	\N
22844509	In auditory scene analysis, population separation and temporal coherence have been proposed to explain how auditory features are grouped together and streamed over time. The present study investigated whether these two theories can be applied to tactile streaming and whether temporal coherence theory can be applied to crossmodal streaming. The results show that synchrony detection between two tones/taps at different frequencies/locations became difficult when one of the tones/taps was embedded in a perceptual stream. While the taps applied to the same location were streamed over time, the taps applied to different locations were not. This observation suggests that tactile stream formation can be explained by population-separation theory. On the other hand, temporally coherent auditory stimuli at different frequencies were streamed over time, but temporally coherent tactile stimuli applied to different locations were not. When there was within-modality streaming, temporally coherent auditory stimuli and tactile stimuli were not streamed over time, either. This observation suggests the limitation of temporal coherence theory when it is applied to perceptual grouping over time.	t	\N
23029426	The ability to detect sudden changes in the environment is critical for survival. Hearing is hypothesized to play a major role in this process by serving as an "early warning device," rapidly directing attention to new events. Here, we investigate listeners' sensitivity to changes in complex acoustic scenes-what makes certain events "pop-out" and grab attention while others remain unnoticed? We use artificial "scenes" populated by multiple pure-tone components, each with a unique frequency and amplitude modulation rate. Importantly, these scenes lack semantic attributes, which may have confounded previous studies, thus allowing us to probe low-level processes involved in auditory change perception. Our results reveal a striking difference between "appear" and "disappear" events. Listeners are remarkably tuned to object appearance: change detection and identification performance are at ceiling; response times are short, with little effect of scene-size, suggesting a pop-out process. In contrast, listeners have difficulty detecting disappearing objects, even in small scenes: performance rapidly deteriorates with growing scene-size; response times are slow, and even when change is detected, the changed component is rarely successfully identified. We also measured change detection performance when a noise or silent gap was inserted at the time of change or when the scene was interrupted by a distractor that occurred at the time of change but did not mask any scene elements. Gaps adversely affected the processing of item appearance but not disappearance. However, distractors reduced both appearance and disappearance detection. Together, our results suggest a role for neural adaptation and sensitivity to transients in the process of auditory change detection, similar to what has been demonstrated for visual change detection. Importantly, listeners consistently performed better for item addition (relative to deletion) across all scene interruptions used, suggesting a robust perceptual representation of item appearance.	t	\N
23145699	Listeners are good at attending to one auditory stream in a crowded environment. However, is there an upper limit of streams present in an auditory scene at which this selective attention breaks down? Here, participants were asked to attend one stream of spoken letters amidst other letter streams. In half of the trials, an initial primer was played, cueing subjects to the sound configuration. Results indicate that performance increases with token repetitions. Priming provided a performance benefit, suggesting that stream selection, not formation, is the bottleneck associated with attention in an overcrowded scene. Results' implications for brain-computer interfaces are discussed.	t	\N
23423817	A variety of perceptual correspondences between auditory and visual features have been reported, but few studies have investigated how rhythm, an auditory feature defined purely by dynamics relevant to speech and music, interacts with visual features. Here, we demonstrate a novel crossmodal association between auditory rhythm and visual clutter. Participants were shown a variety of visual scenes from diverse categories and asked to report the auditory rhythm that perceptually matched each scene by adjusting the rate of amplitude modulation (AM) of a sound. Participants matched each scene to a specific AM rate with surprising consistency. A spatial-frequency analysis showed that scenes with greater contrast energy in midrange spatial frequencies were matched to faster AM rates. Bandpass-filtering the scenes indicated that greater contrast energy in this spatial-frequency range was associated with an abundance of object boundaries and contours, suggesting that participants matched more cluttered scenes to faster AM rates. Consistent with this hypothesis, AM-rate matches were strongly correlated with perceived clutter. Additional results indicated that both AM-rate matches and perceived clutter depend on object-based (cycles per object) rather than retinal (cycles per degree of visual angle) spatial frequency. Taken together, these results suggest a systematic crossmodal association between auditory rhythm, representing density in the temporal domain, and visual clutter, representing object-based density in the spatial domain. This association may allow for the use of auditory rhythm to influence how visual clutter is perceived and attended.	t	\N
23516340	Many sound sources can only be recognised from the pattern of sounds they emit, and not from the individual sound events that make up their emission sequences. Auditory scene analysis addresses the difficult task of interpreting the sound world in terms of an unknown number of discrete sound sources (causes) with possibly overlapping signals, and therefore of associating each event with the appropriate source. There are potentially many different ways in which incoming events can be assigned to different causes, which means that the auditory system has to choose between them. This problem has been studied for many years using the auditory streaming paradigm, and recently it has become apparent that instead of making one fixed perceptual decision, given sufficient time, auditory perception switches back and forth between the alternatives-a phenomenon known as perceptual bi- or multi-stability. We propose a new model of auditory scene analysis at the core of which is a process that seeks to discover predictable patterns in the ongoing sound sequence. Representations of predictable fragments are created on the fly, and are maintained, strengthened or weakened on the basis of their predictive success, and conflict with other representations. Auditory perceptual organisation emerges spontaneously from the nature of the competition between these representations. We present detailed comparisons between the model simulations and data from an auditory streaming experiment, and show that the model accounts for many important findings, including: the emergence of, and switching between, alternative organisations; the influence of stimulus parameters on perceptual dominance, switching rate and perceptual phase durations; and the build-up of auditory streaming. The principal contribution of the model is to show that a two-stage process of pattern discovery and competition between incompatible patterns can account for both the contents (perceptual organisations) and the dynamics of human perception in auditory streaming.	t	\N
23527271	The auditory system creates a neuronal representation of the acoustic world based on spectral and temporal cues present at the listener's ears, including cues that potentially signal the locations of sounds. Discrimination of concurrent sounds from multiple sources is especially challenging. The current study is part of an effort to better understand the neuronal mechanisms governing this process, which has been termed "auditory scene analysis". In particular, we are interested in spatial release from masking by which spatial cues can segregate signals from other competing sounds, thereby overcoming the tendency of overlapping spectra and/or common temporal envelopes to fuse signals with maskers. We studied detection of pulsed tones in free-field conditions in the presence of concurrent multi-tone non-speech maskers. In "energetic" masking conditions, in which the frequencies of maskers fell within the ± 1/3-octave band containing the signal, spatial release from masking at low frequencies (~600 Hz) was found to be about 10 dB. In contrast, negligible spatial release from energetic masking was seen at high frequencies (~4000 Hz). We observed robust spatial release from masking in broadband "informational" masking conditions, in which listeners could confuse signal with masker even though there was no spectral overlap. Substantial spatial release was observed in conditions in which the onsets of the signal and all masker components were synchronized, and spatial release was even greater under asynchronous conditions. Spatial cues limited to high frequencies (>1500 Hz), which could have included interaural level differences and the better-ear effect, produced only limited improvement in signal detection. Substantially greater improvement was seen for low-frequency sounds, for which interaural time differences are the dominant spatial cue.	t	\N
23691185	Listening to and understanding people in a "cocktail-party situation" is a remarkable feature of the human auditory system. Here we investigated the neural correlates of the ability to localize a particular sound among others in an acoustically cluttered environment with healthy subjects. In a sound localization task, five different natural sounds were presented from five virtual spatial locations during functional magnetic resonance imaging (fMRI). Activity related to auditory stream segregation was revealed in posterior superior temporal gyrus bilaterally, anterior insula, supplementary motor area, and frontoparietal network. Moreover, the results indicated critical roles of left planum temporale in extracting the sound of interest among acoustical distracters and the precuneus in orienting spatial attention to the target sound. We hypothesized that the left-sided lateralization of the planum temporale activation is related to the higher specialization of the left hemisphere for analysis of spectrotemporal sound features. Furthermore, the precuneus - a brain area known to be involved in the computation of spatial coordinates across diverse frames of reference for reaching to objects - seems to be also a crucial area for accurately determining locations of auditory targets in an acoustically complex scene of multiple sound sources. The precuneus thus may not only be involved in visuo-motor processes, but may also subserve related functions in the auditory modality.	t	\N
23825404	In a complex auditory scene, a "cocktail party" for example, listeners can disentangle multiple competing sequences of sounds. A recent psychophysical study in our laboratory demonstrated a robust spatial component of stream segregation showing ∼8° acuity. Here, we recorded single- and multiple-neuron responses from the primary auditory cortex of anesthetized cats while presenting interleaved sound sequences that human listeners would experience as segregated streams. Sequences of broadband sounds alternated between pairs of locations. Neurons synchronized preferentially to sounds from one or the other location, thereby segregating competing sound sequences. Neurons favoring one source location or the other tended to aggregate within the cortex, suggestive of modular organization. The spatial acuity of stream segregation was as narrow as ∼10°, markedly sharper than the broad spatial tuning for single sources that is well known in the literature. Spatial sensitivity was sharpest among neurons having high characteristic frequencies. Neural stream segregation was predicted well by a parameter-free model that incorporated single-source spatial sensitivity and a measured forward-suppression term. We found that the forward suppression was not due to post discharge adaptation in the cortex and, therefore, must have arisen in the subcortical pathway or at the level of thalamocortical synapses. A linear-classifier analysis of single-neuron responses to rhythmic stimuli like those used in our psychophysical study yielded thresholds overlapping those of human listeners. Overall, the results indicate that the ascending auditory system does the work of segregating auditory streams, bringing them to discrete modules in the cortex for selection by top-down processes.	t	\N
23926291	Previously, Gygi and Shafiro (2011) found that when environmental sounds are semantically incongruent with the background scene (e.g., horse galloping in a restaurant), they can be identified more accurately by young normal-hearing listeners (YNH) than sounds congruent with the scene (e.g., horse galloping at a racetrack). This study investigated how age and high-frequency audibility affect this Incongruency Advantage (IA) effect. In Experiments 1a and 1b, elderly listeners ( N = 18 for 1a; N = 10 for 1b) with age-appropriate hearing (EAH) were tested on target sounds and auditory scenes in 5 sound-to-scene ratios (So/Sc) between -3 and -18 dB. Experiment 2 tested 11 YNH on the same sound-scene pairings lowpass-filtered at 4 kHz (YNH-4k). The EAH and YNH-4k groups exhibited an almost identical pattern of significant IA effects, but both were at approximately 3.9 dB higher So/Sc than the previously tested YNH listeners. However, the psychometric functions revealed a shallower slope for EAH listeners compared with YNH listeners for the congruent stimuli only, suggesting a greater difficulty for the EAH listeners in attending to sounds expected to occur in a scene. These findings indicate that semantic relationships between environmental sounds in soundscapes are mediated by both audibility and cognitive factors and suggest a method for dissociating these factors.	t	\N
24003112	After hearing a tone, the human auditory system becomes more sensitive to similar tones than to other tones. Current auditory models explain this phenomenon by a simple bandpass attention filter. Here, we demonstrate that auditory attention involves multiple pass-bands around octave-related frequencies above and below the cued tone. Intriguingly, this "octave effect" not only occurs for physically presented tones, but even persists for the missing fundamental in complex tones, and for imagined tones. Our results suggest neural interactions combining octave-related frequencies, likely located in nonprimary cortical regions. We speculate that this connectivity scheme evolved from exposure to natural vibrations containing octave-related spectral peaks, e.g., as produced by vocal cords.	t	\N
24052177	The fundamental perceptual unit in hearing is the 'auditory object'. Similar to visual objects, auditory objects are the computational result of the auditory system's capacity to detect, extract, segregate and group spectrotemporal regularities in the acoustic environment; the multitude of acoustic stimuli around us together form the auditory scene. However, unlike the visual scene, resolving the component objects within the auditory scene crucially depends on their temporal structure. Neural correlates of auditory objects are found throughout the auditory system. However, neural responses do not become correlated with a listener's perceptual reports until the level of the cortex. The roles of different neural structures and the contribution of different cognitive states to the perception of auditory objects are not yet fully understood.	t	\N
24239869	Perceptual representations of auditory stimuli (i.e., sounds) are derived from the auditory system's ability to segregate and group the spectral, temporal, and spatial features of auditory stimuli-a process called "auditory scene analysis". Psychophysical studies have identified several of the principles and mechanisms that underlie a listener's ability to segregate and group acoustic stimuli. One important psychophysical task that has illuminated many of these principles and mechanisms is the "streaming" task. Despite the wide use of this task to study psychophysical mechanisms of human audition, no studies have explicitly tested the streaming abilities of non-human animals using the standard methodologies employed in human-audition studies. Here, we trained rhesus macaques to participate in the streaming task using methodologies and controls similar to those presented in previous human studies. Overall, we found that the monkeys' behavioral reports were qualitatively consistent with those of human listeners, thus suggesting that this task may be a valuable tool for future neurophysiological studies.	t	\N
24475030	In our daily lives, auditory stream segregation allows us to differentiate concurrent sound sources and to make sense of the scene we are experiencing. However, a combination of segregation and the concurrent integration of auditory streams is necessary in order to analyze the relationship between streams and thus perceive a coherent auditory scene. The present functional magnetic resonance imaging study investigates the relative role and neural underpinnings of these listening strategies in multi-part musical stimuli. We compare a real human performance of a piano duet and a synthetic stimulus of the same duet in a prioritized integrative attention paradigm that required the simultaneous segregation and integration of auditory streams. In so doing, we manipulate the degree to which the attended part of the duet led either structurally (attend melody vs. attend accompaniment) or temporally (asynchronies vs. no asynchronies between parts), and thus the relative contributions of integration and segregation used to make an assessment of the leader-follower relationship. We show that perceptually the relationship between parts is biased towards the conventional structural hierarchy in western music in which the melody generally dominates (leads) the accompaniment. Moreover, the assessment varies as a function of both cognitive load, as shown through difficulty ratings and the interaction of the temporal and the structural relationship factors. Neurally, we see that the temporal relationship between parts, as one important cue for stream segregation, revealed distinct neural activity in the planum temporale. By contrast, integration used when listening to both the temporally separated performance stimulus and the temporally fused synthetic stimulus resulted in activation of the intraparietal sulcus. These results support the hypothesis that the planum temporale and IPS are key structures underlying the mechanisms of segregation and integration of auditory streams, respectively.	t	\N
24478375	Adaptation to both common and rare sounds has been independently reported in neurophysiological studies using probabilistic stimulus paradigms in small mammals. However, the apparent sensitivity of the mammalian auditory system to the statistics of incoming sound has not yet been generalized to task-related human auditory perception. Here, we show that human listeners selectively adapt to novel sounds within scenes unfolding over minutes. Listeners' performance in an auditory discrimination task remains steady for the most common elements within the scene but, after the first minute, performance improves for distinct and rare (oddball) sound elements, at the expense of rare sounds that are relatively less distinct. Our data provide the first evidence of enhanced coding of oddball sounds in a human auditory discrimination task and suggest the existence of an adaptive mechanism that tracks the long-term statistics of sounds and deploys coding resources accordingly.	t	\N
24681354	The auditory system is designed to transform acoustic information from low-level sensory representations into perceptual representations. These perceptual representations are the computational result of the auditory system's ability to group and segregate spectral, spatial and temporal regularities in the acoustic environment into stable perceptual units (i.e., sounds or auditory objects). Current evidence suggests that the cortex-specifically, the ventral auditory pathway-is responsible for the computations most closely related to perceptual representations. Here, we discuss how the transformations along the ventral auditory pathway relate to auditory percepts, with special attention paid to the processing of vocalizations and categorization, and explore recent models of how these areas may carry out these computations.	t	\N
24711409	Human perception, cognition, and action are laced with seemingly arbitrary mappings. In particular, sound has a strong spatial connotation: Sounds are high and low, melodies rise and fall, and pitch systematically biases perceived sound elevation. The origins of such mappings are unknown. Are they the result of physiological constraints, do they reflect natural environmental statistics, or are they truly arbitrary? We recorded natural sounds from the environment, analyzed the elevation-dependent filtering of the outer ear, and measured frequency-dependent biases in human sound localization. We find that auditory scene statistics reveals a clear mapping between frequency and elevation. Perhaps more interestingly, this natural statistical mapping is tightly mirrored in both ear-filtering properties and in perceived sound location. This suggests that both sound localization behavior and ear anatomy are fine-tuned to the statistics of natural auditory scenes, likely providing the basis for the spatial connotation of human hearing.	t	\N
24788808	This work analyzed the perceptual attributes of natural dynamic audiovisual scenes. We presented thirty participants with 19 natural scenes in a similarity categorization task, followed by a semi-structured interview. The scenes were reproduced with an immersive audiovisual display. Natural scene perception has been studied mainly with unimodal settings, which have identified motion as one of the most salient attributes related to visual scenes, and sound intensity along with pitch trajectories related to auditory scenes. However, controlled laboratory experiments with natural multimodal stimuli are still scarce. Our results show that humans pay attention to similar perceptual attributes in natural scenes, and a two-dimensional perceptual map of the stimulus scenes and perceptual attributes was obtained in this work. The exploratory results show the amount of movement, perceived noisiness, and eventfulness of the scene to be the most important perceptual attributes in naturalistically reproduced real-world urban environments. We found the scene gist properties openness and expansion to remain as important factors in scenes with no salient auditory or visual events. We propose that the study of scene perception should move forward to understand better the processes behind multimodal scene processing in real-world environments. We publish our stimulus scenes as spherical video recordings and sound field recordings in a publicly available database.	t	\N
24821552	Many studies have shown that attention modulates the cortical representation of an auditory scene, emphasizing an attended source while suppressing competing sources. Yet, individual differences in the strength of this attentional modulation and their relationship with selective attention ability are poorly understood. Here, we ask whether differences in how strongly attention modulates cortical responses reflect differences in normal-hearing listeners' selective auditory attention ability. We asked listeners to attend to one of three competing melodies and identify its pitch contour while we measured cortical electroencephalographic responses. The three melodies were either from widely separated pitch ranges ("easy trials"), or from a narrow, overlapping pitch range ("hard trials"). The melodies started at slightly different times; listeners attended either the leading or lagging melody. Because of the timing of the onsets, the leading melody drew attention exogenously. In contrast, attending the lagging melody required listeners to direct top-down attention volitionally. We quantified how attention amplified auditory N1 response to the attended melody and found large individual differences in the N1 amplification, even though only correctly answered trials were used to quantify the ERP gain. Importantly, listeners with the strongest amplification of N1 response to the lagging melody in the easy trials were the best performers across other types of trials. Our results raise the possibility that individual differences in the strength of top-down gain control reflect inherent differences in the ability to control top-down attention.	t	\N
24841996	Auditory objects, like their visual counterparts, are perceptually defined constructs, but nevertheless must arise from underlying neural circuitry. Using magnetoencephalography (MEG) recordings of the neural responses of human subjects listening to complex auditory scenes, we review studies that demonstrate that auditory objects are indeed neurally represented in auditory cortex. The studies use neural responses obtained from different experiments in which subjects selectively listen to one of two competing auditory streams embedded in a variety of auditory scenes. The auditory streams overlap spatially and often spectrally. In particular, the studies demonstrate that selective attentional gain does not act globally on the entire auditory scene, but rather acts differentially on the separate auditory streams. This stream-based attentional gain is then used as a tool to individually analyze the different neural representations of the competing auditory streams. The neural representation of the attended stream, located in posterior auditory cortex, dominates the neural responses. Critically, when the intensities of the attended and background streams are separately varied over a wide intensity range, the neural representation of the attended speech adapts only to the intensity of that speaker, irrespective of the intensity of the background speaker. This demonstrates object-level intensity gain control in addition to the above object-level selective attentional gain. Overall, these results indicate that concurrently streaming auditory objects, even if spectrally overlapping and not resolvable at the auditory periphery, are individually neurally encoded in auditory cortex, as separate objects.	t	\N
25433224	Pitch plays a fundamental role in audition, from speech and music perception to auditory scene analysis. Congenital amusia is a neurogenetic disorder that appears to affect primarily pitch and melody perception. Pitch is normally conveyed by the spectro-temporal fine structure of low harmonics, but some pitch information is available in the temporal envelope produced by the interactions of higher harmonics. Using 10 amusic subjects and 10 matched controls, we tested the hypothesis that amusics suffer exclusively from impaired processing of spectro-temporal fine structure. We also tested whether the inability of amusics to process acoustic temporal fine structure extends beyond pitch by measuring sensitivity to interaural time differences, which also rely on temporal fine structure. Further tests were carried out on basic intensity and spectral resolution. As expected, pitch perception based on spectro-temporal fine structure was impaired in amusics; however, no significant deficits were observed in amusics' ability to perceive the pitch conveyed via temporal-envelope cues. Sensitivity to interaural time differences was also not significantly different between the amusic and control groups, ruling out deficits in the peripheral coding of temporal fine structure. Finally, no significant differences in intensity or spectral resolution were found between the amusic and control groups. The results demonstrate a pitch-specific deficit in fine spectro-temporal information processing in amusia that seems unrelated to temporal or spectral coding in the auditory periphery. These results are consistent with the view that there are distinct mechanisms dedicated to processing resolved and unresolved harmonics in the general population, the former being altered in congenital amusia while the latter is spared.	t	\N
25654748	In noisy settings, listening is aided by correlated dynamic visual cues gleaned from a talker's face-an improvement often attributed to visually reinforced linguistic information. In this study, we aimed to test the effect of audio-visual temporal coherence alone on selective listening, free of linguistic confounds. We presented listeners with competing auditory streams whose amplitude varied independently and a visual stimulus with varying radius, while manipulating the cross-modal temporal relationships. Performance improved when the auditory target's timecourse matched that of the visual stimulus. The fact that the coherence was between task-irrelevant stimulus features suggests that the observed improvement stemmed from the integration of auditory and visual streams into cross-modal objects, enabling listeners to better attend the target. These findings suggest that in everyday conditions, where listeners can often see the source of a sound, temporal cues provided by vision can help listeners to select one sound source from a mixture.	t	\N
25659464	To probe sensitivity to the time structure of ongoing sound sequences, we measured MEG responses, in human listeners, to the offset of long tone-pip sequences containing various forms of temporal regularity. If listeners learn sequence temporal properties and form expectancies about the arrival time of an upcoming tone, sequence offset should be detectable as soon as an expected tone fails to arrive. Therefore, latencies of offset responses are indicative of the extent to which the temporal pattern has been acquired. In Exp1, sequences were isochronous with tone inter-onset-interval (IOI) set to 75, 125 or 225ms. Exp2 comprised of non-isochronous, temporally regular sequences, comprised of the IOIs above. Exp3 used the same sequences as Exp2 but listeners were required to monitor them for occasional frequency deviants. Analysis of the latency of offset responses revealed that the temporal structure of (even rather simple) regular sequences is not learnt precisely when the sequences are ignored. Pattern coding, supported by a network of temporal, parietal and frontal sources, improved considerably when the signals were made behaviourally pertinent. Thus, contrary to what might be expected in the context of an 'early warning system' framework, learning of temporal structure is not automatic, but affected by the signal's behavioural relevance.	t	\N
25726262	Auditory development involves changes in the peripheral and central nervous system along the auditory pathways, and these occur naturally, and in response to stimulation. Human development occurs along a trajectory that can last decades, and is studied using behavioral psychophysics, as well as physiologic measurements with neural imaging. The auditory system constructs a perceptual space that takes information from objects and groups, segregates sounds, and provides meaning and access to communication tools such as language. Auditory signals are processed in a series of analysis stages, from peripheral to central. Coding of information has been studied for features of sound, including frequency, intensity, loudness, and location, in quiet and in the presence of maskers. In the latter case, the ability of the auditory system to perform an analysis of the scene becomes highly relevant. While some basic abilities are well developed at birth, there is a clear prolonged maturation of auditory development well into the teenage years. Maturation involves auditory pathways. However, non-auditory changes (attention, memory, cognition) play an important role in auditory development. The ability of the auditory system to adapt in response to novel stimuli is a key feature of development throughout the nervous system, known as neural plasticity.	t	\N
22240459	Humans and other animals often communicate acoustically in noisy social groups, in which the background noise generated by other individuals can mask signals of interest. When listening to speech in the presence of speech-like noise, humans experience a release from auditory masking when target and masker are spatially separated. We investigated spatial release from masking (SRM) in a free-field call recognition task in Cope's gray treefrog (Hyla chrysoscelis). In this species, reproduction requires that females successfully detect, recognize, and localize a conspecific male in the noisy social environment of a breeding chorus. Using no-choice phonotaxis assays, we measured females' signal recognition thresholds in response to a target signal (an advertisement call) in the presence and absence of chorus-shaped noise. Females experienced about 3 dB of masking release, compared with a co-localized condition, when the masker was displaced 90° in azimuth from the target. The magnitude of masking release was independent of the spectral composition of the target (carriers of 1.3 kHz, 2.6 kHz, or both). Our results indicate that frogs experience a modest degree of spatial unmasking when performing a call recognition task in the free-field, and suggest that variation in signal spectral content has small effects on both source identification and spatial unmasking. We discuss these results in the context of spatial unmasking in vertebrates and call recognition in frogs.	t	\N
20649227	The lateralization of 250-ms trains of brief noise bursts was measured using an acoustic pointing technique. Stimuli were designed to assess the contribution of the interaural time delay (ITD) of the onset binaural burst relative to that of the ITDs in the ongoing part of the train. Lateralization was measured by listeners' adjustments of the ITD of a pointer stimulus, a 50-ms burst of noise, to match the lateral position of the target train. Results confirmed previous reports of lateralization dominance by the onset burst under conditions in which the train is composed of frozen tokens and the ongoing part contains multiple ambiguous interaural delays. In contrast, lateralization of ongoing trains in which fresh noise tokens were used for each set of two alternating (left-leading/right-leading) binaural pairs followed the ITD of the first pair in each set, regardless of the ITD of the onset burst of the entire stimulus and even when the onset burst was removed by gradual gating. This clear lateralization of a long-duration stimulus with ambiguous interaural delay cues suggests precedence mechanisms that involve not only the interaural cues at the beginning of a sound, but also the pattern of cues within an ongoing sound.	t	\N
21131368	The thalamic reticular nucleus (TRN) is a shell-shaped gamma amino butyric acid (GABA)ergic nucleus, which is uniquely placed between the thalamus and the cortex, because it receives excitatory afferents from both cortical and thalamic neurons and sends inhibitory projections to all nuclei of the dorsal thalamus. A review of the evidence suggesting that the TRN is implicated in the neurobiology of schizophrenia. TRN-thalamus circuits are implicated in bottom-up as well as top-down processing. TRN projections to nonspecific nuclei of the dorsal thalamus mediate top-down processes, including attentional modulation, which are initiated by cortical afferents to the TRN. TRN-thalamus circuits are also involved in bottom-up activities, including sensory gating and the transfer to the cortex of sleep spindles. Intriguingly, deficits in attention and sensory gating have been consistently found in schizophrenics, including first-break and chronic patients. Furthermore, high-density electroencephalographic studies have revealed a marked reduction in sleep spindles in schizophrenics. On the basis of our current knowledge on the molecular and anatomo-functional properties of the TRN, we suggest that this thalamic GABAergic nucleus may be involved in the neurobiology of schizophrenia.	t	\N
22087275	How quickly do listeners recognize emotions from a speaker's voice, and does the time course for recognition vary by emotion type? To address these questions, we adapted the auditory gating paradigm to estimate how much vocal information is needed for listeners to categorize five basic emotions (anger, disgust, fear, sadness, happiness) and neutral utterances produced by male and female speakers of English. Semantically-anomalous pseudo-utterances (e.g., The rivix jolled the silling) conveying each emotion were divided into seven gate intervals according to the number of syllables that listeners heard from sentence onset. Participants (n = 48) judged the emotional meaning of stimuli presented at each gate duration interval, in a successive, blocked presentation format. Analyses looked at how recognition of each emotion evolves as an utterance unfolds and estimated the "identification point" for each emotion. Results showed that anger, sadness, fear, and neutral expressions are recognized more accurately at short gate intervals than happiness, and particularly disgust; however, as speech unfolds, recognition of happiness improves significantly towards the end of the utterance (and fear is recognized more accurately than other emotions). When the gate associated with the emotion identification point of each stimulus was calculated, data indicated that fear (M = 517 ms), sadness (M = 576 ms), and neutral (M = 510 ms) expressions were identified from shorter acoustic events than the other emotions. These data reveal differences in the underlying time course for conscious recognition of basic emotions from vocal expressions, which should be accounted for in studies of emotional speech processing.	t	\N
22384211	Recent behavioral neuroscience research revealed that elementary reactive behavior can be improved in the case of cross-modal sensory interactions thanks to underlying multisensory integration mechanisms. Can this benefit be generalized to an ongoing coordination of movements under severe physical constraints? We choose a juggling task to examine this question. A central issue well-known in juggling lies in establishing and maintaining a specific temporal coordination among balls, hands, eyes and posture. Here, we tested whether providing additional timing information about the balls and hands motions by using external sound and tactile periodic stimulations, the later presented at the wrists, improved the behavior of jugglers. One specific combination of auditory and tactile metronome led to a decrease of the spatiotemporal variability of the juggler's performance: a simple sound associated to left and right tactile cues presented antiphase to each other, which corresponded to the temporal pattern of hands movement in the juggling task. A contrario, no improvements were obtained in the case of other auditory and tactile combinations. We even found a degraded performance when tactile events were presented alone. The nervous system thus appears able to integrate in efficient way environmental information brought by different sensory modalities, but only if the information specified matches specific features of the coordination pattern. We discuss the possible implications of these results for the understanding of the neuronal integration process implied in audio-tactile interaction in the context of complex voluntary movement, and considering the well-known gating effect of movement on vibrotactile perception.	t	\N
22896044	Thresholds of school-aged children are elevated relative to those of adults for intensity discrimination and amplitude modulation (AM) detection. It is unclear how these findings are related or what role stimulus gating and dynamic envelope cues play in these results. Two experiments assessed the development of sensitivity to intensity increments in different stimulus contexts. Thresholds for detecting an increment in level were estimated for normal-hearing children (5- to 10-year-olds) and adults. Experiment 1 compared intensity discrimination for gated and continuous presentation of a 1-kHz tone, with a 65-dB-SPL standard level. Experiment 2 compared increment detection and 16-Hz AM detection introduced into a continuous 1-kHz tone, with either 35- or 75-dB-SPL standard levels. Children had higher thresholds than adults overall. All listeners were more sensitive to increments in the continuous than the gated stimulus and performed better at the 75- than at the 35-dB-SPL standard level. Both effects were comparable for children and adults. There was some evidence that children's AM detection was more adultlike than increment detection. These results imply that memory for loudness across gated intervals is not responsible for children's poor performance but that multiple dynamic envelope cues may benefit children more than adults.	t	\N
23716244	This study investigated monaural envelope correlation perception (Richards 1987) for noise bandwidths ranging from 25 to 1,600 Hz. The high-frequency side of the low band was fixed at 3,000 Hz and the low-frequency side of the high band was fixed at 3,500 Hz. When comodulated, the magnitude spectra of the pair of noise bands were either identical or reflected around the midpoint. Six listeners with normal hearing participated. Listeners showed similar performance for identical and reflected-spectrum conditions, with best performance usually occurring for bandwidths between 200 and 800 Hz. Results were considered in terms of envelope comparisons of waveforms at the outputs of multiple peripheral filters or envelope comparisons of waveforms at the outputs of central filters set to the bandwidths of the noise stimuli. Some aspects of the results were incompatible with the account based on multiple peripheral filters. However, the results of a supplementary condition involving the gating of band subregions indicated that this incompatibility could be accounted for by nonoptimal weighting of peripheral filter outputs.	t	\N
24298171	While watching movies, the brain integrates the visual information and the musical soundtrack into a coherent percept. Multisensory integration can lead to emotion elicitation on which soundtrack valences may have a modulatory impact. Here, dynamic kissing scenes from romantic comedies were presented to 22 participants (13 females) during functional magnetic resonance imaging scanning. The kissing scenes were either accompanied by happy music, sad music or no music. Evidence from cross-modal studies motivated a predefined three-region network for multisensory integration of emotion, consisting of fusiform gyrus (FG), amygdala (AMY) and anterior superior temporal gyrus (aSTG). The interactions in this network were investigated using dynamic causal models of effective connectivity. This revealed bilinear modulations by happy and sad music with suppression effects on the connectivity from FG and AMY to aSTG. Non-linear dynamic causal modeling showed a suppressive gating effect of aSTG on fusiform-amygdalar connectivity. In conclusion, fusiform to amygdala coupling strength is modulated via feedback through aSTG as region for multisensory integration of emotional material. This mechanism was emotion-specific and more pronounced for sad music. Therefore, soundtrack valences may modulate emotion elicitation in movies by differentially changing preprocessed visual information to the amygdala.	t	\N
24736181	Although a number of recent studies have examined functional connectivity at rest, few have assessed differences between connectivity both during rest and across active task paradigms. Therefore, the question of whether cortical connectivity patterns remain stable or change with task engagement continues to be unaddressed. We collected multi-scan fMRI data on healthy controls (N=53) and schizophrenia patients (N=42) during rest and across paradigms arranged hierarchically by sensory load. We measured functional network connectivity among 45 non-artifactual distinct brain networks. Then, we applied a novel analysis to assess cross paradigm connectivity patterns applied to healthy controls and patients with schizophrenia. To detect these patterns, we fit a group by task full factorial ANOVA model to the group average functional network connectivity values. Our approach identified both stable (static effects) and state-based differences (dynamic effects) in brain connectivity providing a better understanding of how individuals' reactions to simple sensory stimuli are conditioned by the context within which they are presented. Our findings suggest that not all group differences observed during rest are detectable in other cognitive states. In addition, the stable differences of heightened connectivity between multiple brain areas with thalamus across tasks underscore the importance of the thalamus as a gateway to sensory input and provide new insight into schizophrenia.	t	\N
24801767	Despite advances in the treatment of schizophrenia spectrum disorders with atypical antipsychotics (AAPs), there is still need for compounds with improved efficacy/side-effect ratios. Evidence from challenge studies suggests that the assessment of gating functions in humans and rodents with naturally low-gating levels might be a useful model to screen for novel compounds with antipsychotic properties. To further evaluate and extend this translational approach, three AAPs were examined. Compounds without antipsychotic properties served as negative control treatments. In a placebo-controlled, within-subject design, healthy males received either single doses of aripiprazole and risperidone (n=28), amisulpride and lorazepam (n=30), or modafinil and valproate (n=30), and placebo. Prepulse inhibiton (PPI) and P50 suppression were assessed. Clinically associated symptoms were evaluated using the SCL-90-R. Aripiprazole, risperidone, and amisulpride increased P50 suppression in low P50 gaters. Lorazepam, modafinil, and valproate did not influence P50 suppression in low gaters. Furthermore, low P50 gaters scored significantly higher on the SCL-90-R than high P50 gaters. Aripiprazole increased PPI in low PPI gaters, whereas modafinil and lorazepam attenuated PPI in both groups. Risperidone, amisulpride, and valproate did not influence PPI. P50 suppression in low gaters appears to be an antipsychotic-sensitive neurophysiologic marker. This conclusion is supported by the association of low P50 suppression and higher clinically associated scores. Furthermore, PPI might be sensitive for atypical mechanisms of antipsychotic medication. The translational model investigating differential effects of AAPs on gating in healthy subjects with naturally low gating can be beneficial for phase II/III development plans by providing additional information for critical decision making.	t	\N
25024207	Historic theories of speech perception (Motor Theory and Analysis by Synthesis) invoked listeners' knowledge of speech production to explain speech perception. Neuroimaging data show that adult listeners activate motor brain areas during speech perception. In two experiments using magnetoencephalography (MEG), we investigated motor brain activation, as well as auditory brain activation, during discrimination of native and nonnative syllables in infants at two ages that straddle the developmental transition from language-universal to language-specific speech perception. Adults are also tested in Exp. 1. MEG data revealed that 7-mo-old infants activate auditory (superior temporal) as well as motor brain areas (Broca's area, cerebellum) in response to speech, and equivalently for native and nonnative syllables. However, in 11- and 12-mo-old infants, native speech activates auditory brain areas to a greater degree than nonnative, whereas nonnative speech activates motor brain areas to a greater degree than native speech. This double dissociation in 11- to 12-mo-old infants matches the pattern of results obtained in adult listeners. Our infant data are consistent with Analysis by Synthesis: auditory analysis of speech is coupled with synthesis of the motor plans necessary to produce the speech signal. The findings have implications for: (i) perception-action theories of speech perception, (ii) the impact of "motherese" on early language learning, and (iii) the "social-gating" hypothesis and humans' development of social understanding.	t	\N
25544613	Perception routinely integrates inputs from different senses. Stimulus temporal proximity critically determines whether or not these inputs are bound together. Despite the temporal window of integration being a widely accepted notion, its neurophysiological substrate remains unclear. Many types of common audio-visual interactions occur within a time window of ∼100 ms. For example, in the sound-induced double-flash illusion, when two beeps are presented within ∼100 ms together with one flash, a second illusory flash is often perceived. Due to their intrinsic rhythmic nature, brain oscillations are one candidate mechanism for gating the temporal window of integration. Interestingly, occipital alpha band oscillations cycle on average every ∼100 ms, with peak frequencies ranging between 8 and 14 Hz (i.e., 120-60 ms cycle). Moreover, presenting a brief tone can phase-reset such oscillations in visual cortex. Based on these observations, we hypothesized that the duration of each alpha cycle might provide the temporal unit to bind audio-visual events. Here, we first recorded EEG while participants performed the sound-induced double-flash illusion task and found positive correlation between individual alpha frequency (IAF) peak and the size of the temporal window of the illusion. Participants then performed the same task while receiving occipital transcranial alternating current stimulation (tACS), to modulate oscillatory activity either at their IAF or at off-peak alpha frequencies (IAF±2 Hz). Compared to IAF tACS, IAF-2 Hz and IAF+2 Hz tACS, respectively, enlarged and shrunk the temporal window of illusion, suggesting that alpha oscillations might represent the temporal unit of visual processing that cyclically gates perception and the neurophysiological substrate promoting audio-visual interactions.	t	\N
19616325	A patient with ankylosing spondylitis, migraine, Parkinson syndrome, renal insufficiency and myopathy, received an implantable-cardioverter-defibrillator because of asymptomatic left ventricular hypertrabeculation/noncompaction as primary prophylaxis against sudden cardiac death. Inadvertently the ventricular lead was placed in a cardiac vein, the patient suffered from pericardial effusion and it was impossible to remove the lead. Implantation of an implantable-cardioverter-defibrillator simply upon the presence of LVHT appears not justified and may be more harmful than beneficial. Studies about the risk of SCD in adults with LVHT are necessary and will hopefully clarify if primary prevention of SCD is indicated.	f	\N
19770797	FX06 is a naturally occurring fibrin-derived peptide demonstrated to confer cytoprotection in the setting of primary percutaneous coronary intervention. Because the effect of FX06 on human platelet, coagulation, and fibrinolysis biomarkers (PCFB) is unknown but is important for further clinical development, we evaluated how FX06 affects PCFB. The in vitro effects of the whole-blood pre-incubation with escalating concentrations of FX06 (4, 25, and 75 μg/mL) were assessed in aspirin-naïve healthy volunteers (n = 10), those with multiple risk factors for vascular disease (n = 10), and patients with documented coronary artery disease (n = 10). The last two groups were treated with aspirin (81 mg/daily). Thirty-two variables of PCFB were measured with the vehicle and for each chosen FX06 dose. Pretreatment of blood samples with FX06 resulted in a moderate but significant and mostly dose-dependent increases of platelet aggregation induced by adenosine diphosphate and collagen. Similarly, the closure time was reduced, suggesting share-induced activation, PECAM-1, GP Ib, GP IIb/IIIa activity, and vitronectin receptors, which were also up-regulated. In contrast, P-selectin and GPIIb antigen expression were reduced after FX06. All other PCFB were predominantly unaffected by FX06, with the exception of the increased plasminogen, decreased protein C activity, and activated von Willebrand factor. We conclude that in the therapeutic range, FX06 in vitro mildly affects hemostasis by way of mostly activating platelets. Applying moderate concomitant antiplatelet strategies should be considered for the adequate protection from vascular thrombotic events in patients treated with FX06. Similar ex vivo study in patients receiving aspirin and clopidogrel is warranted.	f	\N
19854042	Upper urinary tract urothelial carcinoma (UUTUC) is relatively rare, occurring in only 5% of all urothelial cancers. It has not been as extensively studied and reviewed as carcinoma of the bladder. UUTUC has a propensity for multifocality, local recurrence, and development of metastases, which argues for an aggressive treatment approach. Open radical nephroureterectomy (ORNU) with removal of an ipsilateral bladder cuff still remains the gold standard treatment for patients with UUTUC and a normal contralateral kidney, which, however, is being challenged by minimally invasive approaches, such as endoscopic and laparoscopic approaches. They are rapidly evolving as reasonable alternatives of care depending on grade and stage of disease. Adjuvant therapy seems to be safe, although its efficacy is debatable. Immunotherapy appears to be most effective in patients with upper-tract carcinoma in situ. Chemotherapy and radiotherapy also show some improvement in recurrence rates, but there have been no randomized, prospective trials. Gene and molecular-targeted therapy is expected. Several controversies remain in our management, including a selection of endoscopic versus laparoscopic approaches, management strategies on the distal ureter, the role of lymphadenectomy, and the value of immunotherapy, chemotherapy, radiotherapy and genetics and molecular markers in UUTUC. Aims of this paper are to critically review the treatment of UUTUC.	f	\N
20049455	Relapsing polychondritis (RP) is a rare disease which presents chondritis in multiple organs. Characteristic features include auricular chondritis, arthritis, nasal chondritis, ocular inflammation, respiratory tract involvement and audiovestibular damage. Fifty percent of cases of RP are associated with inner ear symptoms such as dizziness and hearing loss. We have recently encountered a case of RP in a 34-year-old man who had recurrent chondritis of both auricles and progressive bilateral profound sensorineural hearing loss; he had been treated many times with steroids, immunosuppressants, plasmapheresis treatments. We perfomed a successful cochlear implant surgery on the left ear of this patient. This raises the possibility of using cochlear implants in treating patients with immune-mediated inner ear disease as well as such RP patients.	f	\N
20373123	Juvenile dermatomyositis (JDM) is a rare childhood disease with autoimmune association. Environmental factors are known to trigger JDM in genetically susceptible individuals (Schmieder et al., Dermatol Online 6:3, 2009). Calcinosis is a well-established complication of JDM. Prevalence is higher in children (30-70%; Özkaya et al., Erciyes Med J 30(1):40-43, 2008). Hyperimmunoglobulin E syndrome is a primary immunodeficiency syndrome with multiple recurrent abscess formation and raised serum immunoglobulin E levels. We report a case of JDM with calcinosis cutis universalis with hyperimmunoglobulin E syndrome. With a previous similar case report (Min et al., Korean J Intern Med 14:95-98, 1999), this could well be a new sequence syndrome where abscesses are the trigger for the onset of JDM.	f	\N
20390341	The estrogen signal is mediated by the estrogen receptor (ER). The specific role of ER-beta, a second ER, in breast carcinogenesis is not known. A number of association studies have been carried out to investigate the relationship between polymorphic sites in the ESR2 gene and breast cancer risk, however, the results are inconsistent. We searched PubMed, Medline, and Web of Science database (updated to 10 January 2010) and identified 13 relevant case-control studies, and approximately 28 single-nucleotide polymorphisms (SNPs) and one micro-satellite marker were reported in the literature. The median number of study subjects was 776 (range 158-13,550). Three genetic variants [(CA)n, rs2987983, and rs4986938] showed significant overall associations with breast cancer, and rs4986938 was reported twice. Because rs4986938 and rs1256049 were the most extensively studied polymorphisms, we subsequently conducted a meta-analysis to evaluate their relationship with breast cancer risk (9 studies of 10,837 cases and 16,021 controls for rs4986938; 8 studies of 11,652 cases and 15,726 controls for rs1256049). For rs4986938, the women harboring variant allele seemed to be associated with a decreased risk either in the dominant model [pooled OR = 0.944, 95% confidence interval (95% CI) 0.897-0.993, fixed-effects] or in the co-dominant model (AG vs. GG) (OR = 0.944, 95% CI 0.895-0.997, fixed-effects). rs1256049 was not associated with breast cancer risk in any model. Five studies had investigated the effect of haplotypes in the ESR2 gene on breast cancer risk, and four of them had positive outcomes. In summary, the present systematic review suggests that SNP rs4986938 as well as haplotypes in the ESR2 gene might be associated with breast cancer. The need for additional studies examining these issues seems of vital importance.	f	\N
20434804	The pathophysiology of tinnitus is obscure and its treatment is therefore elusive. Significant progress in this field can only be achieved by determining the mechanisms of tinnitus generation, and thus, histopathologic findings of the cochlea in presbycusis with tinnitus become crucial. We revealed the histopathologic findings of the cochlea in subjects with presbycusis and tinnitus. The subjects were divided into 2 groups, presbycusis with tinnitus (tinnitus) group and presbycusis without tinnitus (control) group, with each group comprising 8 temporal bones from 8 subjects. We quantitatively analyzed the number of spiral ganglion cells, loss of cochlear inner and outer hair cells, and areas of the stria vascularis and spiral ligament. There was a significantly greater loss of outer hair cells in the tinnitus group compared with the control group in the basal and upper middle turns. The stria vascularis was more atrophic in the tinnitus group compared with the control group in the basal turn. Tinnitus is more common in patients with presbycusis who have more severe degeneration of outer hair cells and stria vascularis.	f	\N
20512338	Hoarseness due to left recurrent laryngeal nerve paralysis (LRLN) caused by identifiable cardiovascular disease is described as Ortner's syndrome or cardiovocal syndrome. This was first reported by Ortner in 1897 to describe left recurrent laryngeal nerve palsy secondary to mitral stenosis. This case report describe a patient with giant cell arteritis with initial presentation of Ortner's syndrome.	f	\N
20579773	Oligomeric β-amyloid (Aβ) has recently been linked to synaptic plasticity deficits, which play a major role in progressive cognitive decline in Alzheimer's disease (AD). Here we present evidence that chronic oral administration of carvedilol, a nonselective β-adrenergic receptor blocker, significantly attenuates brain oligomeric β-amyloid content and cognitive deterioration in 2 independent AD mouse models. We found that carvedilol treatment significantly improved neuronal transmission, and that this improvement was associated with the maintenance of number of the less stable "learning" thin spines in the brains of AD mice. Our novel observation that carvedilol interferes with the neuropathologic, biochemical, and electrophysiological mechanisms underlying cognitive deterioration in AD supports the potential development of carvedilol as a treatment for AD.	f	\N
20678147	Psoriasis is today generally considered a systemic disease. Systemic therapies are used frequently. In Germany fumaric acid esters - FAE (Fumaderm(®) ) - are employed in more than 50 % of the patients requiring such therapy. We report for the first time the development of melanoma in two patients during their treatment with FAE. The logical question is - are the tumors coincidental or might they be treatment-related? Further investigations of pathways and immunologic effects as well as careful reports of side effects are necessary to estimate the risks of malignancy of FAE.	f	\N
20696610	This study investigates the relationship between neck muscle coactivation, neck strength and perceived pain and disability in women with neck pain. Surface electromyography (EMG) was acquired from the sternocleidomastoid (SCM) and splenius capitis (SC) muscles of 13 women with chronic neck pain and 10 controls as they performed 1) maximal voluntary contractions (MVC) in flexion, extension and left and right lateral flexion, 2) ramped contractions from 0% to 50% MVC in flexion and extension and 3) circular contractions in the horizontal plane at 15N and 30N force. Higher values of EMG amplitude were observed for the SC (antagonist) during ramped neck flexion and for the SCM during ramped extension in the patient group (P<0.05). The patients displayed reduced values of directional specificity in the surface EMG of the SCM and SC for the circular contractions (P<0.05). The EMG amplitude of SC during cervical flexion was positively correlated with the patients' pain (R² =0.35, P<0.05) and perceived disability (R² 0.53, P<0.01). An inverse correlation was evident between the amount of activation of SC during cervical flexion and strength (R² =0.54, P<0.01). These observations indicate a relationship between alterations in neuromuscular control in patients with neck pain and functional consequences, including impaired motor performance and increased levels of perceived disability.	f	\N
20733020	To report the clinical course, treatment response and prognosis of eight cases which developed acute-onset postoperative endophthalmitis over a 1-month period. 8 patients who were operated on over a period of 1 month and developed acute postoperative endophthalmitis were evaluated. Five of the patients had cataract surgery, one had cataract surgery combined with silicone extraction, and two patients had pars plana vitrectomy (PPV). Clinical patterns were observed, intraocular cultures were obtained, and the source of the organisms causing the epidemic was investigated. All patients had intravitreal antibiotic injections, three had PPV, and in two patients anterior chamber irrigation was performed. Vitreous cultures showed Cellulosimicrobium cellulans in three cases and Stenotrophomonas maltophilia in one case. Four of the cases were culture negative. Stenotrophomonas maltophilia were also isolated from unused bottles of irrigating solutions. The final visual acuity of the patients ranged between HM and 7/10. All three patients with Cellulosimicrobium cellulans had a final visual acuity of ≥ 5/10. The available irrigating solutions were changed, and the endophthalmitis did not recur. The authors are unaware of any previous reports of postoperative endophthalmitis associated with Cellulosimicrobium cellulans. Prompt management with microbiological support, intravitreal antibiotics and PPV when needed were the key to good visual outcomes in this endophthalmitis outbreak.	f	\N
20849277	The ability for public/veterinary health agencies to assess the risks posed by tick-borne pathogens is reliant on an understanding of the main tick vector species. Crucially, the status, distribution, and changing trends in tick distribution and abundance are implicit requirements of any risk assessment; however, this is contingent on the quality of tick distribution data. Since 2005 the Health Protection Agency has promoted an enhanced tick surveillance program. Through engagement with a variety of public and veterinary health agencies and practitioners (e.g., clinicians and veterinarians), wildlife groups (deer society, zoos, animal refuge centers, and academics), and amateur entomologists, >4000 ticks from 900 separate records across Great Britain have been submitted, representing 14 tick species (Ixodes ricinus, Ixodes hexagonus, Ixodes acuminatus, Ixodes arboricola, Ixodes canisuga, Ixodes frontalis, Ixodes lividus, Ixodes trianguliceps, Ixodes ventalloi, Carios vespertilionis, Dermacentor reticulatus, Haemaphysalis punctata, Hyalomma marginatum, and Amblyomma species). The majority of ticks submitted were I. ricinus (81%), followed by I. hexagonus (10%) and I. frontalis (2.5%). Predominant host groups include companion animals (411 records), humans (198 records), wild birds (111 records), and large wild mammals (88 records), with records also from small/medium wild mammals, livestock, the environment and domestic/aviary birds. The scheme has elucidated the detection of two nonnative tick species, the expansion of previously geographically restricted D. reticulatus and produced ground data on the spread of I. ricinus in southwest England. It has also provided a forum for submission of ticks from the concerned public and particularly those infected with Lyme borreliosis, thus raising awareness among public health agencies of the increased peri-urban tick problem in Britain. Our results demonstrate that it is possible to run a cost-effective nationwide surveillance program to successfully monitor endemic tick species, identify subtle changes in their distribution, and detect the arrival and presence of exotic species.	f	\N
20853354	We report our 10-year experience with percutaneous closure of adult congenital and acquired (non-post-infarct) ventricular septal defects (VSDs) using different types of Amplatzer occluder devices. Adult congenital and acquired VSDs may produce significant morbidity and mortality. Furthermore, such VSDs pose a significant surgical challenge. Between February 2000 and August 2009, data were retrospectively reviewed from 28 patients who underwent 29 procedures for percutaneous device closure of hemodynamically significant VSDs. Seventeen had unrepaired congenital VSDs, 10 had post-operative VSDs (5 with residual patch-margin defects, 4 post-aortic valve replacement, 1 post-myomectomy), and one had an acquired traumatic VSD. INDICATIONS FOR CLOSURE INCLUDED: symptoms related to significant shunt (dyspnea on exertion); unexplained deterioration of LV function, and/or LV dilation; recurrent endocarditis, and pulmonary hypertension. Outcome parameters were procedural success, procedure-related complications, evidence of residual shunt by echocardiography, and improvement in the signs/symptoms for which the procedure was performed. The mean follow-up interval was 68 months. Of the 28 patients studied, a single VSD was present in 26 patients, while one patient had two defects, and one patient had one defect on the LV side with three openings at the RV side. The median size of the defects by echocardiography was 6 mm. A device was successfully implanted in 28 of 29 (97%) procedures and 28 of 28 (100%) patients. PROCEDURE-RELATED COMPLICATIONS OCCURRED IN TWO CASES: one involving an access site hematoma not requiring transfusion as well as nonsustained ventricular tachycardia that resolved spontaneously and the other involving acute mitral regurgitation due to inadvertent trapping of the anterior mitral valve leaflet between the left ventricular disk and the septum that was resolved by recapturing of the disk. There was immediate complete closure in 20 patients (71%). In six cases there was trivial residual shunt and in two patients the residual shunt was mild. At the latest follow-up, four of the eight with a residual shunt had no shunt and in the remaining four the residual shunt was trivial. Among symptomatic patients 18 (64%), there was marked improvement in symptoms and for those patients 17 (61%) for whom the procedure was performed to address left ventricular enlargement, there was reduction or stabilization in LV size on serial echoes. Percutaneous closure of VSDs in the adult patient appears to be safe and effective.	f	\N
20853359	A significant proportion (~ 20%) of patients with complex tibial artery occlusions cannot be treated using a conventional antegrade approach. We report our experience using the retrograde approach for the treatment of complex tibial artery occlusive disease using retrograde pedal/tibial access in 13 limbs from 12 patients. Retrograde pedal/tibial access was achieved in all cases (facilitated by surgical cutdown in one case), and procedural success was achieved in 11 of 13 limbs (85%). Based on this experience, a discussion of clinical and technical aspects of the retrograde pedal/tibial approach is provided, and a new classification for tibial artery occlusive disease is proposed.	f	\N
20878712	Endoscopic evaluation plays a pivotal role in the assessment of treatment response in ulcerative colitis (UC). This study aimed to determine the interobserver agreement (IOA) for assessment of mucosal lesions, and to determine lesions predictive of global assessment of endoscopic severity (GAES). Fifty-one UC patients had digital videorecording of their colonoscopic examinations, edited into videoclips representative of five colonic segments (rectum, sigmoid, descending, transverse, ascending/cecum). Seven gastroenterologists specializing in inflammatory bowel disease (IBD) independently and blindly rated individual lesions and endoscopic severity for each segment and globally. Edema, erythema, stricture, loss of haustral folds, rigidity, and pseudopolyps were scored as absent or present while vascular pattern, granularity, ulceration, and bleeding-friability were scored using a predefined severity scale. The GAES was based on a 4-point scale and a 10-cm visual analog scale (VAS). The IOA among raters was estimated using Lin's concordance correlation coefficient (CCC). Strength of agreement was categorized as excellent (0.81-1.00), good (0.61-0.80), moderate (0.41-0.60), and fair (0.21-0.40). Linear regression analysis was used to identify lesions predictive of overall endoscopic severity and develop a scoring system for clinical use. Granularity, vascular pattern, ulceration, bleeding/friability, and pseudopolyps had good IOA in most segments. There was excellent agreement for VAS and good agreement for GAES and the VAS was significantly associated with GAES (P < 0.001). Granularity, vascular pattern, ulceration, and bleeding-friability were significant predictors of overall endoscopic severity. Granularity, vascular pattern, ulceration, and bleeding-friability demonstrated good reproducibility and were predictors of the GAES in UC patients.	f	\N
20881290	Mutations in PITX2 are associated with Axenfeld-Rieger syndrome (ARS), which involves ocular, dental, and umbilical abnormalities. Identification of cis-regulatory elements of PITX2 is important to better understand the mechanisms of disease. Conserved noncoding elements surrounding PITX2/pitx2 were identified and examined through transgenic analysis in zebrafish; expression pattern was studied by in situ hybridization. Patient samples were screened for deletion/duplication of the PITX2 upstream region using arrays and probes. Zebrafish pitx2 demonstrates conserved expression during ocular and craniofacial development. Thirteen conserved noncoding sequences positioned within a gene desert as far as 1.1 Mb upstream of the human PITX2 gene were identified; 11 have enhancer activities consistent with pitx2 expression. Ten elements mediated expression in the developing brain, four regions were active during eye formation, and two sequences were associated with craniofacial expression. One region, CE4, located approximately 111 kb upstream of PITX2, directed a complex pattern including expression in the developing eye and craniofacial region, the classic sites affected in ARS. Screening of ARS patients identified an approximately 7600-kb deletion that began 106 to 108 kb upstream of the PITX2 gene, leaving PITX2 intact while removing regulatory elements CE4 to CE13. These data suggest the presence of a complex distant regulatory matrix within the gene desert located upstream of PITX2 with an essential role in its activity and provides a possible mechanism for the previous reports of ARS in patients with balanced translocations involving the 4q25 region upstream of PITX2 and the current patient with an upstream deletion.	f	\N
20936300	In Huntington's disease (HD) atrophy of the caudate nucleus and putamen has been described many years before clinical manifestation. Volume changes of the pallidum, thalamus, brainstem, accumbens nucleus, hippocampus, and amygdala are less well investigated, or reported with contradicting results. The aim of our study is to provide a more precise view of the specific atrophy of the subcortical grey matter structures in different stages of Huntington's disease, and secondly to investigate how this influences the clinical manifestations. All TRACK-HD subjects underwent standardised T1-weighted 3T MRI scans encompassing 123 manifest HD (stage 1, n = 77; stage 2, n = 46), 120 premanifest HD (close to onset n = 58, far from onset n = 62) and 123 controls. Using FMRIB's FIRST and SIENAX tools the accumbens nucleus, amygdala, brainstem, caudate nucleus, hippocampus, pallidum, putamen, thalamus and whole brain volume were extracted. Results showed that volumes of the caudate nucleus and putamen were reduced in premanifest HD far from predicted onset (>10.8 years). Atrophy of accumbens nucleus and pallidum was apparent in premanifest HD in the close to onset group (0-10.8 years). All other structures were affected to some degree in the manifest group, although brainstem, thalamus and amygdala were relatively spared. The accumbens nucleus, putamen, pallidum and hippocampus had a strong significant correlation with functional and motor scores. We conclude that volume changes may be a sensitive and reliable measure for early disease detection and in this way serve as a biomarker for Huntington's disease. Besides the caudate nucleus and putamen, the pallidum and the accumbens nucleus show great potential in this respect.	f	\N
20938704	We describe an outbreak of Bacillus cereus bacteremia that occurred at Jichi Medical University Hospital in 2006. This study aimed to identify the source of this outbreak and to implement appropriate control measures. We reviewed the charts of patients with blood cultures positive for B. cereus, and investigated B. cereus contamination within the hospital environment. Genetic relationships among B. cereus isolates were analyzed. Eleven patients developed B. cereus bacteremia between January and August 2006. The hospital linens and the washing machine were highly contaminated with B. cereus, which was also isolated from the intravenous fluid. All of the contaminated linens were autoclaved, the washing machine was cleaned with a detergent, and hand hygiene was promoted among the hospital staff. The number of patients per month that developed new B. cereus bacteremia rapidly decreased after implementing these measures. The source of this outbreak was B. cereus contamination of hospital linens, and B. cereus was transmitted from the linens to patients via catheter infection. Our findings demonstrated that bacterial contamination of hospital linens can cause nosocomial bacteremia. Thus, blood cultures that are positive for B. cereus should not be regarded as false positives in the clinical setting.	f	\N
20950346	Aldosterone plays an important role in the pathophysiology of heart failure. Aldosterone receptor blockade has been shown to reduce morbidity and mortality in human patients with advanced congestive left ventricular heart failure. This study was designed to assess the efficacy and tolerance of long-term low-dose spironolactone when added to conventional heart failure treatment in dogs with advanced heart failure. Eighteen client-owned dogs with advanced congestive heart failure due to either degenerative valve disease (n=11) or dilated cardiomyopathy (n=7) were included in this prospective, placebo-controlled, double-blinded, randomized clinical study. After initial stabilization including furosemide, angiotensin-converting enzyme inhibitors, pimobendan and digoxin, spironolactone at a median dose of 0.52 mg/kg (range 0.49-0.8 mg/kg) once daily (n=9) or placebo (n=9) was added to the treatment, and the dogs were reassessed 3 and 6 months later. Clinical scoring, echocardiography, electrocardiogram, systolic blood pressure measurement, thoracic radiography, sodium, potassium, urea, creatinine, alanine aminotransferase, aldosterone and aminoterminal atrial natriuretic propeptide were assessed at baseline, 3 and 6 months. Survival times were not significantly different between the two treatment groups. Spironolactone was well tolerated when combined with conventional heart failure treatment.	f	\N
20981578	Alzheimer's disease (AD) is a progressive neurodegenerative disorder leading to slow neuronal loss in several brain regions. It is characterised by the presence of cerebral senile plaques comprised of aggregated amyloid-β peptides. Transcriptional regulation of the γ-secretase complex, which cleaves the β-amyloid precursor protein to produce Aβ-peptides, could modulate the pathological phenotype of AD patients. This study investigates whether rosuvastatin, an HMG-CoA reductase inhibitor, modulates the expression of genes involved in the function of the γ-secretase complex, in a human cellular model for Aβ peptide accumulation. In particular, we analysed the effect of the statin combined with apoptotic induction. Experimental apoptosis was induced by thapsigargin treatment, a drug that depletes intracellular calcium stores via inhibition of the calcium ATPase pump. Notably, systemic calcium dysregulation accompanies almost all of the brain pathology processes observed in AD. We found differential transcriptional regulation of some γ-secretase cofactors relative to rosuvastatin treatment, in cells expressing Swedish mutant APP. Interestingly, this statin down-regulated the transcription of some enzyme cofactors, similar to treatment with thapsigargin. However, rosuvastatin neither affected the basal Aβ levels nor counteracted APP processing or Aβ over-production triggered by the thapsigargin. Our results provide evidence that rosuvastatin alters gene expression of the γ-secretase complex without affecting enzyme activity.	f	\N
21040232	Febrile seizures (FSs) relatively represent the most common form of childhood seizures. FSs are not thought of as a true epileptic disease but rather as a special syndrome characterized by its provoking factor (fever) and a typical range of 3 months to 5 years. Although specific genes affecting the majority of FS cases have not been identified yet, several genetic loci for FSs have been reported recently. The aim of this report is to search for the gene responsible for FSs in six affected Tunisian families. A microsatellite marker analysis was performed on the known FS and generalized epilepsy with febrile seizures plus (GEFS+) loci. According to the results obtained by statistical analyses for the six studied families and in agreement with the involvement of SCN1B gene in the GEFS+ syndrome in previous studies, SCN1B on GEFS+1 locus was considered as one of the potential candidate genes and was tested for mutations by direct sequencing. A sequencing analysis of the SCN1B gene revealed a novel mutation (c.374G>T) that changed an arginine residue with leucine at position 125 of the protein. We consider that the variation R125L may affect the protein structure and stability by the loss of hydrogen bonding. Two identified single nucleotide polymorphisms that are located in a neighboring hypothetical polyadenylation were assumed to compose a putative disease-associated haplotype. Our results support that SCN1B is the gene responsible in one amongst the six FS Tunisian families studied and might contribute to the FS susceptibility for the five others.	f	\N
21055462	Environmental factors have a significant impact on biology. Therefore, environmental toxicants through similar mechanisms can modulate biological systems to influence physiology and promote disease states. The majority of environmental toxicants do not have the capacity to modulate DNA sequence, but can alter the epigenome. In the event an environmental toxicant such as an endocrine disruptor modifies the epigenome of a somatic cell, this may promote disease in the individual exposed, but not be transmitted to the next generation. In the event a toxicant modifies the epigenome of the germ line permanently, then the disease promoted can become transgenerationaly transmitted to subsequent progeny. The current review focuses on the ability of environmental factors such as endocrine disruptors to promote transgenerational phenotypes.	f	\N
21073934	Two mouse models, the Coch(G88E/G88E) or "knock-in" and the Coch(-/-) or "knock-out" (Coch null), have been developed to study the human late-onset, progressive, sensorineural hearing loss and vestibular dysfunction known as DFNA9. This disorder results from missense and in-frame deletion mutations in COCH (coagulation factor C homology), encoding cochlin, the most abundantly detected protein in the inner ear. We have performed hearing and vestibular analyses by auditory brainstem response (ABR) and vestibular evoked potential (VsEP) testing of the Coch(-/-) and Coch(G88E/G88E) mouse models. Both Coch(-/-) and Coch(G88E/G88E) mice show substantially elevated ABRs at 21 months of age, but only at the highest frequency tested for the former and all frequencies for the latter. At 21 months, 9 of 11 Coch(-/-) mice and 4 of 8 Coch(G88E/G88E) mice have absent ABRs. Interestingly Coch(-/+) mice do not show hearing deficits, in contrast to Coch(G88E/+), which demonstrate elevated ABR thresholds similar to homozyotes. These results corroborate the DFNA9 autosomal dominant mode of inheritance, in addition to the observation that haploinsufficiency of Coch does not result in impaired hearing. Vestibular evoked potential (VsEP) thresholds were analyzed using a two factor ANOVA (Age X Genotype). Elevated VsEP thresholds are detected in Coch(-/-) mice at 13 and 21 months, the two ages tested, and as early as seven months in the Coch(G88E/G88E) mice. These results indicate that in both mouse models, vestibular function is compromised before cochlear function. Analysis and comparison of hearing and vestibular function in these two DFNA9 mouse models, where deficits occur at such an advanced age, provide insight into the pathology of DFNA9 and age-related hearing loss and vestibular dysfunction as well as an opportunity to investigate potential interventional therapies.	f	\N
21084426	We performed a three-stage genome-wide association study (GWAS) to identify common Parkinson's disease (PD) risk variants in the European population. The initial genome-wide scan was conducted in a French sample of 1039 cases and 1984 controls, using almost 500 000 single nucleotide polymorphisms (SNPs). Two SNPs at SNCA were found to be associated with PD at the genome-wide significance level (P < 3 × 10(-8)). An additional set of promising and new association signals was identified and submitted for immediate replication in two independent case-control studies of subjects of European descent. We first carried out an in silico replication study using GWAS data from the WTCCC2 PD study sample (1705 cases, 5200 WTCCC controls). Nominally replicated SNPs were further genotyped in a third sample of 1527 cases and 1864 controls from France and Australia. We found converging evidence of association with PD on 12q24 (rs4964469, combined P = 2.4 × 10(-7)) and confirmed the association on 4p15/BST1 (rs4698412, combined P = 1.8 × 10(-6)), previously reported in Japanese data. The 12q24 locus includes RFX4, an isoform of which, named RFX4_v3, encodes brain-specific transcription factors that regulate many genes involved in brain morphogenesis and intracellular calcium homeostasis.	f	\N
21085051	The Centers for Disease Control and Prevention recommend hospitals develop guidelines for the appropriate use of vancomycin as part of comprehensive antimicrobial stewardship. The objective of this study was to evaluate the effectiveness and safety of a guideline to restrict vancomycin use in the neonatal intensive care unit (NICU). A vancomycin use guideline was introduced in 2 tertiary care NICUs with low incidences of methicillin-resistant Staphylococcus aureus infections. We compared all infants >72 hours of age who were evaluated for late-onset infection before and after implementation of this guideline. Vancomycin start rates were reduced from 6.9 to 4.5 per 1000 patient-days (35% reduction; P = 0.01) at Brigham and Women's Hospital, and from 17 to 6.4 per 1000 patient-days (62% reduction; P < 0.0001) at Massachusetts General Hospital. The number of infants exposed to vancomycin decreased from 5.2 to 3.1 per 1000 patient-days (40% reduction; P = 0.008) at Brigham and Women's Hospital, and 10.8 to 5.5 per 1000 patient-days (49% reduction; P = 0.009) at Massachusetts General Hospital. Causes of infection, duration of bacteremia, and incidence of complications or deaths attributable to late-onset infection did not change significantly at either institution. Implementation of a NICU vancomycin use guideline significantly reduced exposure of newborns to vancomycin without adversely affecting short-term patient safety. Further studies are required to evaluate the long-term effect of vancomycin restriction on NICU patient safety and microbial ecology, particularly among institutions with higher rates of methicillin-resistant Staphylococcus aureus infections.	f	\N
21102561	Human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) have the potential to differentiate into all cell lineages, including hepatocytes, in vitro. Induced hepatocytes have a wide range of potential application in biomedical research, drug discovery, and the treatment of liver disease. However, the existing protocols for hepatic differentiation of PSCs are not very efficient. In this study, we developed an efficient method to induce hepatoblasts, which are progenitors of hepatocytes, from human ESCs and iPSCs by overexpression of the HEX gene, which is a homeotic gene and also essential for hepatic differentiation, using a HEX-expressing adenovirus (Ad) vector under serum/feeder cell-free chemically defined conditions. Ad-HEX-transduced cells expressed α-fetoprotein (AFP) at day 9 and then expressed albumin (ALB) at day 12. Furthermore, the Ad-HEX-transduced cells derived from human iPSCs also produced several cytochrome P450 (CYP) isozymes, and these P450 isozymes were capable of converting the substrates to metabolites and responding to the chemical stimulation. Our differentiation protocol using Ad vector-mediated transient HEX transduction under chemically defined conditions efficiently generates hepatoblasts from human ESCs and iPSCs. Thus, our methods would be useful for not only drug screening but also therapeutic applications.	f	\N
21104183	Crohn disease is a chronic granulomatous inflammatory disorder that most commonly affects the gastrointestinal tract, particularly the distal small bowel and colon. While certain extraintestinal manifestations of Crohn disease are relatively common and well-known, others, such as metastatic cutaneous involvement, are quite rare and may be difficult to recognize, particularly in the pediatric population. This case report illustrates the magnetic resonance imaging (MRI) appearance of vulvar region cutaneous Crohn disease in an 11-year-old girl.	f	\N
21106231	The purpose of this study was (1) to investigate the association between BMI self-reported at three time points (during their 20s, 5 years before diagnosis, and post-diagnosis) and mortality among 388 women with newly diagnosed epithelial ovarian cancer and (2) weight change between these 3 time points and mortality. Women completed interview-administered questionnaires on average 9 months post-diagnosis. Women were followed 5 years after diagnosis or until death, whichever came first. Cox proportional hazard regression was used to estimate associations between BMI during the 20s, BMI 5 years prior to diagnosis, BMI post-diagnosis (i.e., at the time of interview) and weight changes between these time points and mortality. The 5-year survival rate was 54% (178 deaths, 146 from ovarian cancer). BMI measured continuously at all three time points was associated with a higher risk of ovarian cancer mortality (P≤0.05). The strongest association was observed with BMI in the 20s and all-cause mortality comparing women with BMI≥25 kg/m(2) to BMI<25 kg/m(2) (HR=1.82; 95% CI, 1.02-3.27; P for trend=0.045). For weight change from the 20s to 5 years prior to diagnosis and ovarian cancer specific mortality, we observed a 68% higher risk of ovarian cancer mortality (HR=1.68; 95% CI, 1.11-2.55; P for trend=0.015, comparing women with <10 lbs weight gain to women with ≥10 lbs weight gain). BMI prior to and after diagnosis and weight gain throughout adulthood is associated with ovarian cancer mortality.	f	\N
21135704	To study the role of probiotics on gut permeability and endotoxemia in patients with acute pancreatitis (AP). Bacterial translocation has been implicated in infective complications in AP, which has been shown to be prevented by probiotics. A double-blind, randomized placebo-controlled trial was conducted. Consecutive patients with AP presenting within 72 hours after the onset of abdominal pain or who had been nil orally at the time of presentation for up to 5 days were included in the study. The probiotic group received 4 sachets of Probiotics (2.5 billion bacteria per sachet) whereas the placebo group received 4 sachets of placebo for 7 days. Primary outcome measures were effect on gut permeability [assessed by lactulose/mannitol (L/M) excretion in urine] and endotoxemia assessed by endotoxin-core antibody types IgG and IgM (EndoCab IgG and IgM). Secondary outcome measures were mortality, total hospital/intensive care unit stay, abdominal discomfort, organ failure, C-reactive protein, and prealbumin levels. The study was prematurely stopped after the publication of probiotic prophylaxis in patients with predicted severe acute pancreatitis trial. From March 2007 to May 2008, 50 patients with AP were included in the study (26 in placebo group and 24 in probiotic group). There was no difference after intervention in gut permeability, whereas values of C-reactive protein and immunoglobulins decreased significantly [IgG: 140 (20-920) to 90 (20-600) GGU/mL and IgM: 65 (13-230) to 51 (9-240) GMU/mL] in the probiotic group. No difference was observed in prealbumin values, duration of hospital/intensive care unit stay, and mortality in both the groups. No significant trend was identified for an effect of probiotics on gut permeability or endotoxemia in AP. However, the study was underpowered owing to premature study termination.	f	\N
21172349	Visceral leishmaniasis (VL) is a health issue in Sudan. Our aim was to investigate the involvement of eosinophils and neutrophils in VL by serum and plasma measurements of eosinophil cationic protein (ECP) and myeloperoxidase (MPO) and some key cytokines and chemokines. Blood was collected from 125 VL patients and 181 healthy Sudanese controls from the same rural area. Results showed reduced eosinophil and neutrophil counts in the VL group (P=0.0001 and P=0.002, respectively). Serum-ECP levels were higher in the controls (P<0.0001), while plasma MPO levels were higher in the VL group (P<0.0001). Levels of IL-5, granulocyte macrophage-colony stimulating factor (GM-CSF) and IL-17 were increased among the VL group (P<0.0001, P=0.017 and P=0.03, respectively), whereas eotaxin and IL-8 levels were reduced (P<0.0001 and P=0.002, respectively). Positive correlations were found between IL-8 and ECP/MPO (P<0.0001). We conclude that eosinophil and neutrophil turnover and activity are increased in subjects in rural areas of Sudan. In VL the turnover was further increased, but the relatively low secretory activity of eosinophils and neutrophils in VL may relate to the reduced production and availability of the chemokines eotaxin and IL-8. The combined assay of ECP and MPO in serum and plasma provides further insight into the mechanisms of eosinophil and neutrophil involvement in disease and constitutes a novel approach to the study of disease processes.	f	\N
21184197	The significance of the cerebrospinal fluid (CSF) Apolipoprotein E (APOE) level and whether it might have differential effects on brain function due to the presence of APOE ε 4 allele(s) in HIV-infected patients are unknown. However, APOE ε 4 allele has been associated with greater incidence of HIV-associated dementia and accelerated progression of HIV infection. Here, we show further evidence for the role of APOE ε 4 in promoting cognitive impairment. We measured the APOE levels in the CSF of HIV-infected individuals. HIV+ subjects showed lower CSF APOE proteins than SN controls (-19%, p= 0.03). While SN subjects with or without ε 4 allele showed no difference in CSF APOE levels, ε 4+ HIV+ subjects had similar levels to the SN subjects but higher levels than ε 4- HIV+ subjects (+34%, p= 0.01). Furthermore, while HIV+ subjects with ε 2 or ε 3 allele(s) showed a positive relationship between their CSF APOE levels and cognitive performance on the speed of processing domain (r= +0.35, p= 0.05), ε 4+ HIV+ subjects, in contrast, exhibited a negative relationship such that those with higher levels of CSF APOE(4) performed worse on the HIV Dementia Scale (r= -0.61, p= 0.02), had lower Global Cognitive Scores (r= -0.57, p= 0.03), and had poorer performance on tests involving learning (ε 4 allele x [APOE] interaction, p = 0.01). Our findings also suggest that the relatively higher levels of CSF APOE in ε 4+ HIV+ (having primarily APOE4 isoforms) may negatively impact the brain and lead to poorer cognitive outcomes, while those individuals without the ε 4 allele (with primarily APOE2 or APOE3 isoforms) may show compensatory responses that lead to better cognitive performance.	f	\N
21190758	Assuming selective vulnerability of short association U-fibers in early Alzheimer's disease (AD), we quantified demyelination of the surface white matter (dSWM) with magnetization transfer ratio (MTR) in 15 patients (Clinical Dementia Rating Scale [CDR] 0.5-1; Functional Assessment Staging [FAST]: 3-4) compared with 15 controls. MTRs were computed for 39 areas in each hemisphere. We found a bilateral MTR decrease in the temporal, cingulate, parietal, and prefrontal areas. With linear discriminant analysis, we successfully classified all the participants with 3 variates including the cuneus, parahippocampal, and superior temporal regions of the left hemisphere. The pattern of dSWM changed with the age of AD onset. In early onset patients, we found bilateral posterior demyelination spreading to the temporal areas in the left hemisphere. The late onset patients showed a distributed bilateral pattern with the temporal and cingulate areas strongly affected. A correlation with Mini Mental State Examination (MMSE), Lexis, and memory tests revealed the dSWM impact on cognition. A specific landscape of dSWM in early AD shows the potential of MTR imaging as an in vivo biomarker superior to currently used techniques.	f	\N
21211565	Nuclear receptors (NRs) are ligand-activated transcriptional factors that are involved in various physiological, developmental, and toxicological processes. Farnesoid X receptor (FXR) is a NR that belongs to the NR superfamily. The endogenous ligands of FXR are bile acids. FXR is essential in regulating a network of genes involved in maintaining bile acid and lipid homeostasis. It is clear that FXR is critical for liver and intestinal function. In mice FXR deficiency leads to the development of cholestasis, gallstone disease, nonalcoholic steatohepatitis, liver tumor, and colon tumor. Using mouse models where FXR is deleted either in the whole-body, or selectively in hepatocytes or enterocytes, we start to reveal the importance of tissue-specific FXR function in regulating bile acid and lipid homeostasis. However, a great challenge exists for developing tissue-specific FXR modulators to prevent and treat diseases associated with bile acid or lipid disorders. With further understanding of FXR function in both rodents and humans, this nuclear receptor may emerge as a novel target to prevent and treat liver, gastrointestinal and systemic diseases.	f	\N
21220035	We retrospectively compared the outcomes of 225 patients with adult acquired aplastic anemia (AA) who underwent allogeneic hematopoietic stem cell transplantation (alloHSCT) from matched related donors (MRDs), and those treated by alloHSCT from alternative donors (ADs). Univariate and multivariate analyses of factors associated with survival were performed. Multivariate analysis showed that age at alloHSCT of ≤ 31 years, MRD, successful engraftment, absence of acute graft-versus-host disease (aGVHD), and platelet engraftment at ≤ 21 days, were independent predictors of longer survival. In addition, time to aGVHD and cumulative nonrelapse mortality (NRM) were better in MRD than in AD recipients. Using propensity score matching (PSM), we performed a case-control study comparing 25 patients in each group who underwent alloHSCT from MRDs and ADs. Pretransplantation clinical factors were well balanced in either group. Median survival time was similar, and no statistically significant difference in transplantation outcomes was apparent when MRD and AD recipients were compared. In conclusion, our results suggest that alloHSCT from an AD should be considered earlier in adult patients with AA who do not have an MRD.	f	\N
21224840	Despite little supporting data, thiopurine use is common in pediatric ulcerative colitis (UC). Our aim was to determine outcome following thiopurine use in a multicenter inception cohort of children diagnosed with UC. Data were obtained from a prospective observational study of newly diagnosed children <16 years of age. Data are recorded at diagnosis, 30 days, and quarterly. Patients are managed by physician dictates not protocol. Disease activity is classified by physician global assessment. The primary outcome was corticosteroid (CS)-free inactive UC at 1 year following thiopurine initiation without the need for rescue therapy (infliximab, calcineurin inhibitors, or colectomy). Of 1,490 patients in our registry, 394 have UC (mean age at diagnosis 11.3±3.7 years); 197 (50%) received thiopurine (49% ≤3 months from diagnosis). Also, 84% were receiving CSs and 60% 5-aminosalicylates at thiopurine start. Of the 197 patients, there was insufficient follow-up (41), previous or concomitant use of infliximab (16), or calcineurin inhibitor (7), leaving 133 patients evaluable at 1 year. Of these, 65 (49%) had CS-free inactive UC without rescue therapy. CS-free inactive disease at 1 year after initiating thiopurine was not affected by starting thiopurine ≤3 months vs. >3 months from diagnosis, gender, age, or concomitant treatment with 5-aminosalicylates. Kaplan-Meier analysis showed that the likelihood of remaining free of rescue therapy in the thiopurine-treated patients was 73% at 1 year. Approximately 50% of children with UC starting thiopurine without previous or concomitant biologic or calcineurin inhibitor therapy have CS-free inactive disease 1 year later without the need for rescue therapy.	f	\N
21240517	We investigated whether there exists a hierarchical vulnerability of subcortical structures with respect to the severity of Alzheimer's disease (AD). A total of 236 subjects (179 with AD and 57 with normal cognition) underwent 1.5-T magnetic resonance (MR) imaging. The volumes of the five subcortical structures (amygdala, thalamus, putamen, globus pallidus, and caudate nucleus) and hippocampus were analyzed using a large deformation diffeomorphic metric mapping algorithm. The volume changes were evaluated according to the Clinical Dementia Rating (CDR). Correlation between the volumes of the subcortical structures and scores of the cognitive domain-specific neuropsychological tests were evaluated. Volume loss of the amygdala occurred even in the very mild stage of AD (CDR 0.5), as did volume loss in the hippocampus. Similar reductions in volume occurred in the thalamus and putamen, however during the mild (CDR 1) and moderate (CDR 2) stages of AD, respectively. The globus pallidus and caudate nucleus remained devoid of changes until the moderate stage of AD (p < 0.01). Volume loss in those subcortical structures correlated with the neuropsychological test scores (p < 0.01). Our results suggest that there is a hierarchical vulnerability in subcortical structures according to the clinical severity of AD and that subcortical volume reductions correlate with cognitive impairment.	f	\N
21242863	A retrospective clinical and radiographic study was performed. The purpose of this study was to compare outcomes of patients with degenerative spondylolisthesis and a preexisting degenerative L5-S1 disc treated with a lumbar floating fusion (LFF) versus lumbosacral fusion (LSF). Fusion for treatment of degenerative spondylolisthesis often ends at the L5 level. These patients usually had a preexisting L5-S1 disc degeneration; however, no literature mentions the role of prophylactic LSF in degenerative spondylolisthesis associated with L5-S1 disc degeneration. A total of 107 patients with a minimum 5-year follow-up who had lumbosacral or LFF with pedicle instrumentation for degenerative spondylolisthesis were included. UCLA (University of California, Los Angeles) classification was used to evaluate the radiographic results of the L5-S1 segment. The Oswestry Disability Index (ODI) and modified Brodsky's criteria were used to evaluate patients' clinical results. The incidence of adjacent segment disease (ASD) (includes radiographic and clinical ASD) of both ends was recorded. There were no statistically significant differences in sex, age distribution, or amount of follow-up between the LFF and LSF groups. The LSF group had a higher percentage of patients that underwent total L5 laminectomy with loss of L5-S1 posterior ligament integrity (LSF = 92% vs. LFF = 67%, P = 0.019). The higher incidence of cephalic ASD in the LSF group was statistically significant (LSF = 25% vs. LFF = 9.7%, P = 0.049). Although no patient in the LSF group developed L5-S1 ASD, need for L5-S1 segment revision surgery was not prevented with LSF. Clinical outcomes on the basis of the success rate (LFF = 85.5% vs.LSF = 70.8%, P = 0.103) and ODI difference (LFF = 28.97 ± 15.82 vs. LSF = 23.04 ± 10.97, P = 0.109), there were no statistically significant difference between these two groups. Posterior instrumentation with posterolateral LFF for the treatment of degenerative spondylolisthesis with concomitant L5-S1 disc degeneration results in a high percentage of satisfactory clinical results. Extended fusion to the sacrum did not provide a better clinical result. LSF could not reduce the incidence of revision surgery at the L5-S1 segment and involved greater incidence of cephalic ASD.	f	\N
21246519	Concurrent inhibition of epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) is an active and well tolerated regimen in recurrent head and neck cancer (HNC). In the current phase 1 trial, the authors sought to determine the maximum tolerated dose (MTD) and efficacy of concurrent erlotinib and celecoxib as a radiosensitizing regimen. Fourteen patients with previously irradiated HNC with no distant metastases who required reirradiation were eligible. Treatment consisted of daily erlotinib 150 mg and twice daily celecoxib (escalated from 200 mg to 600 mg using a 3 + 3 design with an expanded cohort at the MTD) starting on Day 1 and was continued during radiation. Daily radiation was started on Day 15, and maintenance erlotinib was recommended. The recommended phase 2 dose of celecoxib was 400 mg. Three dose-limiting toxicities included late in-field orocutaneous fistula (Dose Level 2), osteonecrosis (Dose Level 3), and trismus (Dose Level 3). Acute grade ≥ 3 toxicities were uncommon and included mucositis (21%) and dermatitis (14%). At a median follow-up of 11 months, the 1-year locoregional control, progression-free survival, and overall survival rates were 60%, 37%, and 55%, respectively. Concurrent erlotinib, celecoxib, and reirradiation was a feasible and clinically active regimen in a population of patients with recurrent HNC who had a poor prognosis.	f	\N
21251542	In recent years, a common strategy for the prevention of postsurgical intra-abdominal adhesions has been intrasurgical placement of adhesion barriers into the peritoneal cavity. Osmotic agents, such as various polysaccharides, frequently are used as antiadhesive materials. The effects of these materials on kidney function have not yet been studied. We report a case of an individual with pre-existing chronic kidney disease who developed acute kidney injury after surgical placement of an antiadhesive barrier of macromolecular polysaccharides. A kidney biopsy, performed because of persistent kidney failure, showed tubular cell lesions compatible with osmotic nephrosis lesions. This case suggests that use of polysaccharide-containing antiadhesive barriers can induce severe kidney damage. Such barriers should be used with caution in patients with abnormal kidney function to prevent irreversible damage.	f	\N
21262922	A 2005 report from the Centers for Medicare and Medicaid Services and the Centers for Disease Control Surgical Infection Prevention program indicated that only 41% of prophylactic antibacterials were correctly stopped within 24 h of the end of surgery. Electronic order sets have shown promise as a means of integrating guideline information with electronic order entry systems and facilitating safer, more effective care. The aim was to study the effectiveness of a computer-based antibacterial order set on increasing the proportion of patients who have antibacterial wound prophylaxis discontinued in the appropriate time frame. The authors conducted a quasi-experimental interrupted time-series analysis over an 8-month study period with the implementation of a computer-based order system designed to prevent excessive duration of surgical prophylaxis antibacterials. The primary outcome was the proportion of surgeries with antibacterials discontinued in the appropriate time frame. Additionally, we evaluated the percent of surgeries after implementation of the electronic intervention with chart documentation of infection among surgeries where the prescriber indicated the reason for antibacterial therapy was treatment. The computer-based order intervention significantly improved the proportion of surgeries with timely discontinuation of antibacterials from 38.8% to 55.7% (p < 0.001) in the intervention hospital, while the control hospital remained at 56-57% (p = 0.006 for the difference between treated and control hospitals). In surgeries after intervention implementation where a prescriber indicated the reason for antibacterial therapy was treatment, the prevalence of chart documented infection was only 14%. A computer-based electronic order set intervention increased timely discontinuation of postoperative antibacterials.	f	\N
21278729	Optogenetics is a technique for controlling subpopulations of neurons in the intact brain using light. This technique has the potential to enhance basic systems neuroscience research and to inform the mechanisms and treatment of brain injury and disease. Before launching large-scale primate studies, the method needs to be further characterized and adapted for use in the primate brain. We assessed the safety and efficiency of two viral vector systems (lentivirus and adeno-associated virus), two human promoters (human synapsin (hSyn) and human thymocyte-1 (hThy-1)) and three excitatory and inhibitory mammalian codon-optimized opsins (channelrhodopsin-2, enhanced Natronomonas pharaonis halorhodopsin and the step-function opsin), which we characterized electrophysiologically, histologically and behaviorally in rhesus monkeys (Macaca mulatta). We also introduced a new device for measuring in vivo fluorescence over time, allowing minimally invasive assessment of construct expression in the intact brain. We present a set of optogenetic tools designed for optogenetic experiments in the non-human primate brain.	f	\N
21291294	We have assessed gastroduodenal, endoscopical and histopathological findings in a series of patients with microscopic colitis (MC). We studied 75 patients with MC, 27 with collagenous colitis (CC) and 48 with lymphocytic colitis (LC), and 60 controls. Data of endoscopical findings were collected and biopsies were assessed. Helicobacter pylori infection rate was 15% in MC and 28% in the controls (p = 0.088). Age at diagnosis of MC was higher in H. pylori positive than negative patients (63.4 ± 9.6 vs. 54.4 ± 13.1 years; p = 0.034). Gastric endoscopic erosions were more prevalent in CC than in LC (25.9% vs. 6.2%; p = 0.030) and associated with thick body glands and antral predominance of gastritis in H. pylori positive patients. Rates of focal gastritis (5.6% vs. 6.9%) and lymphocytic gastritis (5.6% vs. 10%) were similar in MC and controls. LC was associated with gastric epithelial lymphocytosis and lymphocytic gastritis. Fifteen patients (20%) had celiac disease. Unlike LC, CC is associated with endoscopic erosions, likely related with the high acid secretion capacity as indicated by the ample body glands and antral predominance of gastritis in H. pylori associated cases of CC. The presence of some divergent gastroduodenal features in LC and CC, and in comparison with those reported in inflammatory bowel disease (IBD), supports the concept that these two conditions differ not only from IBD but also from each other. The findings also suggest the presence of pathogenetic links between colorectal and gastroduodenal abnormalities.	f	\N
21297177	Moderate chronic kidney disease (CKD) (defined by an estimated glomerular filtration rate of 30-60 ml/min) is associated with mild hypertriglyceridemia related to delayed catabolism of triglyceride-rich lipoprotein particles. Altered apolipoprotein C-III (apoC-III) metabolism may contribute to dyslipidemia in CKD. To further characterize the dyslipidemia of CKD, we investigated the kinetics of plasma apoC-III in 7 nonobese, nondiabetic, non-nephrotic CKD subjects and 7 age- and sex-matched healthy controls, using deuterated leucine ([5, 5, 5, ²H₃]leucine), gas chromatography-mass spectrometry, and multicompartmental modeling. Compared with controls, CKD subjects had higher concentrations of plasma and VLDL triglycerides and plasma and VLDL apoC-III (P < 0.05). The increased plasma apoC-III concentration was associated with a decreased apoC-III fractional catabolic rate (FCR) (1.21 ± 0.15 vs. 0.74 ± 0.12 pools/day, P = 0.03). There were no differences between apoC-III production rates of controls and those of CKD subjects. In CKD subjects, plasma apoC-III concentration was significantly and negatively correlated with apoC-III FCR (r = -0.749, P = 0.05) but not with apoC-III production rate. Plasma apoC-III concentration was positively correlated with plasma and VLDL triglycerides and VLDL apoB concentrations and negatively correlated with VLDL apoB FCR (P < 0.05 for all). ApoC-III FCR was negatively correlated with plasma and VLDL triglycerides and VLDL apoB concentration and positively correlated with VLDL apoB FCR (P < 0.05 for all). Altered plasma apoC-III metabolism is a feature of dyslipidemia in moderate CKD. Modification of apoC-III catabolism may be an important therapeutic target for reducing cardiovascular disease risk in moderate CKD.	f	\N
21303529	Evidence indicates that supervised home exercises, combined or not with manual therapy, can be beneficial for patients with non-specific chronic neck pain (NCNP). The objective of the study is to investigate the efficacy of preventive spinal manipulative therapy (SMT) compared to a no treatment group in NCNP patients. Another objective is to assess the efficacy of SMT with and without a home exercise program. Ninety-eight patients underwent a short symptomatic phase of treatment before being randomly allocated to either an attention-group (n = 29), a SMT group (n = 36) or a SMT + exercise group (n = 33). The preventive phase of treatment, which lasted for 10 months, consisted of meeting with a chiropractor every two months to evaluate and discuss symptoms (attention-control group), 1 monthly SMT session (SMT group) or 1 monthly SMT session combined with a home exercise program (SMT + exercise group). The primary and secondary outcome measures were represented by scores on a 10-cm visual analog scale (VAS), active cervical ranges of motion (cROM), the neck disability index (NDI) and the Bournemouth questionnaire (BQ). Exploratory outcome measures were scored on the Fear-avoidance Behaviour Questionnaire (FABQ) and the SF-12 Questionnaire. Our results show that, in the preventive phase of the trial, all 3 groups showed primary and secondary outcomes scores similar to those obtain following the non-randomised, symptomatic phase. No group difference was observed for the primary, secondary and exploratory variables. Significant improvements in FABQ scores were noted in all groups during the preventive phase of the trial. However, no significant change in health related quality of life (HRQL) was associated with the preventive phase. This study hypothesised that participants in the combined intervention group would have less pain and disability and better function than participants from the 2 other groups during the preventive phase of the trial. This hypothesis was not supported by the study results. Lack of a treatment specific effect is discussed in relation to the placebo and patient provider interactions in manual therapies. Further research is needed to delineate the specific and non-specific effects of treatment modalities to prevent unnecessary disability and to minimise morbidity related to NCNP. Additional investigation is also required to identify the best strategies for secondary and tertiary prevention of NCNP. ClinicalTrials.gov: NCT00566930.	f	\N
21305298	Spondyloarthritis (SpA) are diseases with increased gut inflammation. To search for (anti-Saccharomyces cerevisiae) ASCA IgA, ASCA IgG, and anti-endomysial antibodies (EmA-IgA) in a cohort of 70 patients with SpA, we found 18.6% (13/70) positive for IgA-ASCA in the SpA group and 3/57 (5.2%) in the control group (P = 0.031). ASCA IgG and EmA-IgA were found at the same frequency in SpA and controls. No relationship of ASCA IgA positivity could be established with disease activity (measured by ESR, C-reactive protein, and BASDAI), presence of uveitis, or peripheral arthritis neither with functional status measured by BASFI. SpA patients present an increase in the IgA-ASCA positivity without any relationship to disease activity, functional index, clinical profile or the presence of HLA-B27. There is no evidence of higher prevalence of EmA-IgA in SpA patients in the studied sample.	f	\N
21307778	Vitamin D deficiency is a global health problem that has various adverse consequences. Vitamin D is mainly synthesized in the skin by sunlight (UV light) irradiation; therefore, vitamin D status is influenced by geographic locations, seasonal changes, and skin pigmentations. The kidney is involved in the biosynthesis of 1,25-dihydroxyvitamin D and the reuptake of filtered 25-hydroxyvitamin D from the proximal tubules, thus, vitamin D deficiency is highly prevalent in patients with kidney disease who have renal insufficiency. There is a growing body of epidemiological and clinical evidence in the literature that links vitamin D deficiency to cardiovascular disease. The discovery of the vitamin D hormone functioning as an endocrine inhibitor of the renin-angiotensin system provides an explanation for this association. This review will discuss the mechanism underlying the connection between vitamin D and cardiovascular disease and its physiological and therapeutic implications.	f	\N
21312278	Abnormal repetitive behaviors have been reported in Parkinson's disease (PD) during dopamine replacement therapy (DRT) and associated with individual predisposing features, including impulsivity. However, impulsivity and compulsive symptoms have never been explored in PD patients before initiation of DRT. We previously reported a 20% of impulse control disorders (ICD) in an Italian cohort. 103 consecutive newly diagnosed drug-naïve PD patients (means: age = 60.5 ± 9.2 years; duration = 15.4 ± 15.3 months) were screened for compulsive sexual behavior, compulsive buying, intermittent explosive disorder (Minnesota Impulsive Disorders Interview, MIDI), and pathological gambling (South Oaks Gambling Screen, SOGS). Barratt Impulsiveness Scale (BIS-11) and Maudsley Obsessional-Compulsive Questionnaire (MOCQ/R) assessed impulsivity, obsessive-compulsive symptoms, respectively. Depression (GDS-15) and general cognitive status were additionally assessed. We also compared ICDs frequency with our healthy controls. 17.5% of PD patients screened positive for at least one ICD at MIDI (17/103) and SOGS (1/103), though none had a disorder based on DSM-IV criteria. These frequencies were similar to healthy controls. There was a trend toward higher scores in BIS-11 attentive-impulsivity subscale (15.2 ± 4.8 vs. 18.7 ± 4.9; P = 0.007) and in MOCQ/R-Doubting subscale (0.67 ± 1.1 vs. 1.5 ± 1.2; P = 0.007) in PD with ICD. We also observed a positive correlation between GDS-15 and BIS-11. Similar to our healthy control population, we found a significant proportion of early PD patients positive for ICDs before starting treatment. We also found a relationship between impulsivity and depression. A detailed behavioral assessment before starting dopaminergic therapy is recommended.	f	\N
21316322	The role of oxidative stress in patients with chronic kidney disease (CKD) as a potential marker of morbidity and mortality remains poorly evaluated. The aim of the present study aims was thus: to determine plasma levels of malondialdehyde (MDA), end product of lipid peroxidation in patients at different CKD stages (predialysis and dialysis); to evaluate the association between plasma MDA levels and vascular disease or overall and cardiovascular mortality. Plasma MDA levels evaluated by HPLC, pulse wave velocity, aortic calcification score were evaluated in 94 CKD patients (67±13 years, 54% males, 29% at CKD stages 2-3, 32% at stages 4-5, 39% at stage 5D) prospectively followed for mortality. We observed that the plasma MDA levels were increased in patient with CKD and augmented progressively with CKD stages. However, we did not find any independent association between plasma levels of MDA and pulse wave velocity, aortic calcification score, or overall and cardiovascular mortality. Our results suggest that plasma MDA is not a useful biomarker in CKD patients.	f	\N
21317510	Many studies document racial variation, gender differences, and socioeconomic status (SES) patterning in cardiovascular disease (CVD) risk factors but few studies have investigated heterogeneity in SES differences by race/ethnicity or gender. Using data from the Multi-Ethnic Study of Atherosclerosis (N=6,814) and stratified regression models, we investigated race/ethnic differences in the SES patterning of diabetes, hypertension, smoking, and body mass index (BMI). Inverse socioeconomic gradients in hypertension, diabetes, smoking, and BMI were observed in White and Black women but associations were weaker or absent in Hispanic and Chinese women (except in the case of diabetes for Hispanic women). Even greater heterogeneity in social patterning of risk factors was observed in men. In White men all four risk factors were inversely associated with socioeconomic position, although often associations were only present or were stronger for education than for income. The inverse socioeconomic patterning was much less consistent in men of other races/ethnic groups, and higher SES was associated with higher BMI in non-White men. These findings have implications for understanding the causes of social patterning, for the analysis of SES adjusted race/ethnic differences, and for the targeting of interventions.	f	\N
21327566	A synergistic effect of alcohol and hypertension has been suggested to increase the risk for stroke. However, the contribution of alcohol-induced hypertension to stroke morbidity and mortality may be greater than observed, because the effects of different drinking patterns have not been separately investigated. Alcohol-induced transient peaks in systolic blood pressure may predispose to stroke. Recent studies have measured time trends of blood pressure elevations in relation to alcohol consumption. They found a significant morning surge in blood pressure, which was related to alcohol intake in a dose-dependent manner and was independent of smoking. Men with a severe form of hypertension showed a 12-fold increased risk for cardiovascular disease mortality associated with heavy binge drinking. Binge drinking is a significant risk factor for stroke. Hypertensive patients should be warned about the risks of alcohol and urged to avoid binge drinking because of an increased risk for all subtypes of stroke.	f	\N
21329838	We sought to study whether patients with right ventricular failure (RVF) secondary to chronic thromboembolic pulmonary hypertension (CTEPH) have reduced left ventricular (LV) mass, and whether LV mass reduction is caused by atrophy. The LV in patients with CTEPH is underfilled (unloaded). LV unloading may cause atrophic remodeling that is associated with diastolic and systolic dysfunction. We studied LV mass using cardiac magnetic resonance imaging (MRI) in 36 consecutive CTEPH patients (before/after pulmonary endarterectomy [PEA]) and 11 healthy volunteers selected to match age and sex of patients. We studied whether LV atrophy is present in monocrotaline (MCT)-injected rats with RVF or controls by measuring myocyte dimensions and performing in situ hybridization. At baseline, CTEPH patients with RVF had significantly lower LV free wall mass indexes than patients without RVF (35 ± 6 g/m(2) vs. 44 ± 7 g/m(2), p = 0.007) or volunteers (42 ± 6 g/m(2), p = 0.006). After PEA, LV free wall mass index increased (from 38 ± 6 g/m(2) to 44 ± 9 g/m(2), p = 0.001), as right ventricular (RV) ejection fraction improved (from 31 ± 8% to 56 ± 12%, p < 0.001). Compared with controls, rats with RVF had reduced LV free wall mass and smaller LV free wall myocytes. Expression of atrial natriuretic peptide was higher, whereas that of α-myosin heavy chain and sarcoplasmic reticulum calcium ATPase-2 were lower in RVF than in controls, both in RV and LV. RVF in patients with CTEPH is associated with reversible reduction in LV free wall mass. In a rat model of RVF, myocyte shrinkage due to atrophic remodeling contributed to reduction in LV free wall mass.	f	\N
21332905	• To describe a multicentre experience with preoperative platinum-based chemotherapy before radical nephroureterectomy (RNU) in patients with upper tract urothelial carcinoma (UTUC) with loco-regional nodal metastases. • We identified 313 patients from the UTUC Collaboration (over 1200 patients), who underwent RNU with concomitant retroperitoneal lymph node dissection between 1990 and 2007 and met the inclusion criteria for one of three groups. • Group 1 comprised patients who received chemotherapy before RNU because of biopsy-proven loco-regional nodal metastases. • Group 2 consisted of patients who underwent primary RNU and were found to have metastatic nodal disease on final pathological review (node-positive). • Group 3 comprised a comparative cohort of patients treated with primary RNU for invasive or locally advanced (pT2/pT4) node-negative (N0) UTUC. • Groups 1, 2 and 3 included 18, 120 and 175 patients, respectively. The 5-year disease-free survival rates were 49%, 30% and 64%, whereas the 5-year cancer-specific survival rates were 44%, 36% and 69% in groups 1, 2 and 3, respectively. • In group 1, on final pathological evaluation, nine patients were pN0, six patients were pT0 and five patients had pT0N0 disease. Kaplan-Meier survival analyses showed similar recurrence and survival rates in group 1 compared with group 3 (P= 0.14 and P= 0.06, respectively). • Meanwhile, group 2 had significantly lower disease-free and cancer-specific survival rates compared with group 3 (P < 0.001 and P < 0.001, respectively) and compared with group 1 (P= 0.04 and P= 0.06, respectively). • Preoperative chemotherapy followed by aggressive surgical consolidation may yield favourable oncological outcomes in patients with UTUC with loco-regional nodal metastases. • These data support further evaluation of neoadjuvant systemic therapy in patients at risk for locally advanced UTUC.	f	\N
21342667	In Belgium, the 7-valent pneumococcal conjugate vaccine (PCV7) was introduced into the national schedule in 2007. The early impact of PCV7 vaccination on paediatric invasive disease was estimated by comparing pre- and post-vaccination incidence from national surveillance. In children <2 year-olds, vaccine-serotype incidence declined by 96% but non-vaccine-types increased 2-3-fold. Overall invasive disease decreased by 23-46%, depending on adjustment for under-reporting and pre-vaccine trends. Non-vaccine-types 1 and 19A had increased before PCV7 use, suggesting the contribution of other factors. Estimation of PCV7 impact comparing pre- and post-vaccination data should adjust for pre-vaccine trends, and serotype dynamics need further exploration.	f	\N
21349334	The intestinal microbiota is an ecosystem formed by a variety of ecological niches, made of several bacterial species and a very large amount of strains. The microbiota is in close contact with the intestinal mucosa or epithelial interface which is, after the respiratory area, the largest surface of the body, occupying approximately 250-400 m(2). The physiological activities of the microbiota are manifold and are just being unraveled. Based on the observations of the multiple roles played by the microbiota in health and disease, the notion of modifying it with appropriate formulations, i.e. probiotics, is being tested in several settings. This review summarizes the current knowledge on probiotics and discusses both limitations and acquired evidence to support their use in preventive and therapeutic medicine.	f	\N
21350933	This study used data mining techniques to investigate disease forms in various administrative areas and to analyze the differences among various administrative areas in order to further draw up a disease distribution map. It is hoped that may help formulate future public health strategies and to allocate medical resources more appropriately. The major disease forms for residents under the age of 60 were hypertension, hyperglycemia and hyperlipidemia. In regard to the neighboring areas, three neighboring areas, A1, A3, and B9, shared the same disease problems with A4, A5, and B3, while two mountain-area cities, B7 and C10, experienced higher instances of liver function impairment. In terms of the clustering phenomenon among municipally graded administrative areas, the major health problems in Grade A cities were hypertension, hyperglycemia, and hyperlipidemia. The health problems such as liver function impairment and renal dysfunction were more frequently observed in Grade B and Grade C cities.	f	\N
21352090	Autologous chondrocyte implantation (ACI) is considered a promising choice for the treatment of cartilage defects. However, the application of ACI to osteoarthritic patients is, in general, contraindicated. The purpose of this study is to evaluate the efficiency of three-dimensionally structured ACI (3D-ACI; CaReS) in a rat model of knee osteoarthritis (OA). OA-like degenerative changes in the articular cartilage were created by transecting the anterior cruciate ligament (ACLT) in athymic nude rats. Two weeks later, CaReS was transplanted at the cartilage injury sites created by micro-drilling in the patella groove (Chondrocyte-implanted (CI) group: CaReS collagen with human chondrocytes; Collagen group: CaReS collagen without cells; and Sham group: sham operation; n = 15/group). Reverse Transcription Polymerase Chain Reaction (RT-PCR) analysis demonstrated the expression of human-specific type 2 collagen and Sry-type high-mobility-group box 9 (SOX9) in the CI group-not in the other groups-throughout the study period. Double immunohistochemistry for human-specific type 2 collagen and human leukocyte antigen-abacavir (HLA-ABC) at week 4 showed positive staining in the CI group only. Macroscopic assessment showed better repair at the cartilage defect sites in the CI group, compared to the other groups. Histological assessment with toluidine blue staining showed that the thickness of the articular cartilage and semi-quantitative histological scores were higher in the CI group than in the other groups up to week 20. We demonstrate, for the first time, that 3D-ACI is effective in repairing cartilage defects in a rat model of ACLT-induced OA.	f	\N
21354253	Molecular rotors are a form of fluorescent intramolecular charge-transfer complexes that can undergo intramolecular twisting motion upon photoexcitation. Twisted-state formation leads to non-radiative relaxation that competes with fluorescence emission. In bulk solutions, these molecules exhibit a viscosity-dependent quantum yield. On the molecular scale, the fluorescence emission is a function of the local free volume, which in turn is related to the local micro-viscosity. Membrane viscosity, and the inverse; fluidity, are characteristic terms used to describe the ease of movement withing the membrane. Often, changes in membrane viscosity govern intracellular processes and are indicative of a disease state. Molecular rotors have been used to investigate viscosity changes in liposomes and cells, but accuracy is affected by local concentration gradients and sample optical properties. We have developed self-calibrating ratiometric molecular rotors to overcome this challenge and integrated the new molecules into a DLPC liposome model exposed to the membrane-fluidizing agent propanol. We show that the ratiometric emission intensity linearly decreases with the propanol exposure and that the ratiometric intensity is widely independent of the total liposome concentration. Conversely, dye concentration inside liposomes influences the sensitivity of the system. We suggest that the new self-calibrating dyes can be used for real-time viscosity sensing in liposome systems with the advantages of lifetime measurements, but with low-cost steady-state instrumentation.	f	\N
21357888	This review is the summary of a workshop on the role of distal airways in chronic obstructive pulmonary disease (COPD), which took place in 2009 in Vence, France. The evidence showing inflammation and remodelling in distal airways and the possible involvement of these in the pathobiology, physiology, clinical manifestations and natural history of COPD were examined. The usefulness and limitations of physiological tests and imaging techniques for assessing distal airways abnormalities were evaluated. Ex vivo studies in isolated lungs and invasive measurements of airway resistance in living individuals have revealed that distal airways represent the main site of airflow limitation in COPD. Structural changes in small conducting airways, including increased wall thickness and obstruction by muco-inflammatory exudates, and emphysema (resulting in premature airway closure), were important determinants of airflow limitation. Infiltration of small conducting airways by phagocytes (macrophages and neutrophils), dendritic cells and T and B lymphocytes increased with airflow limitation. Distal airways abnormalities were associated with patient-related outcomes (e.g. dyspnoea and reduced health-related quality of life) and with the natural history of the disease, as reflected by lung function decline and mortality. These data provide a clear rationale for targeting distal airways in COPD.	f	\N
21360500	In addition to inducing a self-limited myopathy, statin use is associated with an immune-mediated necrotizing myopathy (IMNM), with autoantibodies that recognize ∼200-kd and ∼100-kd autoantigens. The purpose of this study was to identify these molecules to help clarify the disease mechanism and facilitate diagnosis. The effect of statin treatment on autoantigen expression was addressed by immunoprecipitation using sera from patients. The identity of the ∼100-kd autoantigen was confirmed by immunoprecipitation of in vitro-translated 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) protein. HMGCR expression in muscle was analyzed by immunofluorescence. A cohort of myopathy patients was screened for anti-HMGCR autoantibodies by enzyme-linked immunosorbent assay and genotyped for the rs4149056 C allele, a predictor of self-limited statin myopathy. Statin exposure induced expression of the ∼200-kd/∼100-kd autoantigens in cultured cells. HMGCR was identified as the ∼100-kd autoantigen. Competition experiments demonstrated no distinct autoantibodies recognizing the ∼200-kd protein. In muscle biopsy tissues from anti-HMGCR-positive patients, HMGCR expression was up-regulated in cells expressing neural cell adhesion molecule, a marker of muscle regeneration. Anti-HMGCR autoantibodies were found in 45 of 750 patients presenting to the Johns Hopkins Myositis Center (6%). Among patients ages 50 years and older, 92.3% had taken statins. The prevalence of the rs4149056 C allele was not increased in patients with anti-HMGCR. Statins up-regulate the expression of HMGCR, the major target of autoantibodies in statin-associated IMNM. Regenerating muscle cells express high levels of HMGCR, which may sustain the immune response even after statins are discontinued. These studies demonstrate a mechanistic link between an environmental trigger and the development of sustained autoimmunity. Detection of anti-HMGCR autoantibodies may facilitate diagnosis and direct therapy.	f	\N
21362127	Type 3 von Willebrand disease (VWD) is an autosomal recessive bleeding disorder, characterized by virtually undetectable plasma von Willebrand factor (VWF) and consequently reduced plasma factor VIII levels. Genetic mutations responsible for type 3 VWD are very heterogeneous, scattered throughout the VWF gene and show high variability among different populations. Twenty-five severe VWD patients were studied by direct sequencing of the 51 coding exons of the VWF gene. The total number of VWD type 3 families in Hungary is 24, of which 23 were investigated. Fifteen novel mutations were identified in 31 alleles, five being nonsense mutations (p.Q1238X, p.Q1898X, p.Q1931X, p.S2505X and p.S2568X), four small deletions and insertions resulting in frame shifts (c.1992insC, c.3622delT, c.5315insGA and c.7333delG), one a large partial deletion (delExon1-3) of the 5'-region, four candidate missense mutations (p.C35R, p.R81G, p.C295S, p.C623T) and one a candidate splice site mutation (c.1730-10C>A). Six previously described mutations were detected in 17 alleles, including the repeatedly found c.2435delC, p.R1659X and p.R1853X. Only one patient developed alloantibodies to VWF, carrying a homozygous c.3622delT. We report the genetic background of the entire Hungarian type 3 VWD population. A large novel deletion, most probably due to a founder effect, seems to be unique to Hungarian type 3 VWD patients with high allele frequency. In contrast to previous reports, none of the five patients homozygous for the large partial deletion developed inhibitors to VWF. This discrepancy raises the possibility of selection bias in some of the reports.	f	\N
21363991	Hemorrhagic fever with renal syndrome (HFRS) is an important public health problem in Shandong Province, China. In this study, we combined ecologic niche modeling with geographic information systems (GIS) and remote sensing techniques to identify the risk factors and affected areas of hantavirus infections in rodent hosts. Land cover and elevation were found to be closely associated with the presence of hantavirus-infected rodent hosts. The averaged area under the receiver operating characteristic curve was 0.864, implying good performance. The predicted risk maps based on the model were validated both by the hantavirus-infected rodents' distribution and HFRS human case localities with a good fit. These findings have the applications for targeting control and prevention efforts.	f	\N
21397153	Epidermolysis bullosa acquisita (EBA) is the rarest of the autoimmune bullous diseases (AIBD). It is defined as an AIBD secondary to production of antibodies directed against type VII collagen and then binding to anchoring fibrils in the basal membrane zone (BMZ) of the skin and the Malpighian mucosa. To evaluate risk factors, different clinical forms and diagnostic methods, and the efficacy of treatments. The articles were identified by a search of PubMed and Embase from the initial creation of these databases through to March 2009. We selected generalised reviews and meta-analyses, cases involving unusual and/or serious clinical presentations, studies of immunological tests and homogeneous retrospective series regarding therapy. Of the 206 articles analysed, only two were of an adequate level of proof, with four of intermediate level, and all the others of only low level. EBA affects all age groups (from newborn infants to the very elderly) with a slight predominance in female subjects. Diagnosis must be considered in subjects with black skin of African origin. A drug-induced origin of the disease was reported in 11% of cases of IgA-EBA. Classical EBA (30 to 50% of cases), resembles epidermolysis bullosa hereditaria (EBH), with fragile skin, non-inflammatory bullae, dystrophic scars and milia. Numerous atypical and misleading forms exist. Evocative signs are the presence of mucosal lesions and/or scars. The severity of EBA is determined by the extent of cutaneous lesions, and ophthalmological, ENT and/or oesophageal involvement. Crohn's disease is associated in 25% of cases of EBA. Unequivocal diagnosis is provided by direct immunoelectron microscopy (IEM). Therapeutic efficacy has been reported for dapsone, sulphapyridine and colchicine in milder forms, and for cyclosporine, mycophenolate mofetil, rituximab, intravenous immunoglobulins and extracorporeal photochemotherapy in resistant and severe forms. A number of authors have reported inefficacy of systemic corticosteroids, even in high-dose regimens, with the development of corticosteroid dependence in certain cases. In the absence of any therapeutic trials, it is difficult to select optimal treatment; however, the benefit/risk ratio of systemic corticosteroid treatment is unfavourable.	f	\N
21397734	In this paper we introduce a new technical development of branching processes that can potentially model spread of epidemics by including various stages of infection. In fact, we present an epidemic model that the disease spreads from an individual to another one in such a way that the ability of individual u to infect a susceptible individual depends only on how long u has been infected. For analysis of this model, we introduce a new and special model of the Crump-Mode-Jagers branching processes in discrete time and obtain some of its fundamental properties.	f	\N
21404106	To confirm the efficacy and toxicity of Erlotinib in combination with Gemcitabine and Capecitabine when used as a first-line therapy in metastatic/recurrent pancreatic cancer (PC). Locally advanced PC was excluded. Erlotinib was given at a dose of 100 mg daily from D1 to D28. 1000 mg/m(2) of gemcitabine was given on D1,8,15 and 1660 mg/m(2)/day of capecitabine was given from D1 to 21, repeated every 4 weeks. Response was assessed every 8 weeks. A total of 47 patients were enrolled. Response rate and disease control rate was 32.6% (95% CI, 18.6-46.6%) and 83.7% (95% CI, 72.7-94.7%) respectively. The PFS was 6.5 months (95% CI, 3.4-9.7) and OS was 12.0 months (95% CI, 8.6-15.9). The Gr 3/4 toxicities were: neutropenia (6.8%), thrombocytopenia (3.2%), anemia (1.6%). nausea (1.6%), vomiting (1.6%), anorexia (5.3%), rash (2.4%). The EGFR expression was associated with shorter OS and ERCC2 expression was associated with longer PFS and OS. PFS and OS were not different according to K-RAS mutation or polymorphism of RRM1 and CDA. Erlotinib, gemcitabine and capecitabine combination showed promising efficacy and good tolerability in metastatic PC. This efficacy was observed irrespective of K-RAS mutation, and EGFR expression was poor prognostic factor for OS.	f	\N
21415164	Activation of lipid metabolism is an early event in carcinogenesis and a central hallmark of many cancers. However, the precise molecular composition of lipids in tumors remains generally poorly characterized. The aim of the present study was to analyze the global lipid profiles of breast cancer, integrate the results to protein expression, and validate the findings by functional experiments. Comprehensive lipidomics was conducted in 267 human breast tissues using ultraperformance liquid chromatography/ mass spectrometry. The products of de novo fatty acid synthesis incorporated into membrane phospholipids, such as palmitate-containing phosphatidylcholines, were increased in tumors as compared with normal breast tissues. These lipids were associated with cancer progression and patient survival, as their concentration was highest in estrogen receptor-negative and grade 3 tumors. In silico transcriptomics database was utilized in investigating the expression of lipid metabolism related genes in breast cancer, and on the basis of these results, the expression of specific proteins was studied by immunohistochemistry. Immunohistochemical analyses showed that several genes regulating lipid metabolism were highly expressed in clinical breast cancer samples and supported also the lipidomics results. Gene silencing experiments with seven genes [ACACA (acetyl-CoA carboxylase α), ELOVL1 (elongation of very long chain fatty acid-like 1), FASN (fatty acid synthase), INSIG1 (insulin-induced gene 1), SCAP (sterol regulatory element-binding protein cleavage-activating protein), SCD (stearoyl-CoA desaturase), and THRSP (thyroid hormone-responsive protein)] indicated that silencing of multiple lipid metabolism-regulating genes reduced the lipidomic profiles and viability of the breast cancer cells. Taken together, our results imply that phospholipids may have diagnostic potential as well as that modulation of their metabolism may provide therapeutic opportunities in breast cancer treatment.	f	\N
21418090	To investigate associations between fasting plasma glucose level and the prevalence of acquired colour vision impairment in type 2 diabetes patients without diabetic retinopathy. Participants in this cross-sectional study of male officials aged 20-60 yr in the Japanese Self Defence Force, underwent colour vision testing, ophthalmic examination, a standardized interview and examination of venous blood samples. Ishihara plates, a Lanthony 15-hue desaturated panel and Standard Pseudoisochromatic Plates Part 2 were used to examine colour vision. The Farnsworth-Munsell 100-hue test was performed to define acquired colour vision impairment. Cardiovascular disease risk factors were determined from serum blood samples, physical records and an interview. We performed logistic regression analysis adjusted for age, diagnosed hypertension, dyslipidaemia, cataract, glaucoma, being overweight, smoking status and alcohol intake. Crude and adjusted odds ratios were calculated for three glucose levels, which included normal fasting glucose, impaired fasting glucose and diabetes. Out of a total of 1042 men enrolled, 872 were eligible for the study, and 31 were diagnosed with acquired colour vision impairment. As compared with the subjects with normal fasting glucose (< 5.6 mmol/l), the crude odds ratio for acquired colour vision impairment was 0.93 (95% CI 0.32-2.74) for the subjects with impaired fasting glucose (5.6-6.9 mmol/l) and 8.07 (95% CI 2.48-26.22) for the patients with type 2 diabetes. The multiple-adjusted odds ratios were 0.77 (95% CI 0.25-2.34) for the subjects with impaired fasting glucose and 5.89 (95% CI 1.55-22.40) for the patients with type 2 diabetes. Our findings suggest that there is a dramatically increased prevalence of acquired colour vision impairment in type 2 diabetes patients without diabetic retinopathy which might be attributable to another pathogenesis associated with diabetic retinopathy.	f	\N
21421095	Appendectomy remains one of the most common emergency surgical procedures encountered throughout the United States. With improvements in diagnostic techniques, the efficiency of diagnosis has increased over the years. However, the entity of negative appendectomies still poses a dilemma because these are associated with unnecessary risks and costs to both patients and institutions. This study was conducted to show current statistics and trends in negative appendectomy rates in the United States. A retrospective analysis was conducted using data from the National Inpatient Sample from 1998 to 2007. Adult patients (>18 y) having undergone appendectomies were identified by the appropriate International Classification of Diseases 9th revision codes. Patients with incidental appendectomy and those with appendiceal pathologies, also identified by relevant International Classification of Diseases 9th revision codes, were excluded. The remaining patients represent those who underwent an appendectomy without appendiceal disease. The patients then were stratified according to sex, women were classified further into younger (18-45 y) and older (>45 y) based on child-bearing age. The primary diagnoses subsequently were categorized by sex to identify the most common conditions mistaken for appendiceal disease in the 2 groups. Between 1998 and 2007, there were 475,651 cases of appendectomy that were isolated. Of these, 56,252 were negative appendectomies (11.83%). There was a consistent decrease in the negative appendectomy rates from 14.7% in 1998 to 8.47% in 2007. Women accounted for 71.6% of cases of negative appendectomy, and men accounted for 28.4%. The mortality rate was 1.07%, men were associated with a higher rate of mortality (1.93% vs .74%; P < .001). Ovarian cyst was the most common diagnosis mistaken for appendicitis in younger women, whereas malignant disease of the ovary was the most common condition mistaken for appendiceal disease in women ages 45 and older. The most common misdiagnosis in men was diverticulitis of the colon. There has been a consistent decline in the rates of negative appendectomy. This trend may be attributed to better diagnostics. Gynecologic conditions involving the ovary are the most common to be misdiagnosed as appendiceal disease in women.	f	\N
21422948	This study was designed to characterize the energy metabolism in the patients with acute-on-chronic liver failure (ACLF). Protein-energy malnutrition usually occurs in the patients with chronic liver disease and is exacerbated during the progression of liver failure. Unfortunately, there is limited study to fully elucidate the energy metabolism in the patients with ACLF. A retrospective cohort was designed with a total of 282 patients (100 patients with ACLF, 100 with liver cirrhosis, and 82 with chronic hepatitis B). Resting energy expenditure and the oxidation rates of glucose, lipid, and protein were assessed by indirect heat measurement using the critical care monitor and desktop analysis system, nutritive metabolic investigation system. Survival rate was estimated with the Kaplan-Meier method. There was no significant difference in resting energy expenditure among the patients with ACLF, the liver cirrhosis, and the chronic hepatitis (1402.05±480.07 kcal/d in patients with ACLF, 1274.27±316.36 kcal/d in patients with liver cirrhosis, and 1396.77±384.80 kcal/d in patients with chronic hepatitis). Respiratory quotient (RQ) was significantly lower in the patients with ACLF than those in the liver cirrhosis and the chronic hepatitis B (P=0.000). In patients with ACLF, RQ of the nonsurvival group was significantly lower than the survival group (P=0.000). It is identified from receiver operating characteristic curve analysis that a RQ cutoff value of 0.83 (area under the receiver operating characteristic curve, 0.760) is favorable to predict good prognosis in patients with liver failure, which has a sensitivity of 73.68%, a specificity of 74.42%, and positive predictive value of 79.2% and negative predictive value of 68.1%. In patients with ACLF, RQ was significantly lower in the nonsurvival group than the survival group, thus suggesting that RQ may be used as an indicator of prognosis of liver failure.	f	\N
21426326	To investigate for the first time the natural history and long-term evolution of "familial cortical tremor, myoclonus, and epilepsy." We evaluated the clinical, electrophysiologic, and treatment data of 14 patients from three families linked to 2p11.1-q12.2. A simplified scale was used to score myoclonus severity. Electroencephalography (EEG) studies were reviewed for the evaluation of background activity, paroxysmal abnormalities, and photoparoxysmal response. Data were organized for age groups. Correlation and logistic regression analysis were performed. Patients' mean age was 47.8 ± 22.0 years (range 20-86 years). Mean age at disease onset was 20.2 ± 7.8 years (range 11-40 years); mean follow-up duration was 14.0 ± 5.8 years (range 7-28 years). Evaluation at different age groups revealed a gradual, progressive worsening of the myoclonus in 10 patients (71.4%). Two subjects aged >80 years showed myoclonus interfering with autonomous walking. Myoclonus severity was correlated with disease duration (p<0.001) and patients' age (p=0.001). Six patients (42.8%) experienced seizures, usually between the second and sixth decades of life. Evaluation of EEG long-term evolution revealed progressive slowing of background activity in parallel with the gradual worsening of myoclonus. In contrast, paroxysmal activity and photosensitivity were particularly evident during the intermediate phases of the disease. In addition, psychiatric and neuropsychological dysfunction occurred in more than one third of the patients. We provide data for a slight age-dependent progression and the presence of neuropsychiatric and neuropsychological dysfunction in this unique syndrome, for which the definition of familial or autosomal dominant cortical tremor, myoclonus, and epilepsy (FCTME/ADCME) seems to be, therefore, more appropriate.	f	\N
21429534	Familial combined hyperlipidemia (FCH) is a genetic model of atherogenic dyslipidemia with insulin resistance and early coronary disease. Our objective was to evaluate the presence of carotid alterations as a marker of systemic atherosclerosis in subjects with FCH and assess the effect of 80 mg of atorvastatin per day in carotid plaque thickness after 2 years. 100 non diabetic subjects with FCH in primary prevention were consecutively included. Clinical and biochemical parameters and carotid ultrasonography were performed. Subjects with carotid plaque started treatment with 80 mg of atorvastatin per day for 2 years. 29% of subjects had carotid plaques. We did not find significant differences in any of the parameters between subjects with presence or absence of carotid plaques. Twenty subjects with carotid plaques accepted/agreed to participate in the interventional study. Two years follow-up showed a significant reduction in LDLc (30%) and carotid plaque thickness (10%). Carotid ultrasonography is useful to detect subclinical atherosclerosis in high risk cardiovascular patients such as subjects with FCH. Treatment with high doses of atorvastatin induces the regression of carotid plaque thickness after 2 years follow-up. Our results suggest that intensive treatment with atorvastatin could be useful to reduce the development of cardiovascular disease in this group of patients.	f	\N
21430371	The aim of this study was to evaluate the impact of clinical variables and biologic features on response rate (RR), overall survival (OS) and progression-free survival (PFS) in 111 patients with de novo diffuse large B cell lymphoma (DLBCL). Fifty-three patients were treated with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) and 58 patients were treated with R-CHOP (rituximab + CHOP). The variables predictive of RR in the CHOP group were B symptoms, age, clinical stage, bone marrow involvement, bulky disease, International Prognostic Index (IPI) and Bcl-2; in the R-CHOP group, these variables were bulky disease, bone marrow involvement, IPI and Ki67 expression >80%. Multivariate analysis showed that in patients treated with CHOP, the independent prognostic factors associated with PFS were age, bulky disease, IPI and Bcl-2 and those associated with OS were performance status, clinical stage, IPI and bone marrow involvement. In contrast, in patients treated with R-CHOP, the variable shown by multivariate analysis to be an independent prognostic factor associated with PFS was bulky disease, whereas Ki67 expression >80% was associated with OS and PFS. Our data show that a high Ki67 expression and bulky disease could represent possible predictive factors of poor prognosis, which would help to identify a high-risk subgroup of newly diagnosed DLBCL.	f	\N
21437774	The enormous abundance of lipid molecules in the central nervous system (CNS) suggests that their role is not limited to be structural and energetic components of cells. Over the last decades, some lipids in the CNS have been identified as intracellular signalers, while others are known to act as neuromodulators of neurotransmission through binding to specific receptors. Neurotransmitters of lipidic nature, currently known as neurolipids, are synthesized during the metabolism of phospholipid precursors present in cell membranes. Therefore, the anatomical identification of each of the different lipid species in human CNS by imaging mass spectrometry (IMS), in association with other biochemical techniques with spatial resolution, can increase our knowledge on the precise metabolic routes that synthesize these neurolipids and their localization. The present study shows the lipid distribution obtained by MALDI-TOF IMS in human frontal cortex, hippocampus, and striatal area, together with functional autoradiography of cannabinoid and LPA receptors. The combined application of these methods to postmortem human brain samples may be envisioned as critical to further understand neurological diseases, in general, and particularly, the neurodegeneration that accompanies Alzheimer's disease.	f	\N
21438696	To test the hypothesis of a significant association between resting heart rate (RHR) and coronary artery calcium (CAC). This is a cross-sectional study of a subset of women enrolled in the estrogen-alone clinical trial of the Women's Health Initiative (WHI). We used a longitudinal study that enrolled 998 postmenopausal women with a history of hysterectomy between the ages of 50 and 59 at enrollment at 40 different clinical centers. RHR was measured at enrollment and throughout the study, and CAC was determined approximately 7 years after the baseline clinic visit. The mean (standard deviation [SD]) age was 55 (2.8) years. With adjustment for age and ethnicity, a 10-unit increment in RHR was significantly associated with CAC (SD 1.18, 95% confidence interval [CI] 1.01-1.38), but this was no longer significant after adjustment for body mass index (BMI), income, education, dyslipidemia, diabetes, smoking, and hypertension (SD 1.06, 95% CI 0.90-1.25). In a fully adjusted multivariable model, however, there was a significant interaction (p=0.03) between baseline RHR and systolic blood pressure (SBP) for the presence of any CAC. Compared to women with an RHR < 80 beats per minute (BPM) and an SBP < 140 mm Hg, those who had an RHR ≥ 80 BPM and an SBP ≥ 140 mm Hg had 2.66-fold higher odds (1.08-6.57) for the presence of any CAC. Compared to those with normal BP and RHR, postmenopausal, hysterectomized women with an elevated SBP and RHR have a significantly higher odds for the presence of calcified coronary artery disease.	f	\N
21438811	Hepatic steatosis, considered the first step in the pathophysiologic continuum of non-alcoholic fatty liver disease, is estimated to afflict 30% of the US population and over 75% of patients with Type 2 diabetes. Given the expected rise in the prevalence of obesity and Type 2 diabetes in the following decades, hepatic steatosis will, if not already, become an epidemic. The consequences of hepatic steatosis are numerous, and range from progression to chronic liver disease, with its associated morbidity and mortality, to worsening insulin resistance and Type 2 diabetes, as well as being an independent contributor to cardiovascular disease. All such consequences are more likely to occur in patients with Type 2 diabetes who are already at high risk of cardiovascular events. In this article we review the evidence behind the available therapeutic options for hepatic steatosis, and identify challenges and unmet needs in the field.	f	\N
21439159	The influence of respiratory infections on asthma has not been fully understood. Acute viral and bacterial infections often lead to exacerbations. Less is known about the role of chronic infections, particularly with atypical pathogens. The aim of this study was to evaluate the impact of Chlamydophila pneumoniae and Mycoplasma pneumoniae infections on the control and severity of asthma. Spirometry, skin-prick tests as well as measurement of immunoglobulin G (IgG), IgM, and IgA against C. pneumoniae and M. pneumoniae (ELISA) were performed in 95 patients with persistent asthma and 58 healthy controls. Additionally, in the selected group of asthmatic patients, presence of C. pneumoniae and M. pneumoniae genetic material was tested in induced sputum (polymerase chain reaction [PCR]). IgA against C. pneumoniae was found in 42 (44.2%) asthmatic patients and 17 (29.3%) controls (p < 0.05). It was found more often in the group with uncontrolled asthma (p = 0.001) as well as in nonatopic asthmatic patients (p < 0.05). IgG was detected in 58 asthmatic patients (61%) and 21 (36.2%) controls, more often in cases of uncontrolled (p < 0.05) and nonatopic asthma patients (p < 0.05). Such correlations were not found in relation to M. pneumoniae infections. C. pneumoniae was detected by means of PCR in respiratory secretions of eight asthmatic patients (40%), and M. pneumoniae was detected in two asthmatic patients (10%). In conclusion, C. pneumoniae infections are more frequent in asthmatic patients compared with healthy individuals and in nonatopic asthmatic patients compared to atopic patients. Chronic infection is associated with poor control of asthma.	f	\N
21443521	The inherited disorders of hemoglobin synthesis are the most common monogenic disorders worldwide. They include thalassemias, hemoglobin variants, and hereditary persistence of fetal hemoglobin. β-thalassemia is the most common monogenic disorder in India. Clinical manifestations of β-thalassemia are extremely variable in severity. The reasons for this heterogeneity are not very well understood. Previous studies have shown that the genetic variants that modulate HbF levels have a very strong impact on ameliorating the clinical phenotype. In the present study, 5570 blood samples from suspected cases were analyzed using HPLC, amplification refractory mutation system-PCR and reverse dot blot techniques. Of 5570 individuals, we found 676 cases of β-thalassemia disease. Molecular analysis revealed the presence of different β-thalassemia mutations in the population under study. Patients with β-thalassemia were classified into mild, moderate, and severe according to severity score based on Hb level, age of onset, age at which patients received their first blood transfusion, degree of growth retardation and splenectomy. Patients with β-thalassemia were analyzed for zinc finger and homeoboxes 2 (ZHX2) G779A polymorphism, and the association between ZHX2 gene polymorphism and severity of β-thalassemia was evaluated. We did not find a significant difference in genotypic and allelic frequency of ZHX2 gene between mild and moderate, mild and severe, and moderate and severe cases. There was no significant difference in high and low percentage of HbF in GG, GA, and AA bearing individuals showing that ZHX2 gene variant has no role in ameliorating the severity of β-thalassemia major in the South Indian population from Andhra Pradesh.	f	\N
21458394	Encapsulating peritoneal sclerosis (EPS) is a rare but life-threatening complication of peritoneal sclerosis (PD). In 2000, the International Society for Peritoneal Dialysis outlined diagnostic guidelines and a clinical definition of EPS. Over the intervening years, new evidence was published and several centers became more experienced managing patients with EPS. Although, further networking was initiated (European EPS Working Group), evidence regarding therapy and diagnosis of EPS is still lacking. Multicenter trials are needed to establish evidence regarding the management of EPS. Risk factors for EPS are identified and patients at risk should be monitored closely. In case of emerging signs of EPS, patients should be referred to an EPS-center before initiation of therapy. Morphology and immunohistochemistry will play a central role in the near future. Nowadays, most pathologists are not sophisticated in the pathology of peritoneal biopsies. Clear histological criteria are warranted. For the outcome of the patient, it is crucial that an EPS experienced surgeon conducts surgery.	f	\N
21463281	Dravet syndrome (DS) is an epileptic encephalopathy related mainly to mutations in the SCN1A gene, encoding for neuronal sodium channels. Patients with DS have a high risk of sudden unexpected death in epilepsy (SUDEP). In this study we investigated whether patients with DS present abnormalities in electrical and autonomic cardiac function. To this aim we assessed ventricular repolarization and heart rate variability (HRV) on standard electrocardiography (ECG) and on 24-h ECG Holter monitoring, respectively, in 20 patients affected by DS (6.8 ± 4 years, 11 female). As age- and sex-matched control groups, we also studied 20 patients with other epileptic syndromes receiving antiepileptic drugs (ES/AED, 6.0 ± 5 years, 12 female), 20 patients with other epileptic syndromes without treatment (ES/no-AED, 6.7 ± 4 years, 10 female), and 20 healthy children (HC, 7.2 ± 5 years, 11 females). Data analysis showed that patients with DS had depressed HRV variables compared to both ES patients (ES/AED and ES/no-AED) and HC control group, whereas no significant differences in HRV variables were found between ES patients (with and without treatment) and HC. There was no significant difference between patients with DS and all the other control groups in RR intervals, QT, and QTc interval analysis. In conclusion, DS patients display an imbalance of cardiac autonomic function toward a relative predominance of adrenergic tone compared to both healthy children and patients with other forms of epilepsy, independent of antiepileptic therapy. Follow-up studies should clarify the clinical significance of this autonomic impairment and whether HRV analysis can be helpful in predicting the risk of sudden death in patients with DS.	f	\N
21463368	Oral lichen planus (OLP) is generally accepted as a chronic and T-cell-mediated autoimmune disease, whose immunopathogenesis may involve antigen presentation, T-cell activation and migration as well as, possibly, tumor necrosis factor-alpha (TNF-α)-induced keratinocytes apoptosis. However, present treatment options for OLP are far from being satisfactory. Recent advances in understanding the pathogenesis of OLP, progress in biologics, and the success of biologic therapies in OLP indicate that biologic agents are facing expanding indications in OLP. In this review, we mainly discuss the role of T cells in the pathogenesis of OLP and several biologic therapies that directly and/or indirectly target T cells to treat OLP.	f	\N
21467169	Purpose. To compare the properties of the visual field index (VFI) to those of mean deviation (MD) in patients with glaucoma. Methods. MD and VFI were calculated in data obtained from an ongoing longitudinal study in which patients with glaucoma (N = 109, 204 eyes) were observed for 9.8 years (median, 21 tests) with static automated perimetry. MD and VFI were compared in one test of each eye, and a subset of 30 tests were selected to compare the VFI with the judgments of eight experts who judged the percentage of the remaining visual field. In series of tests obtained over time, rates of change, statistical significance, evidence of nonlinearity, and variability were compared between both indices. Results. In single tests, MD and VFI were closely related (r = 0.88, P < 0.001). The relationship between both indices appeared linear, except in visual fields with MDs better than -5.0 dB where 29 (22%) of 129 eyes exhibited a ceiling effect (VFI = 100%). Based on this relationship, the predicted VFIs for visual fields with MDs of -5, -10, and -15 dB were 91%, 76%, and 60%, respectively. The percentage of remaining visual field suggested by the VFI exceeded the range of the experts' subjective judgments in 16 (53%) of 30 eyes. In series of tests obtained over time, rates of change with the two indices were closely related (r = 0.79, P < 0.001), and statistically significant reductions over time (P < 0.05) occurred in a similar number of eyes (92 [45%] with MD, and 87 [43%] with VFI). Of the 105 eyes with statistically significant (P < 0.05) negative trend in either MD or VFI, 74 (70%) showed such trends with both indices (κ = 0.69). The variability of MD and VFI increased with damage, and there was no evidence that change over time was more linear with VFI than with MD. Conclusions. The VFI provides a simple and understandable metric of visual field damage, but its estimates of remaining visual field were more optimistic than those of the experts. Rates of change over time with both indices were closely related, but the reliance of the VFI on pattern deviation probability maps caused a ceiling effect that may have reduced its sensitivity to change in eyes with early damage. In this group of patients there was no evidence to suggest that the VFI is either superior or inferior to the MD as a summary measure of visual field damage.	f	\N
21468585	Basic transcription element-binding protein 2 (BTEB2) is a regulator of the proliferation and phenotypic changes of vascular smooth muscle cells (SMCs). The aim of the present study was to determine whether or not BTEB2 knockdown inhibits balloon injury-induced neointimal hyperplasia attributed to the proliferation and phenotypic changes of vascular SMCs. We found that the knockdown of BTEB2 with antisense oligonucleotides (Ad-As-BTEB2) significantly reduced the intima/media ratio compared to uninjured arteries and vessels treated with Ad-LacZ. Knockdown of BTEB2 suppresses the proliferation of cultured vascular SMCs, concurrent with the down-regulation of proliferating cell nuclear antigen, angiotensin II type 1 receptor and platelet-derived growth factor BB. In addition, BTEB2 knockdown caused the up-regulation of the differentiation marker smooth muscle α-actin and down-regulation of the dedifferentiation marker embryonic smooth muscle myosin heavy chain. The present study provides direct evidence that BTEB2 plays a critical role in balloon injury-induced neointimal hyperplasia, which is closely linked to vascular SMC proliferation and phenotypic modulation. This study highlights the fact that BTEB2 may be a potential target for the prevention of restenosis after vascular intervention.	f	\N
21473920	Diffusion imaging of post mortem brains has great potential both as a reference for brain specimens that undergo sectioning, and as a link between in vivo diffusion studies and "gold standard" histology/dissection. While there is a relatively mature literature on post mortem diffusion imaging of animals, human brains have proven more challenging due to their incompatibility with high-performance scanners. This study presents a method for post mortem diffusion imaging of whole, human brains using a clinical 3-Tesla scanner with a 3D segmented EPI spin-echo sequence. Results in eleven brains at 0.94 × 0.94 × 0.94 mm resolution are presented, and in a single brain at 0.73 × 0.73 × 0.73 mm resolution. Region-of-interest analysis of diffusion tensor parameters indicate that these properties are altered compared to in vivo (reduced diffusivity and anisotropy), with significant dependence on post mortem interval (time from death to fixation). Despite these alterations, diffusion tractography of several major tracts is successfully demonstrated at both resolutions. We also report novel findings of cortical anisotropy and partial volume effects.	f	\N
21474147	Total proctocolectomy with ileal pouch-anal anastomosis (IPAA) is the gold standard surgical treatment for chronic ulcerative colitis. More recently, this procedure is being performed laparoscopically assisted. Postoperatively, small bowel obstruction (SBO) is one of the more common associated complications. However, it is unknown whether the addition of a laparoscopic approach has changed this risk. This study aims to assess and compare the incidence of SBOs after both open and laparoscopic restorative proctocolectomy. All subjects who underwent restorative proctocolectomy from 1998-2008 were identified from a prospective Colorectal Surgery Database. Medical records were reviewed for all cases of SBO, confirmed by a combination of clinical symptoms and radiologic evidence. Comparisons were made between laparoscopic and open approaches. The incidence of SBO was also subdivided into pre-ileostomy takedown, early post-ileostomy takedown (30 d post), and late post-ileostomy takedown (30 d to 1 y post). Several potential risk factors were also evaluated. Statistical analysis was performed utilizing Fisher's exact (for incidence) or t-tests (for means). Significance was defined as P < 0.05 A total of 290 open cases and 100 laparoscopic cases were identified during this time period. The overall incidence of SBO at 1 y post-ileostomy takedown was 14% (n = 42) in the open group and 16% (n = 16) laparoscopic (P = NS). In the pre-ileostomy takedown period the incidence of SBO was 7% (n = 21) open and 13% (n = 13) laparoscopic (P = NS). While in the post-takedown period, the early incidence was 4% (n = 12) open and 1% (n = 1) laparoscopic and late incidence was 3% (n = 9) open and 2% (n = 2) laparoscopic (P = NS). Factors associated with an increased risk of SBO include coronary artery disease, prior appendectomy and W and J pouch configurations. The burden of postoperative small bowel obstruction after restorative proctocolectomy is not changed with a laparoscopic approach. Most cases occur in the early postoperative period, especially prior to ileostomy reversal.	f	\N
21475985	To investigate the nationwide prevalence of hepatitis E virus (HEV) infection and to characterize HEV genomes among Japanese wild boars (Sus scrofa leucomystax), 578 boars captured in 25 prefectures from 2003 to 2010 were studied. Anti-HEV IgG was detected in 8.1%, and HEV RNA in 3.3% of boars. Among the 19 boar HEV isolates obtained from infected boars, 14 isolates (74%) were classified as genotype 3, 4 isolates (21%) as genotype 4, and the remaining isolate (wbJOY_06) was distantly related to all known HEV isolates of genotypes 1-4, differing by 18.4-25.0% and 18.0-24.3% within the 412-nucleotide sequence of ORF1 and ORF2, respectively. A genotype 4 boar HEV isolate (wbJGF_08-1) obtained herein shared 98.6% identity over the entire genome with a human HEV isolate obtained from a patient who developed acute hepatitis after consuming undercooked wild boar meat, suggesting that wild boars are also reservoirs for genotype 4 HEV in humans.	f	\N
21476292	The performance of a latex agglutination test (Mediace TPLA) in the detection of anti-treponemal antibody was evaluated in comparison with chemical luminescence tests (LumipulsII-N and Architect TPAb) in 346 cases. Anti-treponemal antibody was further determined by immunochromatography and immunoblotting tests and additionally evaluated by a serological test for syphilis with lipoidal antigens. The total concordance rate between the latex agglutination test and chemical luminescence tests ranged from 96% to 97%: the positive concordance rate ranged from 96% to 97%, and the negative concordance rate, from 97% to 98%. The latex agglutination test showed two false positive cases, and each chemical luminescence test showed two false positive cases, respectively. In eight cases, only the latex agglutination test showed negative results; all specimens contained anti-treponemal antibodies. However, none of these was considered to be a false positive and each was treated as syphilis based on the results of confirmatory analysis with immunochromatography and immunoblotting tests and a serological test for syphilis. The discordant results in the latex agglutination test and chemical luminescence tests may be caused by the different antigenisity of each test. With detailed analysis of those sera treated as syphilis, each specimen was found to contain various antibodies against syphilitic antigens, suggesting that there was a different specificity of native and recombinant antigens. Based on the present results for the comparison between the latex agglutination test and chemical luminescence tests, it was considered that further investigation is necessary to clarify the anti-treponemal antibody profile of syphilis at the disease stage.	f	\N
21477408	Ideally putative disease-modifying therapies for Alzheimer's disease (AD) should be tested in patients who have minimal morbidity. Current barriers to such trials in early disease include the lack of disease-specific early biomarkers, insensitivity of quantitative cognitive outcome measures, and expensive trial designs requiring large sample sizes and long duration. This paper describes principles and progress towards a novel trial design that overcomes these problems, utilizing wide-scale cognitive performance screening to define pre-trial cognitive decline trajectories which can serve as trial outcome measures to assess AD disease-modifying efficacy. Theoretical principles important for the detection of intra-individual cognitive decline and a practical example are described. Serial evaluations of community-based volunteers demonstrate how a screening tool method to detect subtle cognitive decline can predict in vivo amyloid pathology as a trigger for etiological evaluation. Trajectories of decline appear consistent over at least two years, suggesting they could be used as a trial inclusion criterion and ameliorable outcome measure together with other AD biomarkers. Informative trial durations could be 6-12 months, or extend to incorporate staggered random withdrawal or start designs, with as few as 20 individuals per treatment arm. This trial methodology offers significant advantages over current AD trial designs, including treatment at earlier stages of disease, shorter trial duration, obviation of informed consent difficulties, smaller sample sizes, reduced cost and--given adequate screening programs--sufficient subjects for multiple simultaneous trials. Importantly, it allows the rapid evaluation of putative treatments that may only be efficacious in pre-dementia states.	f	\N
21478119	The impact of drug-eluting stents (DES) has not been extensively investigated in patients with moderate to severe renal dysfunction, as these patients are consistently excluded from randomised studies. We sought to assess prospectively the effectiveness and safety of the new-generation DES in patients with moderate chronic kidney disease (CKD) and an isolated de novo lesion in the proximal segment of the left anterior descending artery (pLAD). We evaluated 400 consecutive patients with a pLAD lesion. There were 96 patients with moderate CKD (estimated glomerular filtration rate 59 ml/min/1.73 m2) and 304 without CKD. Major adverse cardiac events (MACE) were defined as death, non-fatal myocardial infarction and target lesion revascularisation (TLR). Clinical or telephone follow up was performed. There was a significantly higher incidence of mortality in patients with CKD (n=4) as compared with non-CKD (n=2) (4.16% versus 0.65%, respectively, p=0.03). The rate of non-fatal myocardial infarction was similar in the 2 cohorts (p=0.59), as was the TLR rate (p=0.99). Overall, there were no significant differences regarding MACE between the 2 groups of patients (p=0.19) during the 13.62 ± 6.22 month follow-up period. The rate of angiographic stent thrombosis was 2.08% in the CKD group versus 0.98% in the non-CKD group (p=0.59). New generation DES implantation in patients with CKD and a pLAD lesion is effective and safe, with rates of TLR and stent thrombosis comparable to those in patients with normal renal function. However, the higher mortality in patients with CKD needs further evaluation.	f	\N
21481900	Non-Hodgkin lymphomas are common cancers that can develop in the upper aero-digestive tract. We describe a case of a large B-cell palatine lymphoma with spontaneous clinical regression. A 58-year-old female patient presented with a sub-mucosal lesion of the hard palate. CT scan and magnetic resonance imaging revealed a lesion invading the right posterior palatine canal. At the second consultation, 15 days after performing the biopsy, the lesion had disappeared. PET scan proved the absence of lesion. Lymph node biopsy supported the diagnosis of large B-cell lymphoma. Large B-cell lymphoma of the hard palate is a rare disease. Only 27 cases have been described in the international literature. The anatomopathological analysis is often difficult to perform. The final diagnosis is often made by immunochemistry. The usual treatment is R-CHOP chemotherapy (cyclophosphamide, adriamycin, vincristine, prednisone combined to rituximab) with a 5-year survival rate at 55%.	f	\N
21484828	Anterior interosseous nerve syndrome (AINS) has not been widely recognized as a possible complication following peripheral catheterization. Herein we present a retrospective review of patients with AINS over the last 5 years. Six cases were identified, 4 associated with catheterization. AINS may be a rare complication of catheterization. Magnetic resonance imaging (MRI) may serve as an adjunct diagnostic modality to conventional electromyography (EMG) and nerve conduction studies, especially in patients who are intolerant of pain.	f	\N
21485204	This paper presents a novel matching method of vessels in 3D reconstruction of heart vessel. The directed binary tree was used to describe the topological structure of heart vessel tree's skeleton. Based on topological property and epipolar property, the branch-points and end-points of each branch level could be automatically matched along the direction of blood stream. Thereupon it is easy to couple the corresponding vessels segments of two angiograms projected in different directions. The 3D heart vessel tree was successfully reconstructed from clinic coronary angiograms, which validates the presented method.	f	\N
21489314	The standard treatment for patients with advanced transitional cell carcinoma of the bladder is platin based chemotherapy. Only approximately 50% of the patients respond to chemotherapy. Therefore, molecular predictive markers for identification of chemotherapy sensitive subgroups of patients are highly needed. We selected the transcription factor TFAP2α from a previously identified gene expression signature for chemotherapy response. TFAP2α expression and localization was assessed by immunohistochemistry using a tissue microarray (TMA) containing 282 bladder cancer tumors from patients with locally advanced (pT2-T4(b) and N(1-3)) or metastatic (M(1)) disease. All patients had received cisplatin containing chemotherapy. Furthermore, QPCR analysis of three TFAP2α isoforms was performed on tumor specimens of advanced muscle invasive bladder cancers (T2-4). Using the bladder cell lines T24 and SW780 the relation of TFAP2α and cisplatin and gemcitabine sensitivity as well as cell proliferation was examined using siRNA directed TFAP2α knockdown. TFAP2α protein expression was analyzed on a TMA with cores from 282 advanced bladder cancer tumors from patients treated with cisplatin based combinational chemotherapy. TFAP2α was identified as a strong independent predictive marker for a good response and survival after cisplatin-containing chemotherapy in patients with advanced bladder cancer. Strong TFAP2α nuclear and cytoplasmic staining predicted good response to chemotherapy in patients with lymph node metastasis, whereas weak TFAP2α nuclear staining predicted good response in patients without lymph node metastasis. In vitro studies showed that siRNA mediated knockdown of TFAP2α increased the proliferation of SW780 cells and rendered the cells less sensitive to cisplatin and gemcitabine. In contrast to that T24 bladder cells with mutated p53 showed to be more drug sensitive upon TFAP2α depletion. High levels of nuclear and cytoplasmic TFAP2α protein were a predictor of increased overall survival and progression free survival in patients with advanced bladder cancer treated with cisplatin based chemotherapy. TFAP2α knockdown increased the proliferation of the SW780 bladder cells and reduced cisplatin and gemcitabine induced cell death. The inverse effect was observed in the TP53 mutated T24 cell line where TFAP2α silencing augmented cisplatin and gemcitabine sensitivity and did not stimulate proliferation.	f	\N
21493631	Data on right ventricle (RV) regional function in adults with interatrial shunt are scarce. The aim of the study was to assess the regional RV deformation in the population of adults with uncorrected atrial left-to-right shunt and to establish a potential relationship between its magnitude and RV regional deformation. We studied 40 adults (30F/10M; mean age 39.2 years) with atrial septal defect (ASD) [average pulmonary-to-systemic blood flow ratio (Qp/Qs) 2.1 ± 0.7]. Standard echocardiographic evaluation was completed with right ventricular dimensions, parameters of its global [tricuspid annular plane systolic excursion (TAPSE), fractional area change, myocardial performance index], and regional [strain/strain rate (ε/SR)] function. Among echocardiographic indices describing RV global function, only TAPSE was increased when compared with healthy subjects. No differences in RV deformation data (ε/SR) between ASD patients and control group were found. Non-linear relationship between the differing Qp/Qs and maximal ε in the mid-segments of the RV free wall was observed. In patients with moderate shunt, maximal ε values were higher when compared with the values obtained in mild and large shunts. Regional RV deformation (ε/SR) does not differ significantly in the group of patients with various degrees of the left-to-right shunts when compared with healthy subjects. However, a non-linear correlation between Qp/Qs and ε could be observed. The affected region of the RV wall is the mid-segment and the highest values of ε were recorded in patients with moderate left-to-right shunts.	f	\N
21493742	The risk of a posttransplant recurrence of secondary glomerulonephritis (GN) is quite variable. Histologic recurrence is frequent in lupus nephritis, but the lesions are rarely severe and usually do not impair the long-term graft outcome. Patients with Henoch-Schonlein nephritis have graft survival similar to that of other renal diseases, although recurrent Henoch-Schonlein nephritis with extensive crescents has a poor prognosis. Amyloid light-chain amyloidosis recurs frequently in renal allografts but it rarely causes graft failure. Amyloidosis secondary to chronic inflammation may also recur, but this is extremely rare in patients with Behcet's disease or in those with familial Mediterranean fever, when the latter are treated with colchicine. Double organ transplantation (liver/kidney; heart/kidney), chemotherapy, and autologous stem cell transplantation may be considered in particular cases of amyloidosis, such as hereditary amyloidosis or multiple myeloma. There is little experience with renal transplantation in light-chain deposition disease, fibrillary/immunotactoid GN, or mixed cryoglobulinemic nephritis but successful cases have been reported. Diabetic nephropathy often recurs but usually only after many years. Recurrence in patients with small vessel vasculitis is unpredictable but can cause graft failure. However, in spite of recurrence, patient and graft survival rates are similar in patients with small vessel vasculitis compared with those with other renal diseases. Many secondary forms of GN no longer represent a potential contraindication to renal transplantation. The main issues in transplantation of patients with secondary GN are the infectious, cardiovascular, or hepatic complications associated with the original disease or its treatment.	f	\N
21496186	Certainty is seen as the 'Holy Grail' of science, despite the fact that all science is based in doubt, and that good scientists always leave a door open for an alternative explanation of their findings. Certainty also is a human desire providing comfort and surety. How can these two notions coexist? The way we perceive is the way we see and understand. Perception, however, is not objective; the way we 'know' what the sensory input we receive means arises from matching it against stored images of prior experiences, or put differently, the way we perceive the world depends on successfully predicting our own sensory status. Only large mismatches create new awareness resulting in new learning. At large we are prisoners of our own making, and awareness of the boundaries of our understanding will help to expand our horizon. The four papers of this edition attempt to expand the boundaries of 'common certainty' in terms of statistical interpretation, management of individual patients, disease management and health policy.	f	\N
21498295	Patients suffering from hereditary hyperlipidemia have a high risk for premature cardiovascular disease and death as a consequence of accelerated atherosclerosis. To prospectively and intra-individually compare image quality and detectability of stenoses in contrast enhanced whole-body MRA (WBMRA) at 1.5 and 3 Tesla (T) in patients with hereditary hyperlipidemia. Twenty-seven patients with hereditary hyperlipidemia received a 1.5 and 3 T gadopentetate dimeglumine contrast-enhanced WBMRA. Twenty-three defined arterial segments were analyzed regarding depiction of target vessels and image quality according to a 5-point-scale ('not evaluable' to 'excellent'). Wilcoxon matched pair test was performed for comparison. Forty-three defined arterial segments were analyzed for the degree of stenosis (0%, 1-49%, 50-99% and 100%) as well as vessel alterations such as aneurysms. Chi-square test was performed for comparison. 1.5 T and 3 T scans yielded WBMRA with diagnostic quality in all patients. In seven of 23 arterial segments (30.4%) image quality was rated significantly higher at 3 T, whereas there was no significant difference in the remaining 16 segments between WBMRA at 1.5 T and 3 T. All relevant stenoses (n = 5), occlusions (n = 6), and aneurysms (n = 3) were evaluated similarly at both field strengths. WBMRA can be performed at 1.5 T and 3 T with diagnostic image quality. Image quality was significantly higher at 3 T than at 1.5 T in only 30.4% of the arterial segments. In order to effectively take advantage of the higher field strength, further optimization of sequence parameters and injection protocols for WBMRA at 3 T is necessary.	f	\N
21503392	The rate of transient dilatation can be determined by exercise testing or pharmacological stress test. It is unknown whether the type of stress has an impact on average transient dilatation index values. To compare average transient dilation index values in 99mTc-sestamibi scintigraphy in patients undergoing treadmill stress test, versus dipyridamole stress test. The secondary purpose was to evaluate the impact on the average index value by demographic characteristics, risk factors for coronary artery disease and severity of ischemia. The cross-sectional study included 200 patients between 40 and 70 years old, with or without risk factors for ischemic heart disease, with or without a previous diagnosis of ischemic heart disease. The separation between groups was sequential. The software 4D-MSPECT calculated the transient dilatation index and provided a scoring system for perfusion analysis. The average transient dilation index value of the group undergoing exercise stress test was 1.06 (±0.23). For the group undergoing the dipyridamole stress test, it was 1.10 (±0.22); (p = 0.200). There was no association between the type of stress and the average transient dilatation index values. An association was found between the average index values and age only for those patients from the exercise test group (p = 0.009). The results of our study demonstrate that the transient dilation index does not differ when patients undergo exercise stress test on a treadmill or pharmacological stress by dipyridamole.	f	\N
21506835	Rapid and reliable detection and identification of coccidian oocysts are essential for animal health and foodborne disease outbreak investigations. Traditional microscopy and morphological techniques can identify large and unique oocysts, but they are often subjective and require parasitological expertise. The objective of this study was to develop a real-time quantitative PCR (qPCR) assay using melting curve analysis (MCA) to detect, differentiate, and identify DNA from coccidian species of animal health, zoonotic, and food safety concern. A universal coccidia primer cocktail was designed and employed to amplify DNA from Cryptosporidium parvum, Toxoplasma gondii, Cyclospora cayetanensis, and several species of Eimeria, Sarcocystis, and Isospora using qPCR with SYBR Green detection. MCA was performed following amplification, and melting temperatures (T(m)) were determined for each species based on multiple replicates. A standard curve was constructed from DNA of serial dilutions of T. gondii oocysts to estimate assay sensitivity. The qPCR assay consistently detected DNA from as few as 10 T. gondii oocysts. T(m) data analysis showed that C. cayetanensis, C. parvum, Cryptosporidium muris, T. gondii, Eimeria bovis, Eimeria acervulina, Isospora suis, and Sarcocystis cruzi could each be identified by unique melting curves and could be differentiated based on T(m). DNA of coccidian oocysts in fecal, food, or clinical diagnostic samples could be sensitively detected, reliably differentiated, and identified using qPCR with MCA. This assay may also be used to detect other life-cycle stages of coccidia in tissues, fluids, and other matrices. MCA studies on multiple isolates of each species will further validate the assay and support its application as a routine parasitology screening tool.	f	\N
21507892	Manitoba-oculo-tricho-anal (MOTA) syndrome is a rare condition defined by eyelid colobomas, cryptophthalmos and anophthalmia/microphthalmia, an aberrant hairline, a bifid or broad nasal tip, and gastrointestinal anomalies such as omphalocele and anal stenosis. Autosomal recessive inheritance had been assumed because of consanguinity in the Oji-Cre population of Manitoba and reports of affected siblings, but no locus or cytogenetic aberration had previously been described. This study shows that MOTA syndrome is caused by mutations in FREM1, a gene previously mutated in bifid nose, renal agenesis, and anorectal malformations (BNAR) syndrome. MOTA syndrome and BNAR syndrome can therefore be considered as part of a phenotypic spectrum that is similar to, but distinct from and less severe than, Fraser syndrome. Re-examination of Frem1(bat/bat) mutant mice found new evidence that Frem1 is involved in anal and craniofacial development, with anal prolapse, eyelid colobomas, telecanthus, a shortened snout and reduced philtral height present in the mutant mice, similar to the human phenotype in MOTA syndrome. The milder phenotypes associated with FREM1 deficiency in humans (MOTA syndrome and BNAR syndrome) compared to that resulting from FRAS1 and FREM2 loss of function (Fraser syndrome) are also consistent with the less severe phenotypes resulting from Frem1 loss of function in mice. Together, Fraser, BNAR and MOTA syndromes constitute a clinically overlapping group of FRAS-FREM complex diseases.	f	\N
21508333	c-Src is a non-receptor tyrosine kinase whose activity is induced by phosphorylation at Y418 and translocation from the cytoplasm to the cell membrane. Increased activity of c-Src has been associated with cell proliferation, matrix adhesion, motility, and apoptosis in tumors. Immunohistochemistry suggested that activated (pY(418))-Src activity is increased in cyst-lining autosomal dominant polycystic kidney disease (ADPKD) epithelial cells in human and mouse ADPKD. Western blot analysis showed that SKI-606 (Wyeth) is a specific inhibitor of pY(418)-Src without demonstrable effects on epidermal growth factor receptor or ErbB2 activity in renal epithelia. In vitro studies on mouse inner medullary collecting duct (mIMCD) cells and human ADPKD cyst-lining epithelial cells showed that SKI-606 inhibited epithelial cell proliferation over a 24-h time frame. In addition, SKI-606 treatment caused a striking statistically significant decrease in adhesion of mIMCD and human ADPKD to extracellular collagen matrix. Retained viability of unattached cells was consistent with a primary effect on epithelial cell anchorage dependence mediated by the loss of extracellular matrix (ECM)-attachment due to α(2)β(1)-integrin function. SKI-606-mediated attenuation of the human ADPKD hyperproliferative and hyper-ECM-adhesive epithelial cell phenotype in vitro was paralleled by retardation of the renal cystic phenotype of Pkd1 orthologous ADPKD heterozygous mice in vivo. This suggests that SKI-606 has dual effects on cystic epithelial cell proliferation and ECM adhesion and may have therapeutic potential for ADPKD patients.	f	\N
21537035	To determine if time to diagnosis is associated with stage of disease at diagnosis or survival among women with symptomatic ovarian cancer. A representative sample of Australian women (n = 1,463) with ovarian cancer diagnosed between 2002 and 2005 who participated in a population-based case-control study were interviewed regarding the events leading to their diagnosis and were observed for mortality for 5 years. Of the 1,318 women (90%) who presented to a medical practitioner with symptoms, 55% presented within 1 month, 70% in less than 2 months, and 92% within 6 months of symptom onset. There were no significant differences in the time from symptom onset to first medical practitioner consultation (P = .19) or symptom onset to diagnosis (P = .64) among women with borderline, early (International Federation of Gynecology and Obstetrics [FIGO] stages I to II) or late (FIGO stages III to IV) disease. There was also no association between time to diagnosis and survival; adjusted hazard ratio for long delay (> 12 months from symptom onset to diagnosis) versus short delay (≤ 1 month) was 0.94 (95% CI, 0.68 to 1.30). Women who had asymptomatic cancers diagnosed incidentally (n = 145) were younger and were more likely to have borderline or stage I disease compared with women who had symptomatic ovarian cancer. The results of this study suggest that, once ovarian cancer is symptomatic, reducing the time to diagnosis would not greatly alter stage of disease at diagnosis or survival.	f	\N
21542809	Endometriosis-associated infertility results in reduced ovarian response, fewer oocytes available for fertilization, compromised oocyte quality and higher miscarriage rates. A consistent proportion of women with endometriosis require in vitro fertilization. We sought to clarify the impact of deep infiltrating pelvic disease on antral follicle count and ovarian response to follicle-stimulating hormone (FSH) stimulation in patients with severe endometriosis. Retrospective cohort study. University hospital. Patients with severe endometriosis (stages III-IV; n=51) were divided into two groups regarding localization of endometriosis during surgical staging: ovarian (n=27) and both ovarian and deep infiltrating disease (n=24). A total of 73 long-protocol ovulation induction cycles with recombinant FSH for an intracytoplasmic sperm injection program were given. On day 3 of the cycle, measurements of FSH and luteinizing hormone and an ultrasound evaluation of antral follicle count were performed. Number of oocytes collected at ovum pick up, number of mature oocytes, number of embryos transferred and clinical pregnancy rate. Ovarian reserve in terms of antral follicle count was damaged in both groups but, if adjusted for age, it was significantly lower in the ovarian and pelvic infiltrating group compared with patients having only ovarian endometriosis. Pelvic deep infiltrating disease significantly impacted on the number of oocytes collected at pick up when adjusted for age. Deep infiltrating pelvic disease can negatively affect ovarian reserve in terms of antral follicle count and number of oocytes retrieved. Mechanisms underlying this phenomenon need to be elucidated.	f	\N
21545837	The proteasome is an enzyme complex responsible for targeted intracellular proteolysis. Alterations in proteasome-mediated protein clearance have been implicated in the pathogenesis of aging, Alzheimer's disease (AD) and Parkinson's disease (PD). In such diseases, proteasome inhibition may contribute to formation of abnormal protein aggregates, which in turn activate intracellular unfolded protein responses that cause oxidative stress and apoptosis. In this study, we investigated the protective effect of Insulin-like Growth Factor-I (IGF-1) for neural SH-SY5Y cells treated with the proteasomal inhibitor, Epoxomicin. In SH-SY5Y cells, Epoxomicin treatment results in accumulation of intracellular ubiquitinated proteins and cytochrome c release from damaged mitochondria, leading to cell death, in Epoxomicin time- and dose-dependent manner. In cells treated with small amounts of IGF-1, the same dosages of Epoxomicin reduced both mitochondrial damage (cytochrome c release) and reduced caspase-3 activation and PARP cleavage, both of which are markers of apoptosis. Notably, however, IGF-1-treated SH-SY5Y cells still contained ubiquitinated protein aggregates. This result indicates that IGF-1 blocks the downstream apoptotic consequences of Epoxomicin treatment leading to decreased proteasome function. Clues as to the mechanism for this protective effect come from (a) increased AKT phosphorylation observed in IGF-1-protected cells, vs. cells exposed to Epoxomicin without IGF-1, and (b) reduction of IGF-1 protection by pretreatment of the cells with LY294002 (an inhibitor of PI3-kinase). Together these findings suggest that activation of PI3/AKT pathways by IGF-1 is involved in IGF-1 neuroprotection against apoptosis following proteasome inhibition.	f	\N
21547907	Intraductal papillary mucinous neoplasm (IPMN) consists of four epithelial subtypes. Of those, pancreatobiliary and oncocytic types are recently recognized and relatively uncommon, and usually exhibit high-grade dysplasia. The biological properties and molecular characteristics of these two types have not been well documented. The few molecular studies of the oncocytic type showed absence of KRAS mutations commonly seen in the other subtypes, raising the possibility that the oncocytic type is distinct from the other subtypes. Thus, we examined clinicopathological features and molecular alterations of the two subtypes. The study cohort consisted of 12 pancreatobiliary and 18 oncocytic IPMN cases. KRAS, BRAF, and PIK3CA mutations and TP53, SMAD4, and β-catenin expression were analysed, and the results of molecular and clinicopathological profiles were compared between the two subtypes. KRAS mutations were identified in the oncocytic type, but less frequently than the pancreatobiliary type (17% versus 58%, p = 0.048). BRAF mutation was found in a single oncocytic tumour, and no PIK3CA mutations were seen in any of the study cohort. TP53 overexpression was less frequent in the oncocytic type than in the pancreatobiliary type (11% versus 58%, p = 0.013). Invasive components were present in 50% of the oncocytic and 92% of the pancreatobiliary types, with lymph node metastasis more frequently seen in the latter, corresponding to better outcomes in the former (5-year survival rates: 93% versus 32%, p = 0.014). Our demonstration of KRAS and BRAF mutations in the oncocytic-type IPMN supports a role for the activation of the RAS-MAPK pathway in this tumour type. However, the less frequent TP53 overexpression associated with the significantly lower rates of invasion and nodal disease in the oncocytic type correlates with better outcomes compared to the pancreatobiliary type.	f	\N
21565878	Excessive dynamic airway collapse (EDAC) refers to abnormal and exaggerated bulging of the posterior wall within the airway lumen during exhalation. This condition is pathological if the reduced airway lumen is <50% of the normal. It is a relatively new disease entity that is recognised more easily now with the increased use of multi-detector row CT. EDAC is often asymptomatic and diagnosed incidentally. Although the term excessive dynamic airway collapse is often used interchangeably with tracheobronchomalacia, both entities represent morphologically and physiologically distinct processes. Considering the confusion between the two entities, the prevalence of stand-alone EDAC remains unclear. The prevalence of tracheobronchomalacia and EDAC depends upon the patient population, associated comorbidities and underlying aetiologies, diagnostic tools used and criteria used to define the airway collapse. This review defines EDAC and describes its pathophysiology, precipitating factors, associated symptoms and potential treatments.	f	\N
21571478	To determine the accuracy of magnetic resonance spectroscopy (MRS), perfusion MR imaging (MRP), or volume modeling in distinguishing tumor progression from radiation injury following radiotherapy for brain metastasis. Twenty-six patients with 33 intra-axial metastatic lesions who underwent MRS (n=41) with or without MRP (n=32) after cranial irradiation were retrospectively studied. The final diagnosis was based on histopathology (n=4) or magnetic resonance imaging (MRI) follow-up with clinical correlation (n=29). Cho/Cr (choline/creatinine), Cho/NAA (choline/N-acetylaspartate), Cho/nCho (choline/contralateral normal brain choline) ratios were retrospectively calculated for the multi-voxel MRS. Relative cerebral blood volume (rCBV), relative peak height (rPH) and percentage of signal-intensity recovery (PSR) were also retrospectively derived for the MRPs. Tumor volumes were determined using manual segmentation method and analyzed using different volume progression modeling. Different ratios or models were tested and plotted on the receiver operating characteristic curve (ROC), with their performances quantified as area under the ROC curve (AUC). MRI follow-up time was calculated from the date of initial radiotherapy until the last MRI or the last MRI before surgical diagnosis. Median MRI follow-up was 16 months (range: 2-33). Thirty percent of lesions (n=10) were determined to be radiation injury; 70% (n=23) were determined to be tumor progression. For the MRS, Cho/nCho had the best performance (AUC of 0.612), and Cho/nCho >1.2 had 33% sensitivity and 100% specificity in predicting tumor progression. For the MRP, rCBV had the best performance (AUC of 0.802), and rCBV >2 had 56% sensitivity and 100% specificity. The best volume model was percent increase (AUC of 0.891); 65% tumor volume increase had 100% sensitivity and 80% specificity. Cho/nCho of MRS, rCBV of MRP, and percent increase of MRI volume modeling provide the best discrimination of intra-axial metastatic tumor progression from radiation injury for their respective modalities. Cho/nCho and rCBV appear to have high specificities but low sensitivities. In contrast, percent volume increase of 65% can be a highly sensitive and moderately specific predictor for tumor progression after radiotherapy. Future incorporation of 65% volume increase as a pretest selection criterion may compensate for the low sensitivities of MRS and MRP.	f	\N
21572511	The epidemiology of Chagas disease, until recently confined to areas of continental Latin America, has undergone considerable changes in recent decades due to migration to other parts of the world, including Spain. We studied the prevalence of Chagas disease in Latin American patients treated at a health center in Barcelona and evaluated its clinical phase. We make some recommendations for screening for the disease. We performed an observational, cross-sectional prevalence study by means of an immunochromatographic test screening of all continental Latin American patients over the age of 14 years visiting the health centre from October 2007 to October 2009. The diagnosis was confirmed by serological methods: conventional in-house ELISA (cELISA), a commercial kit (rELISA) and ELISA using T cruzi lysate (Ortho-Clinical Diagnostics) (oELISA). Of 766 patients studied, 22 were diagnosed with T. cruzi infection, showing a prevalence of 2.87% (95% CI, 1.6-4.12%). Of the infected patients, 45.45% men and 54.55% women, 21 were from Bolivia, showing a prevalence in the Bolivian subgroup (n=127) of 16.53% (95% CI, 9.6-23.39%). ALL THE INFECTED PATIENTS WERE IN A CHRONIC PHASE OF CHAGAS DISEASE: 81% with the indeterminate form, 9.5% with the cardiac form and 9.5% with the cardiodigestive form. All patients infected with T. cruzi had heard of Chagas disease in their country of origin, 82% knew someone affected, and 77% had a significant history of living in adobe houses in rural areas. We found a high prevalence of T. cruzi infection in immigrants from Bolivia. Detection of T. cruzi-infected persons by screening programs in non-endemic countries would control non-vectorial transmission and would benefit the persons affected, public health and national health systems.	f	\N
21575881	Mesalazine remains the first line treatment for the induction and the maintenance of remission in mild to moderate ulcerative colitis (UC). Its efficacy as a maintenance treatment after a first flare treated with corticosteroids has not been specifically studied. The aims of our work were to study a cohort of UC patients treated with mesalazine after a course of oral systemic corticosteroids and to identify predictive factors of relapse and of colectomy. We studied retrospectively a cohort of 143 UC patients, who never received immunosuppressive drugs, and treated for the first time with oral corticosteroids for a flare. Among patients responding to corticosteroids, we studied the group treated by mesalazine after the flare. Fifty% (n=52) achieved a complete clinical remission with steroid weaning. In this group, 67% (n=35) received oral mesalazine. Seventy-five % of patients treated by mesalazine relapsed (median 29 months, range: 1-156). Fourteen % required a colectomy (median 11 months, range: 1-24). Kaplan Meier curve showed a relapse rate and a colectomy rate over one year of 26% and 11% respectively. In multivariate analysis, male gender and short duration of disease were predictive factors of the time-to-relapse. No factor was predictive of time-to-colectomy. Maintenance efficacy of mesalazine over one year after a first course of corticosteroids for a disease flare is reasonably high. The longer-term relapse rate becomes higher in male patients with a short disease duration. An immunosuppressive treatment could be discussed in case of further relapse despite improved medication-adherence. Medication-adherence should first be assessed and promoted. An immunosuppressive treatment could be discussed in case of further relapse despite improved medication-adherence.	f	\N
21576904	Mutations in IRAK4 have been associated with recurrent Gram-positive infections in children. Given the central role of IRAK4 in innate immunity signaling, we hypothesized that common genetic variants of IRAK4 may be associated with prevalence of Gram-positive infection in critically ill adults. Haplotype clade tag single nucleotide polymorphisms (SNPs) of the IRAK4 gene were selected and genotyped in a cohort of 1,029 critically ill patients with systemic inflammatory response syndrome (SIRS). We found that a haplotype clade tagged by the A allele of the htSNP G29429A (Ala428Thr) was associated with increased relative risk of Gram-positive infection at admission to ICU (RR = 1.2, p < 0.05). Furthermore, the 29429A allele was associated with decreased lymphoblastoid cell response to CpG (as measured by IL-6 production) (raw values ± 95% CI 40.3 ± 32.3 vs. 85.8 ± 29.4 pg/ml; log-transformed values ± 95% CI 1.13 ± 0.37 vs. 1.55 ± 0.18, p < 0.04). We also found that IRAK4-deficient fibroblasts transfected with an IRAK4 expression plasmid containing the 29429A allele produced less IL-6 in response to lipopolysaccharide (p = 0.07). Our data suggest that the IRAK4 haplotype clade marked by 29429A (428Thr) alters susceptibility to Gram-positive bacteria, by decreasing cellular response to TLR ligands.	f	\N
21585286	β-site APP-cleaving enzyme (BACE1) cleaves the wild type (WT) β-site very slowly (k(cat)/K(m): 46.6 m(-1) s(-1)). Therefore we searched for additional β-secretases and identified three cathepsins that split the WT β-site much faster. Human cathepsin S cleaves the WT β-site (k(cat)/K(m): 54 700 m(-1) s(-1)) 1170-fold faster than BACE1 and cathepsins B and L are 440- and 74-fold faster than BACE1, respectively. These cathepsins split two bonds flanking the WT β-site (K-MD-A), where the K-M bond (85%) is cleaved more efficiently than the D-A bond (15%). Cleavage at the major K-M bond yields Aβ (amyloid β-peptide) extended by N-terminal Met that should be removed to generate Aβ initiated by Asp1. The activity of cytosol and microsomal aminopeptidases on relevant peptides revealed rapid removal of N-terminal Met but not N-terminal Asp. Brain aminopeptidases showed similar specificity. Thus, aminopeptidases would convert Aβ extended by Met into regular Aβ (Asp1) found in amyloid plaques. Earlier studies indicate that Aβ is likely produced in the endosome and lysosome system where cathepsins S, B and L are localized and cysteine cathepsin inhibitors reduce the level of Aβ in cells and animals. Taken together, cathepsins S, B and L deserve further evaluation as therapeutic targets to develop disease modifying drugs to treat Alzheimer's disease.	f	\N
21596857	Femoral and lumbar bone mineral densities (BMDs) were measured in 159 adults enrolled in the Leucémies de l'Enfant et de l'Adolescent program, a French prospective multicentric cohort of childhood leukemia survivors. BMDs were expressed as Z-scores, and multivariate linear regression analyses were used to construct association models with potential risk factors. Mean age at evaluation and follow-up was 23 and 14.7 years, respectively. In the whole cohort, mean femoral Z-score was -0.19 ± 0.08. Two factors were associated with lower femoral BMD transplantation (-0.49 ± 0.15 vs -0.04 ± 0.10 in the chemotherapy group; P = .006) and female sex (-0.34 ± 0.10 vs -0.03 ± 0.13; P = .03). Among patients who received a transplant, the only significant risk factor was hypogonadism (-0.88 ± 0.16 vs -0.10 ± 0.23; P = .04). A slight reduction in lumbar BMD (mean Z-score, -0.37 ± 0.08) was detected in the whole cohort without difference between the transplantation and chemotherapy groups. Among patients who received a transplant, younger age at transplantation was correlated with a low lumbar BMD (P = .03). We conclude that adults who had received only chemotherapy for childhood leukemia have a slight reduction in their lumbar BMD and a normal femoral BMD. Patients who received a transplant with gonadal deficiency have a reduced femoral BMD which might increase the fracture risk later in life.	f	\N
21601991	Cardiovascular disease (CVD) is a major cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE). Due to either infection or disease activity, elevated levels of inflammatory markers and up-regulation of the autoimmune process can contribute to the development of atherosclerosis in SLE patients. Periodontal diseases are among the most prevalent chronic infections in humans and are characterized by pathogen-induced oral inflammatory disease affecting the supporting tissues of teeth. Several cytokines capable of inducing systemic effects are produced during the course of this infection. The presence of these cytokines can be verified by changes in the levels of C-reactive protein (CRP). Periodontal disease is a well-known risk factor for atherosclerosis. The potential for beneficial prevention of CVD events through the use of periodontal treatment has been previously recommended. This review reinforces the hypothesis that periodontal infection could be a risk factor for CVD in patients diagnosed with SLE, and suggests that by reducing the progression of this oral infection, levels of inflammatory markers common to both diseases (SLE and periodontal disease) would likely decrease.	f	\N
21603646	Miniature pigs are useful model animals for humans because they have similar anatomy and digestive physiology to humans and are easy to breed and handle. In this study, whole blood microarray analyses were conducted to evaluate variations of correlation among individuals and ages using specific pathogen-free (SPF) Clawn miniature pigs. Whole blood RNA is easy to handle compared to isolated white blood cell RNA and can be used for health and disease monitoring and animal control. In addition, whole blood is a heterogeneous mixture of subpopulation cells. Once a great change occurs in composition and expressing condition of subpopulations, their associated change will be reflected on whole blood RNA. From 12 to 30 weeks of age, fractions of lymphocytes, monocytes, neutrophils, eosinophils, and basophils in white blood cells showed insignificant differences with age as a result of ANOVA analysis. This study attempted to identify characteristics of age-related gene expression by taking into account the change in the number of expressed genes by age and similarities of gene expression intensity between individuals. As a result, the number of expressed genes was less in fetal stage and infancy period but increased with age, reaching a steady state of gene expression after 20 weeks of age. Variation in gene expression intensity within the same age was great in fetal stage and infancy period, but converged with age. The variation between 20 and 30 weeks of age was comparable to that among 30 weeks individuals. These results indicate that uniformity of laboratory animals is expected for miniature pigs after 20 weeks of age. Furthermore, a possibility was shown that whole blood RNA analysis is applicable to evaluation of physiological state.	f	\N
21607722	It has been only 5 years since the identification of TDP-43 as the major protein component of the ubiquitinated inclusions in FTLD-U. At that time, there were approximately a dozen papers about TDP-43; today, a "TDP-43" search reveals almost 600 papers. It is now clear that the majority of FTLD cases containing tau- and alpha-synuclein-negative, ubiquitin-positive inclusions (FTLD-U) are FTLD-TDP. The spectrum of TDP-43 proteinopathies includes FTLD-TDP with or without ALS, with or without mutations in GRN, VCP, or TARDBP, with or without chromosome 9p linkage, and sporadic and non-SOD1 familial ALS with or without FTLD-TDP. There are four sub-types of FTLD-TDP, and these correlate with specific clinical and genetic profiles. Sub-types are determined by the presence, predominance, and distribution of the various TDP-43 immunopositive insoluble aggregates-neuronal cytoplasmic inclusions, neuronal intranuclear inclusions, and dystrophic neurites. In this paper, FTLD-TDP pathologic sub-types will be described, and examples of each sub-type will be shown, and implications for future research will be discussed.	f	\N
21609376	Differentiating between benign and malignant causes of obstructive jaundice can be challenging, even with the advanced imaging and endoscopic techniques currently available. In patients with obstructive jaundice, the predictive accuracy of bilirubin levels at presentation was examined in order to determine whether such data could be used to differentiate between malignant and benign disease. A total of 1,026 patients with obstructive jaundice were identified. Patients were divided into benign and malignant groups. The benign patients were subgrouped into those with choledocholithiasis and those with inflammatory strictures of the biliary tree. Bilirubin levels at presentation and other demographic data were obtained from case records. Area under the curve (AUC) values for bilirubin as a predictor of malignancy were highly significant for all benign presentations and for those with benign biliary strictures (AUC: 0.8 for both groups; P < 0.001). A bilirubin level > 100 µmol/l was determined to provide the optimum sensitivity and specificity for malignancy in all patients and in those without choledocholithiasis (71.9% and 86.9%, 71.9% and 88.0%, respectively). The application of a bilirubin level > 250 µmol/l achieved specificities of 97.1% and 98.0% in each subgroup of patients, respectively. In patients with obstructive jaundice, bilirubin levels in isolation represent an important tool for discriminating between benign and malignant underlying causes.	f	\N
21621489	The aim of this study is to develop a standardized LC-MS/MS method for accurate measurement of desmosine (DES) and isodesmosine (IDS) in all body fluids as biomarkers for in vivo degradation of matrix tissue elastin in man and animals. A reproducible three-step analytical procedure: (1) sample hydrolysis in 6N HCl, (2) SPE by a CF1 cartridge with addition of acetylated pyridinoline as internal standard (IS), and (3) LC/MSMS analysis by SRM monitoring of transition ions; DES or IDS (m/z 526-481+397) and IS (m/z 471-128) was developed. The method achieves accurate measurements of DES/IDS in accessible body fluids (i.e. urine, plasma, and sputum). LOQ of DES/IDS in body fluids is 0.1 ng/ml. The % recoveries and reproducibility from urine, plasma, and sputum samples are above 99 ± 8% (n = 3), 94 ± 9% (n = 3) and 87 ± 11% (n = 3), with imprecision 8%, 9% and 10%, respectively. The proposed method was applied to measure DES/IDS in body fluids of patients with chronic obstructive pulmonary disease (COPD) and healthy controls. Total DES/IDS in sputum and plasma is increased over normal controls along with the free DES/IDS in urine in patients. DES/IDS can be used to study the course of COPD and the response to therapy. This practical and reliable LC-MS/MS method is proposed as a standardized method to measure DES and IDS in body fluids. This method can have wide application for investigating diseases which involve elastic tissue degradation.	f	\N
21626540	The Movement Disorder Society (MDS) developed out of a merger with two short-lived organizations, the Movement Disorder Society, primarily organized to develop a journal for the subspecialty, and the International Society of Motor Disturbances, primarily organized to develop international congresses. The formal merger of the Movement Disorder Society and the International Society of Motor Disturbances into the Movement Disorder Society took place at the 2nd International Congress of Movement Disorders in Munich, Germany, in June 1992. Whereas the journal, Movement Disorders, and the annual International Congress of Parkinson's Disease and Movement Disorders remain the anchors of the society, the goals now include the development of regional symposia, regional sections, Web-based educational programs, and outreach efforts to include young investigators, wide international membership, and inclusion of non-neurologists, including basic scientists, neurosurgeons, and nonphysician health professionals. Movement Disorders has a continuingly growing subscribership and rising impact factor.	f	\N
21630606	Renal biopsy is the definitive diagnostic test in patients with renal parenchymal disease. Renal biopsy registry is an important tool which can provide valuable data concerning early and correct epidemiological description and clinical correlations of renal diseases. Records of 326 adult renal biopsies performed at our hospital from January 1991 till the end of December 2006 were retrospectively examined. Overall, secondary glomerular diseases (SGD) were predominant (39.9%), followed by primary glomerular diseases (PGD) (30.4%), vascular diseases (13.2%) and TIN (6.7%). Total sclerosis of the kidney did not allow histopathological diagnosis in 5.8% of all biopsied kidneys. Focal and Segmental Glomerular Sclerosis (FSGS), IgA Nephropathy (IgAGN) and Minimal Change Disease (MCD) and Membranous Glomerulopathy (MGN) were the most common PGD, altogether representing 75.7% of all PGD. FSGS was the most frequent (30.3%), followed by IgAGN (21.2%), MCD (19.1%) and MGN in 15.1%. Vasculitis, HIVAN, diabetic nephropathy and amyloidosis were the most common SGD, altogether representing 90% of all SGD. Immune Mediated Glomerulonephritis (IMGN) were the most frequent (32.3%), followed by HIVAN (16.9%), diabetic nephropathy (14.6%) and amyloidosis (10%). Nephroangiosclerosis (benign and malignant nephroangiosclerosis) was the most frequent vascular nephropathy responsible for 79% of all vascular diseases. Thrombotic microangiopathy was seen in 9.3% and atherothrombotic disease in 7% of all vascular diseases. Concerning tubular diseases, chronic TIN accounted for 63.6% of all tubular diseases, followed by light chain-cast nephropathy (22.7%) and acute TIN (13.6%). Because of lack of material, 3.4% of all biopsies could not be analyzed. These data demonstrate that the distribution of biopsy-proved renal diseases in a Belgian population of the Brussels area is strongly influenced by the indications of renal biopsy. Harmonization of these indications might reflect with more accuracy the actual incidence of different nephropathies in a given population. Nation and worldwide renal biopsy registers are important to follow patterns of renal diseases in different populations. This information is important not only for health organizations in order to plan health budget but also for helping clinicians to provide a better care to patients.	f	\N
21641369	Although very late stent thrombosis occurs several years after implantation of sirolimus-eluting stent (SES), the morphologic changes of the stent beyond 2 years have not yet been systematically studied in living patients. The late vascular response to SES was therefore evaluated by serial angioscopic studies at 2 and 5 years after stent implantation. A total of 17 patients with 17 SES underwent a repeated angioscopy procedure at 2 and 5 years. Neointimal stent coverage (NSC) was classified as follows: grade 0, presence of uncovered struts; grade 1, visible struts through a thin neointima; or grade 2, complete neointimal coverage without visible struts. For each patient, the minimum and maximum NSC grade and the existence of in-stent thrombus were recorded. The minimum and maximum NSC grade did not increase between the 2 and 5 years (0.59 ± 0.51 vs 0.88 ± 0.70, P = .17, and 1.82 ± 0.39 vs 1.94 ± 0.24, P = .30, respectively). The prevalence of patients with uncovered struts did not significantly decrease from 2 to 5 years (41% vs 29%, P = .49). During the follow-up period, 3 of 6 thrombi disappeared, whereas new thrombus formation was found in 3 patients without any clinical symptoms. In-stent thrombus did not decrease (35% vs 35%, P > .99). The current serial angioscopic study suggests that incomplete NSC and the prevalence of latent thrombus within the SES segments did not decrease from 2 to 5 years. The risk of stent thrombosis related to incomplete healing of SES may continue for an extended period.	f	\N
21645024	Retinol-binding protein 4 (RBP4), produced by adipocytes and hepatocytes, contributes to an unfavourable lipid profile and insulin resistance, which can contribute to the development of coronary artery disease (CAD). Recently, several studies have shown that epicardial adipose tissue (EAT) differs from subcutaneous adipose tissue (SAT) and plays a role on the physiopathology of CAD because of its proximity to the coronary arteries. We aimed to study the expression and secretion levels of RBP4 in both fat tissues and explore its possible association with CAD. Fifty-eight patients undergoing heart surgery were included in the study. We analysed RBP4 mRNA expression by real-time PCR, protein expression by Western blot and immunohistochemistry, and secretion of EAT and SAT explants from CAD and non-CAD patients by Enzyme Immunoassay. Retinol-binding protein 4 is expressed at similar levels in EAT and SAT, mainly from adipocytes. Protein levels were higher in EAT from CAD than non-CAD patients (0·63 ± 0·09 arbitrary units (a.u).; n = 10) vs (0·41 ± 0·04 a.u.; n = 13, P = 0·039). In contrast, GLUT4 mRNA levels were lower in EAT from CAD than non-CAD patients (6·55 ± 0·16 a.u.; n = 13) vs (7·21 ± 0·18 a.u.; n = 14, P = 0·012). We also found differential expression in SAT between samples from CAD and non-CAD patients [(6·63 ± 0·16 a.u.; n = 14) vs (7·21 ± 0·14 a.u.; n = 14, P = 0·009)]. Besides, EAT releases higher RBP4 levels than SAT after 3, 6, 24 and 48 h of culture. These levels were independent of CAD but significantly higher in diabetic than nondiabetic patients. Retinol-binding protein 4 levels behave differently in EAT and SAT with respect to CAD. However, both adipose tissues have lower GLUT4 levels in patients with CAD. These findings suggest a differential regulation of RBP4 production in EAT and SAT that may be influenced by local factors.	f	\N
21647871	In this phase 1 trial, the authors evaluated sunitinib combined with radiation therapy (RT) for the treatment of primary or metastatic central nervous system (CNS) malignancies. Eligible patients had CNS malignancies that required a (minimum) 2-week course of RT. Sunitinib (37.5 mg) was administered daily for the duration of RT with optional treatment extension of 1 month. Urine was collected at 3 time points for correlative biomarker studies. The primary endpoint was acute toxicity defined according to Common Toxicity Criteria version 3. Fifteen patients were enrolled (12 with CNS metastasis and 3 with primary tumors). RT doses ranged from 14 Gray (Gy) to 70 Gy (1.8-3.5 Gy per fraction). Acute toxicities included hematologic, nausea, hyperglycemia, fatigue, hypocalcemia, and diarrhea. Six patients (40%) developed grade ≤ 2 toxicities. Grade 3 toxicities occurred in 7 patients (47%) and included hematologic toxicity, fatigue, deep vein thrombosis, dysphasia, hyperglycemia, and hyponatremia. No grade 3 through 5 hypertensive events or intracerebral hemorrhages occurred. Two grade 5 adverse events attributed to disease progression occurred. The median follow-up was 34.2 months. Two patients (13%) achieved a partial response, 9 patients (60%) had stable disease, and 2 patients (13%) patients had progressive disease. The 6-month progression-free survival rate for patients who had brain metastasis was 58%. Grade 3 hematologic toxicity was correlated with greater changes in vascular endothelial growth factor levels changes between baseline and the completion of RT. Continuous 37.5-mg sunitinib combined with RT in patients who had CNS malignancies yielded acceptable toxicities and adverse events. The current results indicated that changes in urine vascular endothelial growth factor levels are associated with hematologic toxicity, and this association should be analyzed in a larger cohort. The feasibility, safety, and early response results warrant a phase 2 trial.	f	\N
21653298	US estimates of the Clostridium difficile infection (CDI) burden have utilized International Classification of Disease, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis codes. Whether ICD-9-CM code rank order affects CDI prevalence estimates is important because the National Hospital Discharge Survey (NHDS) and the Nationwide Inpatient Sample (NIS) have varying limits on the number of ICD-9-CM codes collected. ICD-9-CM codes for CDI (008.45), C. difficile toxin assay results, and dates of admission and discharge were collected from electronic hospital databases for adult patients admitted to 4 hospitals in the United States from July 2000 through June 2006. CDI prevalence per 1000 discharges was calculated and compared for NHDS and NIS limits and toxin assay results from the same hospitals. CDI prevalence estimates were compared using the χ(2) test, and the test of equality was used to compare slopes. CDI prevalence measured by NIS criteria was significantly higher than that measured using NHDS criteria (10.7 cases per 1000 discharges versus 9.4 cases per 1000 discharges; P<.001) in the 4 hospitals. CDI prevalence measured by toxin assay results was 9.4 cases per 1000 discharges (P=.57 versus NHDS). However, the CDI prevalence increased more rapidly over time when measured according to the NHDS criteria than when measured according to toxin assay results (β=1.09 versus 0.84; P=.008). Compared with the NHDS definition, the NIS definition captured 12% more CDI cases and reported significantly higher CDI rates. Rates calculated using toxin assay results were not different from rates calculated using NHDS criteria, but CDI prevalence appeared to increase more rapidly when measured by NHDS criteria than when measured by toxin assay results.	f	\N
21659502	Despite high vaccination coverage rates, there has been a gradual increase in reported pertussis cases. Although whooping cough affects all ages, young infants continue to suffer the greatest pertussis disease burden. Adolescents and adults are the primary source of infection for young babies. In this paper, we report two cases involving the likely transmission of pertussis from mothers to infants in Tunisia.	f	\N
21665106	Radiating leg pain is a common symptom presenting in manual therapy practices. Although this symptom has been reported as a complication of endometriosis, its prevalence and characteristics have not been studied. We surveyed members of a national endometriosis support group with endometriosis using a self-administered, mailed questionnaire. The main outcome measures were the prevalence and characteristics of leg pain. Of 94 respondents, leg pain was reported by 48 women (51%), and was bilateral in 59% of these symptomatic women. The likelihood of experiencing leg pain was related to weight gain since age 18, age, and height. The most common treatments tried included exercise, over-the-counter medications, and massage therapy, all with variable results. These data support leg pain as a prevalent complication of endometriosis, and that the disease may affect multiple peripheral nerves. Manual therapists should remain aware to this possible etiology for radiating pain.	f	\N
21674011	Intestinal luminal microbiota likely contribute to the etiology of necrotizing enterocolitis (NEC), a common disease in preterm infants. Microbiota development, a cascade of initial colonization events leading to the establishment of a diverse commensal microbiota, can now be studied in preterm infants using powerful molecular tools. Starting with the first stool and continuing until discharge, weekly stool specimens were collected prospectively from infants with gestational ages ≤32 completed weeks or birth weights≤1250 g. High throughput 16S rRNA sequencing was used to compare the diversity of microbiota and the prevalence of specific bacterial signatures in nine NEC infants and in nine matched controls. After removal of short and low quality reads we retained a total of 110,021 sequences. Microbiota composition differed in the matched samples collected 1 week but not <72 hours prior to NEC diagnosis. We detected a bloom (34% increase) of Proteobacteria and a decrease (32%) in Firmicutes in NEC cases between the 1 week and <72 hour samples. No significant change was identified in the controls. At both time points, molecular signatures were identified that were increased in NEC cases. One of the bacterial signatures detected more frequently in NEC cases (p<0.01) matched closest to γ-Proteobacteria. Although this sequence grouped to the well-studied Enterobacteriaceae family, it did not match any sequence in Genbank by more than 97%. Our observations suggest that abnormal patterns of microbiota and potentially a novel pathogen contribute to the etiology of NEC.	f	\N
21674889	Awareness of the clinical importance of second-line chemotherapy for incurable gastric cancer has been increasing. To assess the clinical validity of the new concept that second-line chemotherapy following predetermined cycles of first-line chemotherapy would improve survival, we conducted a phase II study. Patients with pathologically proven incurable gastric adenocarcinoma and adequate organ functions were enrolled. S-1 or S-1 plus cisplatin was administered as first-line chemotherapy. The number of cycles of S-1-based chemotherapy was determined to be three as a maximum unless there was disease progression. The treatment was followed by weekly administration of paclitaxel. The primary endpoint was overall survival and the secondary endpoints were progression-free survival and safety. Thirty-seven patients were eligible for enrollment. Twenty-eight patients (76%) underwent the second-line chemotherapy with paclitaxel after completion of S-1-based chemotherapy or disease progression. Treatment-related grade 3 or 4 toxicity was noted in 14 patients during S-1-based chemotherapy, and in 6 patients during paclitaxel treatment. The median survival time was 455 days and the median progression-free survival was 229 days. Sequential set chemotherapy with three cycles of S-1-based chemotherapy followed by weekly paclitaxel is feasible. The survival results are equivalent to those of other current regimens using S-1.	f	\N
21681643	Long-term central venous catheter (CVC) implantation has become more affordable in Taiwan since 1995. Surgical removal of the catheter may be the essential treatment for catheter-related bloodstream infections (CRBSI). The aim of this study was to evaluate the clinical features and microbial isolates in pediatric cancer patients with removal of CVC for CRBSI. The records of positive blood culture from hospitalized pediatric oncology patients between 1995 and 2004 were reviewed. One hundred and forty-three patients implanted with a long-term CVC were further identified. Seventeen catheters in 16 patients developed catheter-related bacteremia that needed catheter removal. The rate of catheter removal was 11.9%. The median device life was 7.7 months. Six catheters were removed within 3 months of insertion. Nine of the 17 catheters were removed from patient younger than 2 years. Eight infections occurred during severe neutropenia, and 6 patients had refractory or relapsed underlying disease. The cultural isolates were Gram-negative bacilli in 7, Gram-positive in 5, fungi in 5, and atypical mycobacterium in 1. The frequency of catheter removal for infection control was significantly higher in the first 5 years (1994-1999) compared to the last 5 years (2000-2004) (30.9 vs. 4.0%, p = 2.3 × 10(-4)). Factors such as microbiological isolates, age of infection, the status of malignancy, and neutropenia are related to catheter outcome. The reduction in patients with positive cultures needing removal of the catheters can be related to improved nursing care and more aggressive antibiotic therapy.	f	\N
21685330	Lymphatic metastasis constitutes a critical route of disease dissemination, which limits the prognosis of patients with pancreatic ductal adenocarcinoma (PDAC). As lymphangiogenesis has been implicated in stimulation of lymphatic metastasis by vascular endothelial growth factor-C (VEGF-C) and VEGF-D, we studied the effect of the angioregulatory growth factor angiopoietin-2 (Ang-2) on PDAC progression. Ang-2 was found to be expressed in transformed cells of human PDAC specimens, with corresponding Tie-2 receptors present on blood and lymphatic endothelium. In vitro in PDAC cells, Ang-2 was subject to autocrine/paracrine TGF-β stimulation (2-fold induction, P=0.0106) acting on the -61- to +476-bp element of the human Ang-2 promoter. In turn, Ang-2 regulated the expression of genes involved in cell motility and tumor suppression. Orthotopic PDAC xenografts with forced expression of Ang-2, but not Ang-1, displayed increased blood and lymphatic vessel density, and an enhanced rate of lymphatic metastasis (6.7- to 9.1-fold, P<0.01), which was prevented by sequestration of Ang-2 via coexpression of soluble Tie-2. Notably, elevated circulating Ang-2 in patients with PDAC correlated with the extent of lymphatic metastasis. Furthermore, median survival was reduced from 28.4 to 7.7 mo in patients with circulating Ang-2 ≥ 75th percentile (P=0.0005). These findings indicate that Ang-2 participates in the control of lymphatic metastasis, constitutes a noninvasive prognostic biomarker, and may provide an accessible therapeutic target in PDAC.	f	\N
21689845	To describe the number of urethral dilations, urethrotomies, and urethroplasties performed on men with a diagnosis of urethral stricture disease seeking care in the Veterans Affairs (VA) health care system in southern California and southern Nevada over a 5-year period. To date, few health services research studies have evaluated patterns of care for urethral stricture disease using national datasets. We analyzed stricture treatment for male veterans with an ICD-9 diagnosis code for urethral stricture in the National Patient Care Database (NPCD). Encounters for urethral stricture procedures performed were identified based on the presence of Physicians Current Procedural Terminology Coding System (4th edition, CPT-4) codes for treatments performed during the fiscal years 2002-2006. A total of 1457 men carried a diagnosis of urethral stricture disease during the index time period. Of these, 333 men (23%) underwent 431 procedures. Of the 216 men who underwent urethral dilations, 170 (79%) underwent only 1 procedure and 26 (12%) underwent 2 procedures. Of the 79 men who underwent urethrotomy, 76 (96%) underwent 1 procedure. Sixteen men (5%) underwent a urethroplasty, 8 of whom underwent a perineal urethrostomy. The vast majority of men treated for stricture disease underwent only 1 such procedure over a 5-year time period. Further research is required to investigate whether this is a quality-of-care issue or patients refusing intervention. It is possible that some patients may be temporized for a significant period with dilation/urethrotomy, whereas those with rapid recurrence require early urethroplasty.	f	\N
21690452	Laparoscopy is increasingly used in colon and rectal procedures. However, little is known regarding the incidence of venous thromboembolism (VTE) in laparoscopic colorectal (LC) compared with that in open colorectal (OC) procedures. We aimed to compare the incidences and to highlight the risk factors of developing VTE after LC and OC surgery. Analysis of the Nationwide Inpatient Sample data from 2002 through 2006. National database. Patients who underwent elective LC and OC surgery from 2002 through 2006. Incidence of VTE during initial hospitalization after LC and OC surgery; VTE classified by surgical site, pathology type, and at-risk patient population. Over a 60-month period, 149,304 patients underwent LC or OC resection. Overall, the incidence of VTE was significantly higher in OC cases (2036 of 141,456 [1.44%]) compared with the incidence in LC cases (65 of 7848 [0.83%]) (P < .001). When stratified according to pathologic condition and surgical site, the overall rate of VTE was highest in patients with inflammatory bowel disease and in those undergoing rectal resections. Patients who underwent OC surgery were almost twice as likely to develop VTE compared with patients who underwent LC surgery. We also identified malignancy, obesity, and congestive heart failure as statistically significant (P < .05) risk factors for VTE in OC and LC surgery. On the basis of data from a large clinical data set, the incidence of perioperative VTE is lower after LC than after OC surgery. These findings may help colorectal surgeons use appropriate VTE prophylaxis for patients undergoing colorectal procedures.	f	\N
21699733	Itch sensation is one of the major sensory experiences of human and animals. Recent studies have proposed that gastrin releasing peptide (GRP) is a key neurotransmitter for itch in spinal cord. However, no direct evidence is available to indicate that GRP actually mediate responses between primary afferent fibers and dorsal horn neurons. Here we performed integrative neurobiological experiments to test this question. We found that a small population of rat dorsal horn neurons responded to GRP application with increases in calcium signaling. Whole-cell patch-clamp recordings revealed that a part of superficial dorsal horn neurons responded to GRP application with the increase of action potential firing in adult rats and mice, and these dorsal horn neurons received exclusively primary afferent C-fiber inputs. On the other hands, few A(δ) inputs receiving cells were found to be GRP positive. Finally, we found that evoked sensory responses between primary afferent C fibers and GRP positive superficial dorsal horn neurons are mediated by glutamate but not GRP. CNQX, a blocker of AMPA and kainate (KA) receptors, completely inhibited evoked EPSCs, including in those Fos-GFP positive dorsal horn cells activated by itching. Our findings provide the direct evidence that glutamate is the principal excitatory transmitter between C fibers and GRP positive dorsal horn neurons. Our results will help to understand the neuronal mechanism of itch and aid future treatment for patients with pruritic disease.	f	\N
21699956	The NMDA glutamate hypofunction model of schizophrenia is based in part upon acute effects of NMDA receptor blockade in humans and rodents. Several laboratories have reported glutamate system abnormalities following prenatal exposure to immune challenge, a known environmental risk factor for schizophrenia. Here we report indices of NMDA glutamate receptor hypofunction following prenatal immune activation, as well as the effects of treatment during periadolescence with the atypical antipsychotic medications risperidone and paliperidone. Pregnant Sprague-Dawley rats were injected with polyinosinic:polycytidylic acid (poly I:C) or saline on gestational day 14. Male offspring were treated orally via drinking water with vehicle, risperidone (0.01mg/kg/day), or paliperidone (0.01mg/kg/day) between postnatal days 35 and 56 (periadolescence) and extracellular glutamate levels in the prefrontal cortex were determined by microdialysis at PD 56. Consistent with decreased NMDA receptor function, MK-801-induced increases in extracellular glutamate concentration were markedly blunted following prenatal immune activation. Further suggesting NMDA receptor hypofunction, prefrontal cortex basal extracellular glutamate was significantly elevated (p<0.05) in offspring of poly I:C treated dams. Pretreatment with low dose paliperidone or risperidone (0.01mg/kg/day postnatal days 35-56) normalized prefrontal cortical basal extracellular glutamate (p<0.05 vs. poly I:C vehicle-treatment). Pretreatment with paliperidone and risperidone also prevented the acute MK-801-induced increase in extracellular glutamate. These observations demonstrate decreased NMDA receptor function and elevated extracellular glutamate, two key features of the NMDA glutamate receptor hypofunction model of schizophrenia, during periadolescence following prenatal immune activation. Treatment with the atypical antipsychotic medications paliperidone and risperidone normalized basal extracellular glutamate. Demonstration of glutamatergic abnormalities consistent with the NMDA glutamate receptor hypofunction model of schizophrenia as an early developmental consequence of prenatal immune action provides a model to identify novel early interventions targeting glutamatergic systems which play an important role in both positive and negative symptoms of schizophrenia.	f	\N
21700931	Caloric restriction (CR) confers cardioprotection against ischemia/reperfusion injury. However, the exact mechanism(s) underlying CR-induced cardioprotection remain(s) unknown. Recent evidence indicates that Sirtuins, NAD(+)-dependent deacetylases, regulate various favorable aspects of the CR response. Thus, we hypothesized that deacetylation of specific mitochondrial proteins during CR preserves mitochondrial function and attenuates production of reactive oxygen species during ischemia/reperfusion. The objectives of the present study were (1) to investigate the effect of CR on mitochondrial function and mitochondrial proteome and (2) to investigate what molecular mechanisms mediate CR-induced cardioprotection. Male 26-week-old Fischer344 rats were randomly divided into ad libitum-fed and CR (40% reduction) groups for 6 months. No change was observed in basal mitochondrial function, but CR preserved postischemic mitochondrial respiration and attenuated postischemic mitochondrial H(2)O(2) production. CR decreased the level of acetylated mitochondrial proteins that were associated with enhanced Sirtuin activity in the mitochondrial fraction. We confirmed a significant decrease in the acetylated forms of NDUFS1 and cytochrome bc1 complex Rieske subunit in the CR heart. Low-dose resveratrol treatment mimicked the effect of CR on deacetylating them and attenuated reactive oxygen species production during anoxia/reoxygenation in cultured cardiomyocytes without changing the expression levels of manganese superoxide dismutase. Treatment with nicotinamide completely abrogated the effect of low-dose resveratrol. These results strongly suggest that CR primes mitochondria for stress resistance by deacetylating specific mitochondrial proteins of the electron transport chain. Targeted deacetylation of NDUFS1 and/or Rieske subunit might have potential as a novel therapeutic approach for cardioprotection against ischemia/reperfusion.	f	\N
21703749	Few studies have focused on the full complement of cardiac arrest cases seen in hospital emergency departments (ED). The aims of our study were to describe cardiac arrest visits in the ED by using a nationally representative sample of U.S. adults. ED data from the 2001-2007 National Hospital Ambulatory Medical Care Survey (NHAMCS) were analyzed. Cardiac arrest visits were considered to be those with an International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code of 427.5 as the primary diagnosis. From 2001 to 2007, adults in the U.S. made an estimated 600,729,000 ED visits. Of those, 1,001,000 (0.17%) had a primary diagnosis of cardiac arrest. The majority of patients with such visits were dead on arrival or died in the ED (74.0%). The mean age for cardiac arrest visits was 66.7 years (95% confidence interval [CI], 64.6-68.8 years). Women had a lower rate of cardiac arrest visits than men (age-adjusted odds ratio [AOR], 0.6; 95% CI, 0.5-0.8), and the privately insured (AOR, 0.4; 95% CI, 0.2-0.7) and those with government insurance (AOR, 0.5; 95% CI, 0.3-0.9) had a lower proportion of cardiac arrest ED visits than uninsured persons. In addition, increasing age was a significant predictor of cardiac arrest visits. Cardiac arrest visits did not vary significantly by race, geographic region, or metropolitan statistical area. ED visits classified as cardiac arrest represent 1 in 600 visits and these visits differ by age, sex, payment source, and arrival time at the ED.	f	\N
21704888	The safety of long-acting β2 agonists (LABA) for the treatment of persistent asthma remains a topic of ongoing debate. To evaluate the risk of serious asthma-related events among patients treated with formoterol, a meta-analysis of all Novartis-sponsored controlled clinical trials was conducted. Forty-five randomized, placebo- and active-controlled, parallel-group or crossover studies with formoterol were included. Background inhaled corticosteroid (ICS) use was permitted in all studies; however, in only 2 studies was ICS randomized as study medication. Sub-analyses of the pooled data were performed according to age (5-12; 13-18; >18 years), baseline ICS use, and lung function. Odds ratios (OR) and 95% confidence intervals (CIs) were calculated between formoterol (twice-daily), albuterol (salbutamol) 4 times per day (active control), and placebo. Patients were randomized to formoterol (n = 5,367), placebo (n = 2,026), and albuterol (n = 976). Two deaths were reported, 1 each in the formoterol (asthma exacerbation) and the placebo (hemorrhagic pancreatitis) groups. No statistically significant differences in serious asthma exacerbations were observed compared with placebo in adolescents and adults. In children, a higher frequency of hospitalizations was observed among patients treated with formoterol compared with placebo (OR 8.4; 95% CI: 1.1-65.3). A trend toward fewer exacerbations was observed among subjects reporting concomitant ICS use at baseline. This analysis supports current guideline recommendations for the use of LABAs only as add-on therapy to ICS.	f	\N
21706339	The prostate gland is the most common site of neoplastic disorders in men. The pathogenesis of inflammatory cells, prostatic intraepithelial neoplasia (PIN) lesions, and prostate cancer is still under investigation. Inflammatory cells by producing free radicals are considered as major and universal contributors to cancerogenesis. PIN is regarded as a precursor lesion to prostate cancer or a marker signaling the vulnerability of the epithelium to neoplastic transformation [1]. Differentiation markers that are frequently changed in early invasive carcinoma are also changed in PIN lesions. In this study, prostate tissue samples obtained during surgical operation and classified as various disease states (inflammation, PIN lesions, and cancer) were examined. The samples were measured by means of microbeam synchrotron-radiation-induced X-ray emission (micro-SRIXE). Special attention was paid to examine the relationship between the earlier-mentioned disorders and changes in relative concentrations of S, K, Ca, Fe, Cu, and Zn. Applying the image-processing program ImageJ enabled us to select the areas of interest from two-dimensional maps of various prostate samples according to the histopathologist's evaluation. Detailed analysis of micro-SRIXE spectra based on multivariate methods shows significant differences between elemental concentrations in inflammatory cells, PIN lesions, and cancerous tissues, which confirms that this method can be used to distinguish various pathological states in prostate tissues. Information obtained in this way may provide better understanding of the biochemistry of unhealthy prostate tissues, thus opening the way to find new medicines/treatments to prevent or slow down some harmful intracellular processes.	f	\N
21712520	Data have shown that preprocedural statin therapy reduces periprocedural myocardial infarction after percutaneous coronary intervention (PCI). However, whether preprocedural statins improve clinical outcomes in patients with stable coronary artery disease (CAD) has not been established. We aimed to evaluate the clinical effectiveness of preprocedural statin therapy in patients with stable CAD undergoing PCI. We conducted an observational study of 12 980 patients, age >65 years with stable CAD, who underwent PCI from December 1, 2003, to March 31, 2008. Using propensity score-matching analysis, 3098 unique matched pairs (6196 patients) who had similar likelihood of receiving preprocedural statins were identified. Additional analyses adjusting for postprocedural statins as a time-varying variable were performed. The main outcome measure was a composite of death or recurrent acute coronary syndrome. In the propensity-matched cohort, at 90 days, the primary outcome of death and acute coronary syndrome occurred in 5.6% in the preprocedural statin group as compared with 7.4% in the no-pretreatment group (P=0.005). Improved clinical outcomes associated with preprocedural statins were still observed at 2 years (16.7% versus 19.3%, P=0.007). The effectiveness of preprocedural statins was most pronounced at 90 days after PCI (adjusted hazard ratio, 0.80; 95% confidence interval, 0.65 to 0.98) but was no longer significant at 1 year (adjusted hazard ratio, 0.92; 95% confidence interval, 0.79 to 1.07) after accounting for postprocedural statin therapy. Preprocedural statin therapy was associated with significant reduction in the risk of death or recurrent acute coronary syndrome in stable CAD patients after PCI. These findings support the routine use of preprocedural statins for suitable candidates.	f	\N
21722500	To describe the MRI features of gout tophi in the soft-tissues or joints of the limbs by low-field extremity-dedicated MRI. Nine consecutive patients, 8M/1W, affected by chronic tophaceous gout were studied. Mean patients' age was 71.3±11.5 years, mean disease duration 98.1±44.9 months, and mean serum uric acid concentration 9.2±2.8 mg/L. Diagnosis was based on the ACR classification criteria for gout, and by identification of MSU crystals in the tophi and synovial fluid. Conventional radiograms and MRI with an extremity-dedicated system were obtained of the joint areas involved by tophi. At T1 weighted MRI images, all tophi showed a homogeneous intermediate signal intensity, similar to that of muscle. Conversely, in T2 weighted images, a wide spectrum of signal intensity patterns was observed. The pattern of contrast enhancement was variable from intense homogeneous to peripheral and heterogeneous. Capsulo-ligamentous structures were often thickened and degenerated and, on occasion, could be recognised as inhomogeneous, hypointense ribbon-shaped elements in the context of the tophus. In only two cases, tendons were infiltrated by tophaceous matter. Bone marrow oedema (BME) and erosions were seen in 8 out of 10 bones adjacent to tophi. The MRI appearance of gout tophi using an extremity-dedicated machine is similar to that described in the literature using whole body machines. BME adjacent to the tophus was a frequent finding. This technique may occasionally help in the differential diagnosis of nodules and in the follow-up of the disease. It also represents a useful tool to investigate the pathogenesis of gout and to better understand its clinical progression.	f	\N
21726837	Data are lacking on the efficacy and safety of a loading dose (LD) of clopidogrel in elderly patients with acute myocardial infarction (AMI). FAST-MI is a nationwide registry that was carried out over a 1-month period in 2005 and included consecutive patients with AMI admitted to intensive care units <48 hours from symptom onset in 223 participating centers. We assessed the impact of a clopidogrel LD (≥300 mg) compared to a conventional dose (<300 mg) on bleeding, need for blood transfusion, and 30-day and 12-month survivals in 791 elderly patients (≥75 years old, mean age 81 ± 4 years, 48% women, 35% with ST-segment elevation MI) included in this registry. Fifty-nine percent (466 patients) received a clopidogrel LD. Follow-up was >99% complete. Major bleeding and blood transfusions were not significantly different in patients who received a clopidogrel LD (3.2% vs 3.7%, p = 0.72; 5.4% vs 6.2%, p = 0.64, respectively). Early mortality was also not significantly different (10.1 vs 10.8, p = 0.76). Using multivariate analyses, clopidogrel LD did not significantly affect major bleeding or transfusion (odds ratio 1.03, 95% confidence interval 0.49 to 2.17, p = 0.94) and 12-month mortality (hazard ratio 1.00, 95% confidence interval 0.72 to 1.40, p = 0.98). In conclusion, the present data showed that in elderly patients admitted for AMI, use of a LD of clopidogrel compared to a conventional dose was not associated with increased in-hospital bleeding, need for transfusion, or mortality. Large-scale randomized trials are still needed to identify the optimal LD of clopidogrel for elderly patients admitted for AMI.	f	\N
21727012	The lung is the most common site for extrahepatic metastasis from hepatocellular carcinoma (HCC). We previously reported in a series of 20 patients that pulmonary metastasectomy for HCC is feasible in selected patients. The objective of this study was to re-evaluate the long-term outcomes and prognostic factors with an additional 25 patients. We retrospectively analyzed the records of 45 consecutive patients who underwent pulmonary metastasectomy due to HCC at our institution between 1990 and 2010. Thirty-nine patients underwent hepatectomy or liver transplantation, whereas six patients underwent locoregional therapy for primary liver lesions. Twenty-seven patients died during a median 17.6-month follow-up period. The 2-year disease-free survival (DFS) was 19.5%. The 5-year overall survival (OS) was 40.9%. History of recurrence and serum des-gamma-carboxy prothrombin (DCP) level >40 mAU ml(-1) at initial pulmonary resection were unfavorably associated with OS in univariate analysis. Pulmonary metastasectomy for HCC in selected patients resulted in relatively good outcomes with regard to OS. History of recurrence and serum DCP levels were shown to be candidates of prognostic factors for OS.	f	\N
21735745	A 42-year-old Japanese woman was referred to our university hospital due to progressive anemia and bilateral hilar lymphadenopathy with diffuse ground-glass attenuation on chest computed tomography in December 2009. She had suffered from exertional dyspnea and fatigue for several months. Laboratory findings on admission demonstrated leukocytosis (10,950/ul), elevation of C-reactive protein (4.7 mg/dl), IL-6 (19.9 pg/ml), IgG4 (567 mg/dl) and polyclonal hyper gamma-globulinemia. Chest computed tomography represented mediastinal and bilateral hilar lymphadenopathy with diffuse centrilobular fine nodules and intralobular septal thickening. Histopathological findings of the specimens obtained by thoracoscopic lung and mediastinal lymph node biopsies revealed massive infiltration of IgG4-positive plasma cells in lung tissue and lymph nodes. Pathological findings and high levels of C-reactive protein and interleukin-6 suggested a diagnosis of multicentric Castleman's disease (MCD). In addition, pathological findings of peribronchiolar infiltration of IgG4-positive plasma cells and lymphoid follicles with infiltration of IgG4-positive plasma cells with a high level of IgG4 were indicative of the complication of IgG4-related lung disease. Radiological and serological findings improved rapidly soon after the initiation of oral corticosteroid treatment. It was speculated that this case indicated the close relationship between MCD and IgG4-related lung disease.	f	\N
21737965	Bartonella henselae is the causative agent of cat scratch disease (CSD) in humans. Cats are the main reservoir of this bacterium and may infect humans through scratches and bites. The purpose of this study was to determine the B. henselae seroprevalence in cats in Turkey. A total of 298 cats blood samples were collected from six different provinces of Turkey. Sera were tested for the presence of anti-B. henselae IgG antibodies by indirect fluorescent antibody test (IFA). The seroprevalence of B. henselae was 27.9% (83/298) for the cats examined in this study. The seroprevalence of cats by province was significantly higher in Bursa (41.3%), Adana (33.9%), Aydin (27.5%) and Burdur (32.3%) than in Kayseri (17.9%) and Istanbul (12.5%). Statistically significant differences were not observed between cat sexes and living conditions of cats. The results revealed that B. henselae is an important zoonotic pathogen in Turkey.	f	\N
21751546	Intravenous immunoglobulin (IVIG) products are derived from plasma pools of thousands of healthy donors. These immunoglobulin concentrates contain large number of antibodies as well trace levels various other immunologically active molecules. Therapeutic Ig formulations contain intact IgG molecules, with variable amounts of monomeric and dimeric form existing in a dynamic equilibrium. Paradoxically, IgG can exert both pro-and anti-inflammatory activities, depending on its concentration. IVIG have been used for the treatment of primary immunodeficiency disorders for more than 25 years. IVIG products are also effective in the treatment of autoimmune and inflammatory disorders; however, the precise mechanism (s) of action is not known. Clinical and laboratory studies have documented various mechanisms of action of IVIG. The complex network of immunological reactions resulting from the infusion of IVIG includes changes in several cytokines, interactions with dendritic cells, T-and B-cell effects, macrophage effects, mediated by distinct Fc-gamma receptors. IVIG is also a recently recognized modifier of complement activation and injury. The complement--scavenging ability of Ig implies expansion of the use of IVIG to all disease in which generation of complement fragments plays a crucial role in pathogenesis. Recent studies showed that the anti-inflammatory activity of IVIG result from a minor population of the pooled IgG molecules that contains terminal a-2,6 sialic acid linkages on their Fc-linked glycans. This fully processed glycan is found in 1-3% of IgG in IVIG, which may explain the requirement for a high dose of IVIG. Recent data demonstrate, that the anti-inflammatory properties of IVIG can be recapitulated with fully recombinant preparation of appropriately sialylated IgG Fc fragments. This recombinant preparation had a 35 fold enhanced activity and potentially could be used at much lower doses than IVIG preparation in the treatment of autoimmune disorders.	f	\N
21764110	The impact of diffusion-weighted imaging (DWI) and apparent diffusion coefficients (ADCs) of MR imaging on the evaluation of residual Uterine Cervical Carcinoma after Radiation Therapy, in addition to conventional MR images. Fourty-nine women presenting with a uterine cervical cancer were examined with 1.5 T MRI and DWI, 8 (4-20) weeks after treatment. Treatment response was determined based on the histopathological results after therapy and was classified as a complete response (CR) or residual disease (RD). Post-treatment DWI and ADC results were compared. Five (11%) and 44 (89%) patients were considered as having histologically-proven RD or a CR respectively. The mean ADC of cervical tissue for all patients was 1.74±0.324×10(-3) mm(2)/s and the SD was 1.94±1.11×10(-4). The mean ADC was 1.62±0.21×10(-3) mm(2)/s (SD=1.45×10(-4)) for the 5 patients with RD versus 1.76±0.33×10(-3) mm(2)/s (SD=1.99×10(-4)) for the 44 patients with a CR (p=0.09). Using 1.7×10(-3) mm(2)/s as a radiological cut-off value for the ADC, all patients classified as having histologically-proven RD had a mean ADC of ≤1.7×10(-3). In 12 (25%) cases, RD was suspected on T2-weighted MRI images alone. Eight of these cases were considered as false positives compared to the histological results. Their mean ADC was 1.98×10(-3) mm(2)/s and none of them had an ADC of <1.7×10(-3) mm(2)/s. Although our results were not statistically significant, ADC values could potentially be used to predict and monitor the response of uterine cervical cancer.	f	\N
21769106	Strong and unidirectional associations exist between the severity of cardiovascular calcifications and mortality in patients with advanced chronic kidney disease. In the past 10 years, a wealth of experimental and clinical information has been published on the key pathophysiological events that contribute to the development and progression of vascular and soft-tissue calcifications. These processes involve a sensitive balance of calcification inhibition, induction and removal. The traditional view of regarding secondary hyperparathyroidism and elevated calcium × phosphate product as the pivotal risk factors for calcification has been challenged by data demonstrating a role for other, more subtle and complex pathomechanisms. These mechanisms include the loss of endogenous calcification inhibitors, deficient clearance of calcified debris, effects of vitamin K and vitamin D, and the action of calcification inducers as in osteogenic transdifferentiation. In this Review, we describe our current knowledge of the factors involved in the passive and active regulation of extraosseous calcification processes, with an assessment of their importance as targets for future diagnostic and therapeutic interventions.	f	\N
21776811	Tumor characterization employing a voxel-wise analysis of image signal facilitates the determination of the spatial distribution of tumor attributes, and when employed for therapy response assessment offers the promise of greater sensitivity to change than conventional approaches. However, the accuracy of a voxel-wise analysis of change is limited by local registration uncertainties that can disrupt the spatiotemporal correspondence between assessed voxels. We present a method for assessing voxel correspondence strength using a multiresolution local histogram-based measure of image structure similarity. When employed in a longitudinal tumor imaging context, a voxel similarity measure must be robust to intensity variations that can arise from the image acquisition, treatment effects, or changes in underlying disease processes. Consequently, the local histogram-based similarity measure is evaluated for sensitivity to structural change and robustness to intensity variation and is compared against normalized mutual information and normalized cross-correlation. T1-weighted (T1W) magnetic resonance (MR) images of glioblastoma acquired as part of a longitudinal response assessment study are first rigidly registered, and then similarity between spatially corresponding voxels is evaluated using multiresolution local histograms. Region-based and nonuniform intensity changes of varying magnitude as well as deformations to image structure are applied individually and in combination to the test images. Statistical analysis is used to test for interaction effects between the applied perturbations and the value of the local histogram similarity function. Pair-wise voxel similarity maps are computed for pairs of longitudinal clinical MR image volumes and compared with observed patterns of change on conventional imaging. The simulations demonstrated that the local histogram measure was robust to intensity modulations applied to increasing region sizes and exhibited a strong negative correlation with the magnitude of local deformation. No statistically significant interaction effects were observed upon the value of the local histogram similarity function when deformation was applied in conjunction with a nonuniform intensity change. Pair-wise voxel similarity maps were consistent with image change observed on T1W MR imaging and revealed patterns of change not apparent in conventional image sequences. A measure of local histogram image structure similarity can be used to assess the strength of voxel to voxel correspondences independently of intensity nonuniformities. The metric can provide a local estimate of the limits of achievable correspondence underlying the registration and voxel-wise comparison of signal in longitudinal imaging used for assessing tumor response to treatment.	f	\N
21779916	Metastatic pulmonary calcification can be caused by a number of diseases, most common being end-stage renal disease. Most of the patients are asymptomatic, and imaging with computed tomography is useful in making a diagnosis. Demonstration of pulmonary and chest wall vessel calcification is characteristic. We report a case of a 60-year-old patient with chronic renal failure on dialysis, presenting with gradual onset dyspnea, who showed metastatic pulmonary calcification on chest imaging.	f	\N
21784472	Long-term ketamine abuse in humans causes significant lower urinary tract symptoms. However, the etiology of ketamine associated cystitis is still not clear. We created a mouse model of ketamine induced lower urinary tract dysfunction to explore the pathogenesis of this condition. Female C57BL/6 mice randomly distributed into control and ketamine groups received daily intraperitoneal injection of saline and ketamine (100 mg/kg), respectively. Cystometry was done in each group at 4, 8 and 16 weeks. After sacrifice the bladders were harvested for isometric muscle tension recording and immunohistochemical examination. After 8 weeks of treatment body weight growth was significantly decreased in ketamine treated mice. Cystometry revealed a significantly decreased intercontraction interval (mean±SEM 237±9 vs 360±20 seconds, p<0.001) and decreased bladder capacity (0.1±0.004 vs 0.13±0.006 ml, p<0.001) in ketamine vs saline injected mice. Increased adenosine triphosphate evoked detrusor contraction developed in the ketamine group. Immunohistochemical examination revealed increased P2X1 receptor expression in ketamine treated mouse bladders while M2 and M3 receptor expression was unchanged. At 8 weeks mice treated with ketamine showed increased voiding frequency and decreased bladder capacity, the same symptoms that develop in human ketamine abusers. Enhanced noncholinergic contractions and P2X1 receptor expression in the ketamine bladder indicate that dysregulation of purinergic neurotransmission may underlie detrusor overactivity in cases of ketamine induced bladder dysfunction.	f	\N
21785215	Sinus node dysfunction (SND) is a major public health problem that is associated with sudden cardiac death and requires surgical implantation of artificial pacemakers. However, little is known about the molecular and cellular mechanisms that cause SND. Most SND occurs in the setting of heart failure and hypertension, conditions that are marked by elevated circulating angiotensin II (Ang II) and increased oxidant stress. Here, we show that oxidized calmodulin kinase II (ox-CaMKII) is a biomarker for SND in patients and dogs and a disease determinant in mice. In wild-type mice, Ang II infusion caused sinoatrial nodal (SAN) cell oxidation by activating NADPH oxidase, leading to increased ox-CaMKII, SAN cell apoptosis, and SND. p47-/- mice lacking functional NADPH oxidase and mice with myocardial or SAN-targeted CaMKII inhibition were highly resistant to SAN apoptosis and SND, suggesting that ox-CaMKII-triggered SAN cell death contributed to SND. We developed a computational model of the sinoatrial node that showed that a loss of SAN cells below a critical threshold caused SND by preventing normal impulse formation and propagation. These data provide novel molecular and mechanistic information to understand SND and suggest that targeted CaMKII inhibition may be useful for preventing SND in high-risk patients.	f	\N
21791221	This manuscript provides a survey of research findings catered to the development of effective countermeasures against nerve agent poisoning over the past decade. New neuropathophysiological distinctive features as regards organophosphate (OP) intoxication are presented. Such leading neuropathophysiological features include recent data on nerve agent-induced neuropathology, related peripheral or central nervous system inflammation and subsequent angiogenesis process. Hence, leading countermeasures against OP exposure are down-listed in terms of pre-treatment, protection or decontamination and emergency treatments. The final chapter focuses on the description of the self-repair attempt encountered in lesioned rodent brains, up to 3months after soman poisoning. Indeed, an increased proliferation of neuronal progenitors was recently observed in injured brains of mice subjected to soman exposure. Subsequently, the latter experienced a neuronal regeneration in damaged brain regions such as the hippocampus and amygdala. The positive effect of a cytokine treatment on the neuronal regeneration and subsequent cognitive behavioral recovery are also discussed in this review. For the first time, brain cell therapy and neuronal regeneration are considered as a valuable contribution towards delayed treatment against OP intoxication. To date, efficient delayed treatment was lacking in the therapeutic resources administered to patients contaminated by nerve agents.	f	\N
21797955	The outcome of HCC after transplantation (OLT) in children is not well known. Unfavorable features based on adult reports may lead to contraindicate OLT even in children. We reviewed a cohort of children with cirrhosis and HCC to evaluate their outcome after primary transplantation. We considered children with cirrhosis and HCC who had a primary OLT. We retrospectively recorded demographic, medical and surgical features, and MC as predictors of outcome. Among 456 children transplanted in the last 15 yr, 10 (2%), median age at diagnosis 1.8 yr (range 0.5-7.2), had HCC in biliary atresia (3), BSEP deficiency (3), tyrosinemia type 1 (2), complications of choledocal cyst and glycogen storage disease type IV (1 each). At HCC discovery, median AFP was 2322 ng/mL (3-35,000), high or rising in 9/10 patients. Six patients were outside the MC. Median time on the waiting list was 38 days (1-152). Two patients died from early complications of OLT. In the other eight patients, there was no tumor recurrence after a median follow-up of four yr. Children with cirrhosis may develop HCC at a very young age. The outcome appears excellent even outside MC. Primary liver transplantation is advisable for children with cirrhosis, HCC, and no extrahepatic disease.	f	\N
21802018	The cost associated with asthma impairment in children with severe asthma has not been determined. To assess the asthma cost burden in children with severe or difficult-to-treat asthma based on asthma impairment. Children aged 6 to 12 years in The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens study with available data at baseline (n = 628), month 12 (n = 385), and month 24 (n = 280) corresponding to the National Heart, Lung, and Blood Institute asthma guidelines' impairment domain were included. Children were categorized as either very poorly controlled (VPC), not well controlled (NWC), or well controlled (WC) and assessed cross-sectionally and longitudinally. Mean total asthma costs based on direct (medication usage, unscheduled office visits, emergency department visits, hospitalizations) and indirect (school/work days lost) asthma costs were assessed. Mean annual total asthma costs were more than twice as high in the VPC group compared with NWC and WC groups (baseline: $7,846, $3,526, $3,766.44, respectively; month 12: $7,326, $2,959, $2,043, respectively; month 24: $8,879, $3,308, $1,861, respectively (all P < .001). Indirect costs accounted for approximately half the total asthma costs for VPC asthma patients at each time point. Significantly lower costs were observed for patients whose impairment status improved or temporarily improved from VPC after baseline. The economic burden of severe or difficult-to-treat asthma in children is associated with VPC asthma and improvement in asthma control and is associated with reducing cost. Further attention to patients with poorly controlled asthma, through better management strategies or more effective medications, may significantly reduce this burden of illness.	f	\N
21803694	The use of experimental model systems has expedited the elucidation of pathogenetic mechanisms of renal developmental disease in humans and the identification of genes that orchestrate developmental programming during nephrogenesis. We conducted studies to evaluate the role of AHR polymorphisms in the disruption of renal developmental programming by benzo(a)pyrene (BaP). We used metanephric cultures of C57BL/6J (C57) mice expressing the Ahr(b-1) allele and B6.D2N-Ahr(d)/J (D2N) mice expressing a mutant allele deficient in ligand binding (Ahr(d)) to investigate molecular mechanisms of renal development. Deficits in fetal programming were evaluated in the offspring of pregnant mice treated with BaP during nephrogenesis. Hydrocarbon challenge of metanephri from C57 mice altered Wilms' tumor suppressor gene (Wt1) mRNA splice variant ratios and reduced mRNAs of the Wt1 transcriptional targets syndecan-1 (Sdc1) paired box gene 2 (Pax2), epidermal growth factor receptor (Egfr), and retinoic acid receptor, alpha (Rarα). These changes correlated with down-regulation of effectors of differentiation [secreted frizzled-related sequence protein 1 (Sfrp1), insulin-like growth factor 1 receptor (Igf1r), wingless-related MMTV-integration site 4 (Wnt4), Lim homeobox protein 1 (Lhx1), E-cadherin]. In contrast, metanephri from D2N mice were spared hydrocarbon-induced changes in Wt1 splice variant ratios and deficits of differentiation. We observed similar patterns of dysmorphogenesis and progressive loss of renal function at postnatal weeks 7 and 52 in the offspring of pregnant C57 but not D2N mice gavaged with 0.1 or 0.5 mg/kg BaP on gestation days 10-13. These findings support a functional link between AHR and WT1 in the regulation of renal morphogenesis and raise important questions about the contribution of human AHR polymorphisms to the fetal origins of adult-onset kidney disease.	f	\N
21804097	Proper understanding of the roles of, and interactions between genetic, lifestyle, environmental and psycho-social factors in determining the risk of development and/or progression of chronic diseases requires access to very large high-quality databases. Because of the financial, technical and time burdens related to developing and maintaining very large studies, the scientific community is increasingly synthesizing data from multiple studies to construct large databases. However, the data items collected by individual studies must be inferentially equivalent to be meaningfully synthesized. The DataSchema and Harmonization Platform for Epidemiological Research (DataSHaPER; http://www.datashaper.org) was developed to enable the rigorous assessment of the inferential equivalence, i.e. the potential for harmonization, of selected information from individual studies. This article examines the value of using the DataSHaPER for retrospective harmonization of established studies. Using the DataSHaPER approach, the potential to generate 148 harmonized variables from the questionnaires and physical measures collected in 53 large population-based studies (6.9 million participants) was assessed. Variable and study characteristics that might influence the potential for data synthesis were also explored. Out of all assessment items evaluated (148 variables for each of the 53 studies), 38% could be harmonized. Certain characteristics of variables (i.e. relative importance, individual targeted, reference period) and of studies (i.e. observational units, data collection start date and mode of questionnaire administration) were associated with the potential for harmonization. For example, for variables deemed to be essential, 62% of assessment items paired could be harmonized. The current article shows that the DataSHaPER provides an effective and flexible approach for the retrospective harmonization of information across studies. To implement data synthesis, some additional scientific, ethico-legal and technical considerations must be addressed. The success of the DataSHaPER as a harmonization approach will depend on its continuing development and on the rigour and extent of its use. The DataSHaPER has the potential to take us closer to a truly collaborative epidemiology and offers the promise of enhanced research potential generated through synthesized databases.	f	\N
21813382	Living donor liver transplantation (LDLT) has recently emerged as an effective therapeutic alternative for patients with end-stage liver disease. In the meantime, the health-related quality of life (HRQoL) of the donors is becoming better appreciated. Here we aimed to review the current literature and summarize the effects of liver donation on the long-term HRQoL of living donors. A literature search of PubMed using "donors", "living donor liver transplantation", "health-related quality of life", and "donation" was performed, and all the information was collected. The varied postoperative outcomes of liver donors are attributive to the different evaluation instruments used. On the whole, donors experienced good long-term physical and mental well-being with a few complaining of compromised quality of life due to mild symptoms or psychiatric problems. The psychosocial dimension has received increasing attention with the vocational, interpersonal and financial impact of liver donation on donors mostly studied. Generally, donors have a good HRQoL after LDLT. Nevertheless, to achieve an ideal donor outcome, further work is necessary to minimize the negative effects as well as to incorporate recent progress in regenerative medicine.	f	\N
21824495	Sandfly fever (SF) is an arthropod-borne disease, which has not yet been reported from Ankara. In the summer of 2007, the disease started to be seen in our region, surprisingly causing severe clinical presentations. This report reviews the clinical and laboratory findings of patients with sandfly virus infection of disease outbreaks in 2008 and 2009. A retrospective single-centre descriptive study was performed. Clinically suspected cases were defined on the basis of epidemiologic history and clinical and laboratory findings. The sera samples of the suspected patients were sent to Germany for diagnostic assistance. 50 patients were included in the study. Fever, headache, photophobia, conjunctivitis, myalgia, arthralgia, nausea, abdominal pain and anorexia were common symptoms. Although the fever lasted only 3-6 days, complete recovery required up to 30 days. Leukopenia, thrombocytopenia and elevated serum aspartate-aminotransferase and alanine-aminotransferase levels were remarkable findings. The viral-load of Sandfly fever Turkey Virus (SFTV) was detected in the serum of acute patients ranged from 3.19×10(6) to 2.79×10(9) viral RNA molecules/ml. As a result we want to underline that the new type of sandfly virus causes a severe clinical picture with elevated liver enzymes and thrombocytopenia, to an extent not described before in the literature, which might be due to the elevated viral-load observed.	f	\N
21832975	In the United States, approximately one in three new human immunodeficiency virus (HIV) infections are transmitted via heterosexual contact. To monitor HIV risk behaviors and HIV prevalence among heterosexuals and other populations, CDC surveys persons in selected metropolitan statistical areas (MSAs), using the National HIV Behavioral Surveillance System (NHBS). This report summarizes data collected from heterosexuals in 24 MSAs with a high prevalence of acquired immunodeficiency syndrome (AIDS) that participated in NHBS during 2006-2007. Of 14,837 heterosexuals aged 18-50 years who were interviewed and tested, 2.0% were HIV infected. HIV prevalence was higher among those with lower socioeconomic status (SES). For example, HIV prevalence was 2.8% among participants with less than a high school education compared with 1.2% among those with more than a high school education, 2.6% among participants who were unemployed compared with 1.0% among those who were employed, and 2.3% among participants with annual household incomes at or below the poverty level compared with 1.0% among those with incomes above the poverty level. This association between HIV prevalence and SES could not be attributed to factors commonly associated with HIV infection risk in heterosexuals, such as using crack cocaine, exchanging sex for things such as money or drugs, or being diagnosed with a sexually transmitted disease (STD). Based on the association observed between HIV prevalence and SES, HIV prevention activities targeted at heterosexuals in urban areas with high AIDS prevalence should be focused on those with lower SES.	f	\N
21835304	A fundamental challenge in analyzing exome-sequence data is distinguishing pathogenic mutations from background polymorphisms. To address this problem in the context of a genetically heterogeneous disease, retinitis pigmentosa (RP), we devised a candidate-gene prioritization strategy called cis-regulatory mapping that utilizes ChIP-seq data for the photoreceptor transcription factor CRX to rank candidate genes. Exome sequencing combined with this approach identified a homozygous nonsense mutation in male germ cell-associated kinase (MAK) in the single affected member of a consanguineous Turkish family with RP. MAK encodes a cilium-associated mitogen-activated protein kinase whose function is conserved from the ciliated alga, Chlamydomonas reinhardtii, to humans. Mutations in MAK orthologs in mice and other model organisms result in abnormally long cilia and, in mice, rapid photoreceptor degeneration. Subsequent sequence analyses of additional individuals with RP identified five probands with missense mutations in MAK. Two of these mutations alter amino acids that are conserved in all known kinases, and an in vitro kinase assay indicates that these mutations result in a loss of kinase activity. Thus, kinase activity appears to be critical for MAK function in humans. This study highlights a previously underappreciated role for CRX as a direct transcriptional regulator of ciliary genes in photoreceptors. In addition, it demonstrates the effectiveness of CRX-based cis-regulatory mapping in prioritizing candidate genes from exome data and suggests that this strategy should be generally applicable to a range of retinal diseases.	f	\N
21846442	Cardiac rhabdomyoma (CR) is the cardiac tumour most commonly diagnosed in utero. Eighty percent of CRs are associated with tuberous sclerosis (TS). TS is a rare multi-system disease, with autosomal dominant genetic transmission. If the parents of an affected child do not have features of TS, then either one parent is mosaic for the TS gene mutation or the affected child is the result of a de novo germline mutation. We present a case of a dizygotic twin pregnancy complicated by CRs in both fetuses at 24 weeks. Twin A died in utero at 28 weeks. Preterm labour and delivery of twin B occurred at 33 weeks. Twin B had multiple small CRs and a large apical CR. At six weeks after delivery, the CRs had disappeared or reduced in size. Regression in the third trimester or postnatally is the natural course of CRs. Molecular testing for TS identified two variants in the TSC2 gene. The parents were clinically unaffected; however, the father was subsequently found on an MRI of the head to have cortical tubers, and he was found to carry the pathogenic TSC2 mutation. Since dizygotic twin pregnancy is akin to two consecutive pregnancies, the etiology in our case is due to one parent having subclinical TS. To the best of our knowledge, this is the first such case to be reported.	f	\N
21852013	We compared the intergenerational variations of the clinical phenotype between 30 patients affected with multiple autoimmune syndrome (MAS) and their affected first- and second-degree relatives. Mean age at onset was always significantly higher in the previous generation than in probands for all the considered diseases.	f	\N
21852664	Observational studies have reported an association between metabolic syndrome (MetS) and microalbuminuria or proteinuria and chronic kidney disease (CKD) with varying risk estimates. We aimed to systematically review the association between MetS, its components, and development of microalbuminuria or proteinuria and CKD. DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS AND POPULATION: We searched MEDLINE (1966 to October 2010), SCOPUS, and the Web of Science for prospective cohort confidence interval (CI) studies that reported the development of microalbuminuria or proteinuria and/or CKD in participants with MetS. Risk estimates for eGFR <60 ml/min per 1.73 m(2) were extracted from individual studies and pooled using a random effects model. The results for proteinuria outcomes were not pooled because of the small number of studies. Eleven studies (n = 30,146) were included. MetS was significantly associated with the development of eGFR <60 ml/min per 1.73 m(2) (odds ratio, 1.55; 95% CI, 1.34, 1.80). The strength of this association seemed to increase as the number of components of MetS increased (trend P value = 0.02). In patients with MetS, the odds ratios (95% CI) for development of eGFR <60 ml/min per 1.73 m(2) for individual components of MetS were: elevated blood pressure 1.61 (1.29, 2.01), elevated triglycerides 1.27 (1.11, 1.46), low HDL cholesterol 1.23 (1.12, 1.36), abdominal obesity 1.19 (1.05, 1.34), and impaired fasting glucose 1.14 (1.03, 1.26). Three studies reported an increased risk for development of microalbuminuria or overt proteinuria with MetS. MetS and its components are associated with the development of eGFR <60 ml/min per 1.73 m(2) and microalbuminuria or overt proteinuria.	f	\N
21855111	The EHF (Ets homologous factor) gene was previously shown to be overexpressed in ovarian/primary peritoneal serous carcinoma compared to malignant mesothelioma using gene expression arrays. The objective of this study was to validate this finding at the mRNA level in a larger series. We analyzed the diagnostic role of EHF in 98 ovarian serous carcinoma effusions, 23 malignant mesothelioma specimens (20 effusions, 3 surgical specimens), and 28 primary ovarian serous carcinomas using quantitative real-time polymerase chain reaction. Expression levels of EHF in ovarian carcinoma were additionally investigated for association with clinicopathologic parameters and survival. Quantitative real-time polymerase chain reaction analysis showed significantly higher expression of EHF mRNA in ovarian carcinoma effusions and in primary ovarian carcinoma compared to malignant mesothelioma effusions (P < .001 for both). EHF mRNA expression was additionally higher in primary ovarian carcinomas compared to effusions of this cancer (P < .001). In univariate analysis for all patients with effusions, higher EHF mRNA levels were associated with a trend for shorter progression-free survival (P = .066), which became significant in analysis of 45 patients with primary diagnosis pre-chemotherapy effusions (P = .01). In Cox multivariate analysis, EHF mRNA expression was an independent predictor of poor progression-free survival for all patients and patients with primary diagnosis pre-chemotherapy effusions (P = .033 and P = .009, respectively). EHF mRNA levels differentiate ovarian carcinoma from malignant mesothelioma and may thus be of diagnostic value in this setting. EHF may be a novel prognostic marker in ovarian carcinoma.	f	\N
21872587	Decline in verbal fluency is the most consistent and persistent cognitive impairment documented after deep brain stimulation of the subthalamic nucleus in Parkinson's disease. The mechanisms of this deficit are unclear. We aimed to identify and characterise verbal fluency related processing within the subthalamic nucleus through analysis of local field potentials. Local field potentials were recorded from deep brain stimulation electrodes implanted in the subthalamic nuclei of 8 patients (16 sides) with Parkinson's disease, when patients were on medication. Patients performed phonemic and semantic verbal fluency tasks and a control word repetition task to control for the motor output involved in response generation. Significant increases in local field potential Power (p ≤ 0.05) were seen across a broad gamma frequency band (30-95 Hz) during both verbal fluency tasks, after controlling for motor output. Increases in gamma local field potential Power of +7.5% ± 2.3% (SEM) in the semantic fluency task and +6.9% ± 2.0% in the phonemic fluency task were derived when averaging across all electrode contact pairs. Gamma changes recorded from contacts lying in the left hemisphere (dominant in verbal fluency) correlated with average number of correct responses generated (r=0.81 p=0.015) and measures of 'switching' (r=0.79 p=0.020) particularly strongly in the semantic fluency task. Frequency specific power changes observed during task performance are consistent with involvement of the subthalamic nucleus in switching during verbal fluency. Antagonism of such task-related activity with high frequency stimulation of this nucleus may explain the impairments reported.	f	\N
21876350	We proposed a new method to estimate dry weight (DW) using single frequency bioimpedance. We hypothesized that the change in whole body resistance at 50 kHz (R(50)) was proportional to the ultrafiltration volume (UFV) during a hemodialysis (HD) session. When the targeted resistance estimated in healthy subjects was reached, the patient achieved his/her DW. UFV and R(50) were monitored in 40 HD patients. Another 43 HD patients were stratified into 2 groups to validate this method. The change in whole body resistance was proportional to UFV in each of the 40 HD patients. In the DW(decrease) group, pre-dialysis systolic blood pressure (n = 29, 154.5 ± 22.8 vs. 146.9 ± 22.3, p < 0.05) and antihypertensive medicine (4.7 ± 3.6 vs. 3.3 ± 2.2, p < 0.05) decreased without adverse symptoms change. In the DW(increase) group, the number of adverse symptoms in 1 week (n = 14, 26 vs. 6, p < 0.05) decreased without a change in systolic blood pressure. This method may become a convenient and cheaper way to estimate DW in HD patients.	f	\N
21884641	Breast cancer is a complex and heterogeneous disease. Gene expression profiling has contributed significantly to our understanding of this heterogeneity at a molecular level, refining taxonomy based on simple measures such as histological type, tumour grade, lymph node status and the presence of predictive markers like oestrogen receptor and human epidermal growth factor receptor 2 (HER2) to a more sophisticated classification comprising luminal A, luminal B, basal-like, HER2-positive and normal subgroups. In the laboratory, breast cancer is often modelled using established cell lines. In the present review we discuss some of the issues surrounding the use of breast cancer cell lines as experimental models, in light of these revised clinical classifications, and put forward suggestions for improving their use in translational breast cancer research.	f	\N
21884662	Asthma is a frequent illness in young adults and is characterized by airway hyper responsiveness (AHR) and airway inflammation. Asthma is a complex disease and AHR as well as inflammation may be limited, although characteristic symptoms are present. The clinical experience in asthma treatment is that not all asthmatics have a satisfactory effect of the different drugs. Asthma has been found to develop from one disease to a multifaceted disease with numerous different possibilities. More research is needed in strategic asthma management in the search for tailored treatment strategy.	f	\N
21889188	We report the sixth autopsy case of a patient with aceruloplasminemia. He was the younger brother of the first reported autopsy case of this disease. Among autopsy cases with aceruloplasminemia reported to date, he had the longest duration of neurologic disorders. The neuropathologic findings showed that the basal ganglia and dentate nuclei were most severely affected. The most striking finding in the present case was that marked iron deposition was evident in the cerebral cortex. Many enlarged or deformed astrocytes and globular structures, both of which were heavily iron loaded, were found in the cerebral cortex as well as in the basal ganglia. Pyramidal neurons in his cerebral cortex were fewer in number than observed in the previous reported cases. There was a negative correlation between the number of cortical pyramidal neurons and globular structures. The present case clearly indicates that the neuropathologic process in aceruloplasminemia extends beyond the basal ganglia to the cerebral cortex with time.	f	\N
21889832	Higher radiation dose levels have been shown to be associated with improved tumor-control outcomes in localized prostate cancer (PCa) patients. Identify predictors of biochemical tumor control and distant metastases-free survival (DMFS) outcomes for patients with clinically localized PCa treated with conformal external-beam radiotherapy (RT) as well as present an updated nomogram predicting long-term biochemical tumor control after RT. This retrospective analysis comprised 2551 patients with clinical stages T1-T3 PCa. Median follow-up was 8 yr, extending >20 yr. Prescription doses ranged from 64.8 to 86.4 Gy. A total of 1249 patients (49%) were treated with neoadjuvant and concurrent androgen-deprivation therapy (ADT); median duration of ADT was 6 mo. A proportional hazards regression model predicting the probability of biochemical relapse and distant metastases after RT included pretreatment prostate-specific antigen (PSA) level, clinical stage, biopsy Gleason sum, ADT use, and radiation dose. A nomogram predicting the probability of biochemical relapse after RT was developed. Radiation dose was one of the important predictors of long-term biochemical tumor control. Dose levels < 70.2 Gy and 70.2-79.2 Gy were associated with 2.3- and 1.3-fold increased risks of PSA relapse compared with higher doses. Improved PSA relapse-free survival (PSA-RFS) outcomes with higher doses were observed for all risk groups. Use of ADT, especially for intermediate- and high-risk patients, was associated with significantly improved biochemical tumor-control outcomes. A nomogram predicting PSA-RFS was generated and was associated with a concordance index of 0.67. T stage, Gleason score, pretreatment PSA, ADT use, and higher radiation doses were also noted to be significant predictors of improved DMFS outcomes. Higher radiation dose levels were consistently associated with improved biochemical control outcomes and reduction in distant metastases. The use of short-course ADT in conjunction with RT improved long-term PSA-RFS and DMFS in intermediate- and high-risk patients; however, an overall survival advantage was not observed.	f	\N
21890816	A multicentre cohort follow-up study of a large number of patients with gastric mucosa-associated lymphoid tissue (MALT) lymphoma was conducted to elucidate the long-term outcome of the disease after Helicobacter pylori eradication. 420 patients with gastric low-grade MALT lymphoma who had undergone successful H pylori eradication and been followed up for at least 3 years were registered from 21 participating institutes. Responders to treatment were defined as patients whose post-treatment biopsies showed complete histological response (ChR) or probable minimal residual disease (pMRD). Treatment failure was defined as the status of progressive disease or lymphoma relapse after ChR/pMRD. 323 patients (77%) responded to H pylori eradication. A logistic regression analysis showed that absence of H pylori, submucosal invasion determined by endoscopic ultrasonography and t(11;18)/API2-MALT1 were independent predictors of resistance to H pylori eradication. During the follow-up periods ranging from 3.0 to 14.6 years (mean 6.5 years, median 6.04 years), the disease relapsed in 10 of 323 responders (3.1%) while progressive disease was found in 27 of 97 non-responders (27%). Thus, 37 of 420 patients (8.8%) were regarded as treatment failures. Of these 37 patients, transformation into diffuse large B cell lymphoma occurred in nine patients. Among the non-responders and relapsed patients, 17 patients were subjected to a 'watch and wait' strategy while 90 patients underwent second-line treatments including radiotherapy (n=49), chemotherapy (n=26), surgical resection (n=6), chemoradiotherapy (n=5), antibiotic treatment (n=2), rituximab monotherapy (n=1) or endoscopic resection (n=1). Probabilities of freedom from treatment failure, overall survival and event-free survival after 10 years were 90%, 95% and 86%, respectively. Cox multivariate analysis revealed endoscopic non-superficial type to be an independent prognostic factor for adverse freedom from treatment failure, overall survival and event-free survival. The excellent long-term outcome of gastric MALT lymphoma after H pylori eradication was confirmed by this large-scale follow-up study.	f	\N
21896508	The interaction between transcription factor (TF) and transcription factor binding site (TFBS) is essential for gene regulation. Mutation in either the TF or the TFBS may weaken their interaction and thus result in abnormalities. To maintain such vital interaction, a mutation in one of the interacting partners might be compensated by a corresponding mutation in its binding partner during the course of evolution. Confirming this co-evolutionary relationship will guide us in designing protein sequences to target a specific DNA sequence or in predicting TFBS for poorly studied proteins, or even correcting and rescuing disease mutations in clinical applications. Based on six, publicly available, experimentally validated TF-TFBS binding datasets for the basic Helix-Loop-Helix (bHLH) family, Homeo family, High-Mobility Group (HMG) family and Transient Receptor Potential channels (TRP) family, we showed that the evolutions of the TFs and their TFBSs are significantly correlated across eukaryotes. We further developed a mutual information-based method to identify co-evolved protein residues and DNA bases. This research sheds light on the dynamic relationship between TF and TFBS during their evolution. The same principle and strategy can be applied to co-evolutionary studies on protein-DNA interactions in other protein families. All the datasets, scripts and other related files have been made freely available at: http://jjwanglab.org/co-evo. junwen@uw.edu. Supplementary data are available at Bioinformatics online.	f	\N
21904924	The distribution of complement component 4 (C4) gene copy number (GCN) has been validated in European populations. Meanwhile, C4 gene has been identified as a susceptibility gene for systemic lupus erythematosus (SLE). However, the association and the possible phenotype significance remain to be determined intensely in the Chinese population. This study was designed to validate the distribution of C4 GCNs in Chinese Han and the correlation between C4 GCNs and SLE using quantitative real-time polymerase chain reaction in 924 SLE patients and 1,007 controls. The results presented distribution of C4 GCNs in healthy populations and also showed that lower C4 GCN was a risk factor for SLE and higher C4 GCN was a protective factor against the disease susceptibility, which was similar to the report in the Caucasian population. Furthermore, we found the association between C4A GCN and disease subphenotypes of arthritis with SLE. We conclude that the association of C4 GCN with SLE was replicated in Chinese Han population, which highlighted the importance of C4 in SLE pathogenesis of diverse populations.	f	\N
21912125	Women undergoing isolated coronary artery bypass graft (CABG) surgery have been previously shown to be at an independently increased risk for post-operative morbidity and mortality. However, there are considerably less data on whether this trend remains true in patients undergoing concomitant aortic valve replacement (AVR) and CABG surgery. The aim of our study was to investigate this pertinent issue. Data obtained between June 2001 and December 2009 by the Australasian Society of Cardiac and Thoracic Surgeons Cardiac Surgery Database Program were retrospectively analysed. Demographic, operative data and post-operative complications were compared between male and female patients using χ(2) and t tests. Long-term survival analysis was performed using Kaplan-Meier survival curves and the log-rank test. Independent risk factors for short- and long-term mortality were identified using binary logistic and Cox regression, respectively. Concomitant AVR and CABG surgery was undertaken in 2,563 patients; 31.8% were female. Female patients were older (mean age 76 vs. 73 years; p < 0.001) and presented more often with hypertension (p < 0.001) but less often with severely impaired ejection fraction (p < 0.001), peripheral vascular disease (p < 0.001) and triple vessel disease (p < 0.001). Women did not demonstrate an increased risk of 30-day mortality (4.8 vs. 3.3%) on univariate (p = 0.069) or multivariate (p = 0.236) analysis. Female gender was independently associated with post-operative myocardial infarction (p = 0.022) and red blood cell transfusion (p < 0.001). There was no difference in long-term survival between men and women on multivariate analysis (p = 0.413). Female gender is not associated with poorer short- or long-term outcomes after concomitant CABG and AVR surgery.	f	\N
21913717	Hepatocellular carcinoma (HCC) is one of the leading causes of mortality from solid organ malignancy worldwide. Because of the complexity of proteins within liver cells and tissues, the discovery of therapeutic targets of HCC has been difficult. To investigate strategies for decreasing the complexity of tissue samples for detecting meaningful protein mediators of HCC, we employed subcellular fractionation combined with 1D-gel electrophoresis and liquid chromatography-tandem mass spectrometry analysis. Moreover, we utilized a statistical method, namely, the Power Law Global Error Model (PLGEM), to distinguish differentially expressed proteins in a duplicate proteomic data set. Mass spectrometric analysis identified 3045 proteins in nontumor and HCC from cytosolic, membrane, nuclear, and cytoskeletal fractions. The final lists of highly differentiated proteins from the targeted fractions were searched for potentially translocated proteins in HCC from soluble compartments to the nuclear or cytoskeletal compartments. This analysis refined our targets of interest to include 21 potential targets of HCC from these fractions. Furthermore, we validated the potential molecular targets of HCC, MATR3, LETM1, ILF2, and IQGAP2 by Western blotting, immunohistochemisty, and immunofluorescent microscopy. Here we demonstrate an efficient strategy of subcellular tissue proteomics toward molecular target discovery of one of the most complicated human disease, HCC.	f	\N
21915990	Investigations of rare cell types in peripheral blood samples, such as tumor, fetal, and endothelial cells, represent an emerging field with several potentially valuable medical applications. Peripheral blood is a particularly attractive body fluid for the detection of rare cells as its collection is minimally invasive and can be repeated throughout the course of the disease. Because the number of rare cells in mononuclear cells can be very low (1 in 10 million), a large number of cells must be quickly screened, which places demanding requirements on the screening technology. While enrichment technology has shown promise in managing metastatic disease, enrichment can cause distortions of cell morphology that limit pathological identification, and the enrichment targeting adds additional constraints that can affect sensitivity. Here, we describe a new approach for detecting rare leukemia cells that does not require prior enrichment. We have developed an immunocytochemical assay for identification of leukemia cells spiked in peripheral blood samples, and a high-speed scanning instrument with high numerical aperture and wide field of view to efficiently locate these cells in large sample sizes. A multiplex immunoassay with four biomarkers was used to uniquely identify the rare cells from leukocytes and labeling artifacts. The cytometer preserves the cell morphology and accurately locates labeled rare cells for subsequent high resolution imaging. The sensitivity and specificity of the approach show promise for detection of a low number of leukemia cells in blood (1 in 10 million nucleated cells). The method enables rapid location of rare circulating cells (25 M cells/min), no specific enrichment step, and excellent imaging of cellular morphology with multiple immunofluorescent markers. The cell imaging is comparable to other imaging approaches such as laser scan cytometry and image flow cytometry, but the cell analysis rate is many orders of magnitude faster making this approach practical for detection of rare cells.	f	\N
21916327	Serum dioxin studies of Vietnam (VN) veterans, military historical records of tactical herbicide use in Vietnam, and the compelling evidence of the photodegradation of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and other aspects of environmental fate and low bioavailability of TCDD are consistent with few, if any, ground troop veterans being exposed to Agent Orange. That conclusion, however, is contrary to the presumption by the Department of Veterans Affairs (DVA) that military service in Vietnam anytime from January 9, 1962 to May 7, 1975 is a proxy for exposure to Agent Orange. The DVA assumption is inconsistent with the scientific principles governing determinations of disease causation. The DVA has nonetheless awarded Agent Orange-related benefits and compensation to an increasing number of VN veterans based on the presumption of exposure and the published findings of the Institute of Medicine that there is sufficient evidence of a "statistical association" (a less stringent standard than "causal relationship") between exposure to tactical herbicides or TCDD and 15 different human diseases. A fairer and more valid approach for VN veterans would have been to enact a program of "Vietnam experience" benefits for those seriously ill, rather than benefits based on the dubious premise of injuries caused by Agent Orange.	f	\N
21917357	To know the relative weight of the diagnosis of detrusor overactivity (DO) in the Urodynamic Units of Spain and relate the prevalence of the overactive bladder (OB) syndrome. An epidemiological, descriptive, retrospective, multicenter, national study conducted according to registered data in 47 Urodynamic Units covering the Spanish geographic area in the different areas of health distributed among the regional communities. These data inform about the health care received by 35% of the Spanish population. Urodynamic diagnoses and related variables, recorded during 2007 and 2008, were collected. A mean of 346.45 (SD=304.03) and 349.72 (SD=296.49) urodynamics studies per care unit were performed in women during 2007 and 2008, respectively and 181.20 (SD=212.71) and 195.68 (SD=257.58) in men. The relative weight of the diagnosis of non-neurogenic DO in women per unit was 31.39% and 35.28%, in 2007 and 2008, and in men was 21.06% and 20.43%. The diagnostic capacity of DO was 19.28 new cases per 100,000 inhabitants/year. The diagnosis of non-neurogenic DO in the woman accounts for one third of all the urodynamic/year diagnoses and more than half of the diagnoses of DO. In men, DO accounts for 25% of the diagnoses, the most frequent one being that associated with benign prostatic hyperplasia, followed by that of neurogenic cause. Approximately half of the DO diagnoses in children correspond to non-neurogenic DO. The differences between the capacity of diagnosis of DO (ratio per 100,000 inhabitants) is far from many of the estimations of the prevalence of OB (relationship %). The doubt may exist about whether part of this quota is secondary and not-idiopathic, given the large difference between the frequency of OB and the capacity of diagnosis of DO.	f	\N
21917441	Idiopathic pulmonary fibrosis (IPF) is a lethal lung disorder of unknown etiology. The disease is likely the result of complex interactions between genetic and environmental factors. Evidence suggests that certain environmental factors, such as cigarette smoking and metal dust exposures, or comorbidities like gastroesophageal reflux, and type 2 diabetes mellitus (DM2) may increase risk to develop IPF. Substantial uncertainty remains, however, regarding these and other putative risk factors for IPF. In this study we performed a case-control analysis including 100 patients with IPF and 263 controls matched for age sex and place of residence. We used a structured questionnaire to identify potential risk factors for IPF, including environmental and occupational exposures as well as the relevance of family history of pulmonary fibrosis. The multivariate analysis revealed that family history of pulmonary fibrosis [OR = 6.1, CI95% 2.3-15.9; p < 0.0001] was strongly associated with increased risk of IPF. Actually, 20% of the cases reported a parent or sibling with pulmonary fibrosis. Gastroesophageal reflux [OR = 2.9, CI: 1.3-6.6; p = 0.007], former cigarette smoking [OR = 2.5, CI: 1.4-4.6, p = 0.003], and past or current occupational exposure to dusts, smokes, gases or chemicals [OR = 2.8, CI: 1.5-5.5; p = 0.002] were also associated with the disease. Despite being a significant risk factor on univariate analysis DM2 was not significant in multivariate analysis. These findings indicate that family history of pulmonary fibrosis is a strong risk factor for IPF. Also, we confirmed that occupational exposures, gastroesophageal reflux and former smoking increase the risk for this disease.	f	\N
21918487	Although the use of embryonic stem cells to treat disease has caused much controversy, one type of stem cell treatment has slowly and steadily shown promise but has not engendered negative ethical media attention: the use of umbilical stem cells. Umbilical cord blood (UCB) contains stem cells that have already successfully treated a variety of diseases, including leukemias, lymphomas, hemoglobinopathies, immunodeficiencies, and disorders of metabolism; ongoing research continues to explore additional diseases for potential treatment. Cord blood can be stored in private banks or public banks. Private cord blood banks save cord blood for use by the family only, at a cost. Public cord blood banks accept donations and the cord blood is then used for the general public and/or research. A review of the literature finds that public banking is the preferred recommendation over private unless there is a known family member with a disease that can currently be treated with cord blood. This article discusses cord blood banking options as well as the ethical issues and barriers facing both healthcare providers and patients when dealing with cord blood banking.	f	\N
21924425	Recent genome-wide association studies (GWAS) have identified associations with myocardial infarction and coronary artery disease (CAD), but the mechanisms underlying these associations remain largely unclear. Carotid intima-media thickness (IMT) is a measure of early arterial remodeling and arteriosclerosis. Therefore, if CAD associated SNPs are also associated with carotid IMT; it suggests that they are acting via the early stages of the atherosclerotic process. In three large community based independent populations (CAPS, KORA and Young Finns) of European ancestry in which common carotid IMT had been measured (total 4961 individuals), we determined whether SNPs that have been associated with CAD in GWAS studies are also associated with carotid IMT. Associations with plaque were not examined. We identified 11 SNPs and one haplotype previously associated with CAD. None of these were associated with common carotid IMT. We found no evidence that SNPs associated with CAD on GWAS are also associated with carotid IMT. This suggests these genetic associations are not acting via early vessel remodeling or early arteriosclerosis.	f	\N
21925097	The aim of this pilot study was to evaluate the feasibility of long-term subcutaneous application of low-dose IL-2 in children with malignancies at very high risk of relapse who underwent highly T cell and B cell depleted HLA-identical (MUD) or full haplotype mismatched related hematopoetic stem cell transplantation. We studied 11 patients with acute leukemias / myelodysplastic syndrome and juvenile myelomonocytic leukemia (active disease and/or second stem cell transplantation, n = 8; ≥CR 2, n = 2) and relapsed or progressive Ewing's sarcoma (n = 2) who received prophylactic IL-2 treatment for a high probability of disease recurrence after allo-HSCT. Toxicities from IL-2 were transient fever, fatigue and local inflammation. In one patient GvHD grade III with no clear association to IL-2 administration occurred. IL-2 administration was started at median day 57 (range 13-154) post-transplant for a mean duration of 28 days (range 15-250). IL-2 administration clearly increased NK cell activity. 3 of 11 patients (ALL, AML, multifocal Ewings sarcoma) survived with a follow-up of ten years. In conclusion, long-term low-dose IL-2 subcutaneous application is feasible in children due to a low side effect profile even after HLA mismatched transplantation and may be a strategy to prevent relapse in pediatric malignancies with extremely high risk of relapse.	f	\N
21926372	Ryanodine receptor 1 (RyR1) is a Ca(2+) release channel located in the sarcoplasmic reticulum membrane of skeletal muscle. More than 200 variants in RyR1 have been identified in DNA from patients with malignant hyperthermia (MH) and congenital myopathies; only 30 have been sufficiently studied so as to be identified as MH-causative mutations. The Ala4894Thr RyR1 variant was found in a Japanese patient with susceptibility to MH, and the Ala4894Pro variant in a rare case of myopathy: congenital neuromuscular disease with uniform type 1 fiber (CNMDU1). We hypothesized that different Ala4894 variants of RyR1 cause different pathophysiological changes that are identifiable by having differing pharmacological sensitivities to RYR1 agonists. Expression vector with a mutation in RYR1 corresponding to the Ala4894Thr, Ala4894Pro, Ala4894Ser, or Ala 4894Gly variant of human RyR1 was transfected into human embryonic kidney 293 cells. At 72 hours after transfection, we determined the intracellular Ca(2+) changes induced by caffeine and 4-chloro-m-cresol (4CmC), in the presence or absence of dantrolene. Ala4894Thr-transfected cells and Ala4894Ser-transfected cells were more sensitive to caffeine than the wild type, and Ala4894Thr-transfected cells were also more sensitive to 4CmC than the wild type, whereas Ala4894Pro-transfected cells had no response to caffeine or 4CmC. Ala4894Gly-transfected cells were significantly less sensitive to caffeine than the wild type. In addition, the responses of Ala4894Thr-transfected cells and Ala4894Ser-transfected cells to caffeine were suppressed by dantrolene. We concluded that different Ala4894 variants of RyR1 lead to different agonist/antagonist sensitivities, which may predict differing RYR1 functionality during excitation-contraction coupling and sensitivity to MH. The hypersensitive Ala4894Thr-RyR1 is associated with MH and the poorly functional Ala4894Pro-RyR1 with CNMDU1.	f	\N
21934067	The role of CRP as a regulator of inflammation is not fully understood. Structural rearrangement in CRP results in expression of potent proinflammatory actions. Proteolysis of CRP yields the C-terminal peptide Lys(201)-Pro-Gln-Leu-Trp-Pro(206). Here, we investigated the impact of this peptide on neutrophil interactions with endothelial cells and platelets, critical inflammatory events triggering acute coronary artery disease. CRP peptide 201-206 induced L-selectin shedding from human neutrophils and inhibited L-selectin-mediated neutrophil adhesion to TNF-α-activated HCAECs under nonstatic conditions. CRP peptide 201-206 also attenuated shear-induced up-regulation of platelet P-selectin expression, platelet capture of neutrophils, and subsequent homotypic neutrophil adhesion in human whole blood. Anti-CD32 but not anti-CD16 or anti-CD64 mAb effectively prevented the inhibitory actions of CRP peptide 201-206. Substitution of Lys(201), Gln(203), or Trp(205) with Ala in CRP peptide 201-206 resulted in loss of the biological activities, whereas peptides in which Pro(202), Leu(204), or Pro(206) was substituted with Ala retained biological activity. We identified amino acid residues involved in CRP peptide 201-206-FcγRII (CD32) interactions, which mediate potent antineutrophil and antiplatelet adhesion actions, and these findings open up new perspectives for limiting inflammation and thrombosis underlying coronary artery disease.	f	\N
21935854	A 65-year-old woman presented with reduced general condition and dyspnoea that was progressive over the last months. Clinical findings revealed an exophthalmus on the right, xanthelasm and mild peripheral oedema. Previously, a pericardiocentesis had been performed due to a large pericardial effusion. A previous CT scan showed a mass attached to the pericardium extending through the atrio-ventricular groove and a thickened aorta. In addition, a retroperitoneal fibrosis and an occlusion of both Aa. iliacae internae were found. The ECG showed sinus rhythm. Laboratory findings demonstrated a microcytic anemia and a renal failure. Chest radiography showed a large cardiac silhouette, while the transthoracic echocardiography revealed a recurrent large pericardial effusion. A PET/CT scan of the chest and abdomen showed a tissue infiltration of the retroperitoneal structures, a mass surrounding the right coronary artery and the right orbita. Finally, a femur biopsy confirmed the diagnosis of Erdheim-Chester disease. With the diagnosis Erdheim-Chester disease we started a high dose immunsuppressive therapy using glucocorticoids and interferon-a. Tumour size slightly decreased during the following 2 months, however the patient developed a severe urosepsis and died from multiorgan failure. We report a case of an Erdheim-Chester disease with cardiovascular involvement primarily diagnosed due to a recurrent large pericardial effusion. In case of cardial tumors with interatrial septum or coronary artery involvement together with cerebral manifestations, an Erdheim-Chester disease should be taken into account.	f	\N
21938677	Cyclosporine A is a potent immunosuppressant used to prevent organ transplant rejection and treat various autoimmune diseases. However, cyclosporine A can also induce gingival overgrowth, which is characterized by increased extracellular matrix due to an altered balance between collagen synthesis and degradation. This study proposed to verify whether trans-glutaminase 2, an enzyme thought to be responsible for the assembly and remodelling of extracellular matrix, plays any role in the pathogenesis of cyclosporine A-induced gingival overgrowth. Cyclosporine A-induced gingival overgrowths were collected from 21 liver transplant patients and case-controlled with 20 non-hyperplastic gingival biopsies from healthy patients who had previous periodontal treatment. In both groups, the presence and tissue distribution of transglutaminase 2 were determined by immunohistochemistry and analyzed in comparison with the tissue morphology and expression of lymphocyte-related antigens (CD3 and CD20) and a vessel-related marker (CD34). Transglutaminase 2 expression showed a significant increase (2.6-fold) in the stromal component of cyclosporine A-treated patients compared with controls (p<0.001), which suggested that transglutaminase 2 had a role in the pathogenesis of the disease. Further studies should investigate the therapeutic effect of anti-transglutaminase 2 drugs (putrescine or 1,4-diamino-butane) in these patients.	f	\N
21946897	Genetic factors may play a role in fibrosis progression in patients with chronic hepatitis C (CHC). A cirrhosis risk score (CRS7) with seven single nucleotide polymorphisms was previously shown to correlate with cirrhosis in patients with CHC. This study aimed to assess the validity of CRS7 as a marker of fibrosis progression and cirrhosis and as a predictor of clinical outcomes in patients with CHC. A total of 938 patients (677 Caucasians, 165 African-Americans, and 96 Hispanic/Other) in the Hepatitis C Antiviral Long-term Treatment against Cirrhosis Trial were studied. CRS7 was categorized a priori as high risk (n=440), medium risk (n=310), or low risk (n=188). Patients were assessed for four possible outcomes: fibrosis progression, cirrhosis, clinical outcomes [decompensation or hepatocellular carcinoma (HCC)], or HCC alone. Twenty-nine percent (142/493) developed an increase in fibrosis score by greater than or equal to 2 points on follow-up biopsies, 58% had cirrhosis on one or more biopsies, 35% developed at least one clinical outcome, and 13% developed HCC. CRS7 (trend test) was associated with risk for fibrosis progression (P=0.04) with adjusted hazard ratio of 1.27 (95% confidence interval: 1.01-1.58) and with cirrhosis (P=0.05) with adjusted odds ratio of 1.19 (1.00-1.41). Rates of HCC and clinical outcomes were increased in patients with higher CRS7 scores, but were not statistically significant (P=0.12 clinical outcomes, and P=0.07 HCC). A single nucleotide polymorphism in AZIN1 was significantly associated with fibrosis progression. CRS7 was validated as a predictor of fibrosis progression and cirrhosis among Hepatitis C Antiviral Long-term Treatment against Cirrhosis patients, who all had advanced fibrosis. CRS7 was not predictive of clinical outcome.	f	\N
21953291	Although tumor reduction via present-day prehepatectomy chemotherapy can render initially unresectable disease potentially resectable, little is known about the effects of such chemotherapy on liver metastases with known attachment to or invasion of major intrahepatic vessels. We histologically assessed the relationships of liver tumors to major intrahepatic vessels after chemotherapy. In 45 patients who underwent chemotherapy and hepatectomy with pretreatment images showing metastases attached to or invading major intrahepatic vessels, 77 metastases showed attachment to or invasion of 96 vessels. Using postchemotherapy imaging, 11 of 77 metastases (14.3%) appeared separated from 12 of 96 major hepatic vessels (12.5%). Among 83 vessels later examined pathologically, 29 showed direct invasion (35%) and 10 showed attachment (12%). Tumors involved another 9 vessels (11%) that were separated surgically from the tumor and preserved during hepatectomy. Tumor attachment that exceeded 25% of vessel circumferences via imaging after chemotherapy was a factor associated with pathological vascular invasion or attachment according to multivariate analysis (relative risk, 8.449; 95% confidence interval, 1.961-36.415; P = .0042). Liver metastasis attachment to or invasion of major intrahepatic vessels is difficult to eradicate even with otherwise effective chemotherapy.	f	\N
21955617	Osteoarthritis (OA) is a degenerative joint disease characterized by progressive loss of articular cartilage, subchondral bone sclerosis, osteophyte formation, and synovial inflammation, causing substantial physical disability, impaired quality of life, and significant health care utilization. Traditionally, non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase (COX)-2 inhibitors, have been used to treat pain and inflammation in OA. Besides its anti-inflammatory properties, evidence is accumulating that celecoxib, one of the selective COX-2 inhibitors, has additional disease-modifying effects. Celecoxib was shown to affect all structures involved in OA pathogenesis: cartilage, bone, and synovium. As well as COX-2 inhibition, evidence indicates that celecoxib also modulates COX-2-independent signal transduction pathways. These findings raise the question of whether celecoxib, and potentially other coxibs, is more than just an anti-inflammatory and analgesic drug. Can celecoxib be considered a disease-modifying osteoarthritic drug? In this review, these direct effects of celecoxib on cartilage, bone, and synoviocytes in OA treatment are discussed.	f	\N
21959310	We report 9 patients with pleural biopsies referred because of concern about infiltration of what appeared to be chest wall fat by pan-keratin-positive spindled cells, a finding that led to a consideration of desmoplastic mesothelioma. All patients showed pleural effusions/pleural thickening on computed tomographic scan. Pleural biopsy showed a greatly thickened and fibrotic paucicellular pleura with circular fat-like spaces and, sometimes, adjacent oblate spaces mostly deep in the fibrotic area. Indistinct, keratin-positive, spindle cells arranged parallel to the pleural surface coursed between these fat-like spaces. S-100 stains were negative around the fat-like spaces. Vimentin stains showed that the spaces did not have a cellular lining of any kind. Sometimes the spaces contained faintly hematoxyphilic material that was Alcian blue positive, and similar material was seen in the fibrotic stroma. Follow-up with periods ranging from 6 to 30 months revealed that 8 cases had stable disease on chest imaging or by clinical findings. One case had slowly progressive pleural thickening. These observations suggest that spaces resembling fat may be encountered in fibrotic pleurae and that horizontally oriented keratin-positive spindled cells between the fat-like spaces deep in the fibrotic portion of a thickened pleura represent a benign finding seen in some cases of organizing pleuritis/fibrothorax. The spaces themselves are probably artifacts derived from the biopsy procedure and/or cutting artifacts. In contrast, in true desmoplastic mesotheliomas there is downward, rather than horizontal, growth of keratin-positive spindled cells running between clearly definable fat cells.	f	\N
21963153	Multimorbidity is increasing in frequency. It can be quantitatively measured and is a major correlate of high use of health services resources of all types, especially over time. The ACG System for characterizing multimorbidity is the only widely used method that is based on combinations of different TYPES of diagnoses over time, rather than the presence or absence of particular conditions or numbers of conditions. It incorporates administrative data (as from claims forms or medical records) on all types of encounters and is not limited to diagnoses captured during hospitalizations or other places of encounter. It can be employed in any one or combination of analytic models, and can incorporate medication use if desired. It is being used in clinical care, management of health services resources, in health services research to control for degree of morbidity, and in understanding morbidity patterns over time. In addition to its research uses, it is being employed in many countries in various applications as a policy to better understand health needs of populations and tailor health services resources to health needs.	f	\N
21970661	Toxoplasma gondii is a major cause of chronic parasitic infection in the world. This protozoan can cause retino-choroiditis in newborns and in adults, both immunocompetent and immunodeficient. This disease tends to be recurrent and can lead to severe visual impairment. The authors review current knowledge on the role of parasite genetics in influencing susceptibility to ocular toxoplasmosis and on the immuno-pathogenesis of this disease.	f	\N
21971930	The development of drug resistance represents a major complication in the effective treatment of breast cancer. Epigenetic therapy, through the use of histone deacetylase inhibitors (HDACi) or demethylation agents, is an emerging area of therapeutic targeting in a number of ontological entities, particularly in the setting of aggressive therapy-resistant disease. Using the well-described HDAC inhibitor trichostatin A (TSA) we demonstrate the suppression of in vitro clonogenicity in the previously described apoptosis-resistant MCF-7TN-R breast carcinoma cell line. Additionally, recent work has demonstrated that these agents can alter the expression profile of microRNA signatures in malignant cells. Using an unbiased microRNA microarray analysis, changes in miRNA expression of MCF-7TN-R cells treated with TSA for 24 h were analyzed. We observed significant up-regulation of 22 miRNAs and down-regulation of 10 miRNAs in response to TSA treatment. Our results demonstrate that the HDACi, TSA, exerts anticancer activity in the apoptosis-resistant MCF-7TN-R breast carcinoma cell line. This activity is correlated with TSA alteration of microRNA expression profiles indicative of a less aggressive phenotype.	f	\N
21973247	Mortality level and cause of death trends are evaluated to chart the epidemiological transition in Fiji. IMPLICATIONS for current health policy are discussed. Published data for infant mortality rate (IMR), life expectancy (LE) and causes of death for 1940-2008 were assessed for quality, and compared with mortality indices generated from recent Ministry of Health death recording. Trends in credible mortality estimates are compared with trends in proportional mortality for cause of death. IMR declined from 60 deaths (per 1,000) in 1945 to below 20 by 2000. IMR for 2006-08 is estimated at 18-20 deaths per 1,000 live births. Excessive LE estimates arise by imputing from the IMR using inappropriate models. LE increased, but has been stable at 64 years for males and 69 years for females since the late 1980s and early 1990s respectively. Proportional mortality from diseases of the circulatory system has increased from around 20% in the 1960s to more than 45%. Extensive variation in published mortality estimates was indentified, including clearly incompatible ranges of IMR and LE. Mortality decline has stagnated. Relatively low IMR and proportional mortality trends suggest this is largely due to chronic diseases (especially cardiovascular) in adults. Reconciliation of mortality data in Fiji to reduce uncertainty is urgently needed. Fiji's health services and donor partners should place continued and increased emphasis on effective control strategies for cardiovascular disease.	f	\N
21978795	Objective of this study was to evaluate the acute cardiovascular and respiratory effects of switching on the deep brain stimulation in the follow up of nine Parkinson's disease patients with subthalamic nucleus stimulation and six cluster headache patients with posterior hypothalamic area stimulation. Systolic and diastolic blood pressure, heart rate, and respiratory rate were monitored continuously during supine rest in both groups. Each patient was assessed in two conditions: resting supine with stimulator off and with stimulator on. In supine resting condition switching on the DBS induced no significant changes (p>0.05) in systolic and diastolic blood pressure as well as in heart rate and respiratory rate, in both groups of patients, either taking 1 min or 10 heartbeats as a sample for analysis. Switching on the DBS does not modify heart rate, blood pressure nor respiratory rate in both Parkinson and cluster headache patients under resting conditions.	f	\N
21985741	Rarely, a patient presents to a surgeon for evaluation of an adrenal incidentaloma where the final pathology is primary malignancy. For primary adrenal lymphoma, fewer than 100 cases have been reported in the literature. We report a case of unilateral primary adrenal aggressive B cell lymphoma discovered incidentally in a 41-year-old female. Preoperative testing demonstrated the 6-cm mass to be biochemically silent. Subsequently, the patient underwent a laparoscopic adrenalectomy. Following pathologic diagnosis of B cell lymphoma, a metastatic workup was negative, and she underwent treatment with systemic chemotherapy. She is currently disease free 6 months postoperatively. Primary adrenal lymphoma should be considered in patients with unilateral adrenal incidentaloma. We believe that adherence to guidelines of resection of incidentalomas allowed for early surgical intervention and possible cure.	f	\N
21986202	Parkinson's disease is a common neurodegenerative disorder characterized by α-synuclein (α-Syn)-containing Lewy body formation and selective loss of dopaminergic neurons in the substantia nigra. We have demonstrated the modulating effect of noopept, a novel proline-containing dipeptide drug with nootropic and neuroprotective properties, on α-Syn oligomerization and fibrillation by using thioflavin T fluorescence, far-UV CD, and atomic force microscopy techniques. Noopept does not bind to a sterically specific site in the α-Syn molecule as revealed by heteronuclear two-dimensional NMR analysis, but due to hydrophobic interactions with toxic amyloid oligomers, it prompts their rapid sequestration into larger fibrillar amyloid aggregates. Consequently, this process rescues the cytotoxic effect of amyloid oligomers on neuroblastoma SH-SY5Y cells as demonstrated by using cell viability assays and fluorescent staining of apoptotic and necrotic cells and by assessing the level of intracellular oxidative stress. The mitigating effect of noopept against amyloid oligomeric cytotoxicity may offer additional benefits to the already well-established therapeutic functions of this new pharmaceutical.	f	\N
21987744	The filoviruses, Marburg virus and Ebola virus, cause severe hemorrhagic fever with a high mortality rate in humans and nonhuman primates. Among the most-promising filovirus vaccines under development is a system based on recombinant vesicular stomatitis virus (rVSV) that expresses a single filovirus glycoprotein (GP) in place of the VSV glycoprotein (G). Importantly, a single injection of blended rVSV-based filovirus vaccines was shown to completely protect nonhuman primates against Marburg virus and 3 different species of Ebola virus. These rVSV-based vaccines have also shown utility when administered as a postexposure treatment against filovirus infections, and a rVSV-based Ebola virus vaccine was recently used to treat a potential laboratory exposure. Here, we review the history of rVSV-based vaccines and pivotal animal studies showing their utility in combating Ebola and Marburg virus infections.	f	\N
21994137	Proctitis is a common problem and is most frequently associated with inflammatory bowel diseases. However, the incidence of infectious proctitis appears to be rising, especially in men who have sex with men. This may be due to the rise of people participating in receptive anal sex as well as the increase in sexually transmitted infections. The most frequently reported pathogens include Neisseria gonorrhoeae, Chlamydia trachomatis, Treponema pallidum, and herpes simplex. Symptoms of infectious proctitis can include rectal blood and mucous discharge, anorectal pain, ulcers, and occasionally lymphadenopathy and fever. History and physical examination are crucial in establishing a diagnosis, supported by endoscopy, histology, serology, culture and PCR. Treatment with antibiotics or antivirals is usually initiated, either empirically or after establishing a diagnosis. Co-infections, HIV testing, and treatment of sexual partners should always be considered.	f	\N
22002662	The destruction of blood-brain barrier (BBB) and blood-nerve barrier (BNB) has been considered to be a key step in the disease process of a number of neurological disorders including cerebral ischemia, Alzheimer's disease, multiple sclerosis, and diabetic neuropathy. Although glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) facilitate neuronal or axonal regeneration in the brain or peripheral nerves, their action in the BBB and BNB remains unclear. The purpose of the present study was to elucidate whether these neurotrophic factors secreted from the brain or peripheral nerve pericytes increase the barrier function of the BBB or BNB, using our newly established human brain microvascular endothelial cell (BMEC) line or peripheral nerve microvascular endothelial cell (PnMEC) line. GDNF increased the expression of claudin-5 and the transendothelial electrical resistance (TEER) of BMECs and PnMECs, whereas BDNF did not have this effect. Furthermore, we herein demonstrate that the GDNF secreted from the brain and peripheral nerve pericytes was one of the key molecules responsible for the up-regulation of claudin-5 expression and the TEER value in the BBB and BNB. These results indicate that the regulation of GDNF secreted from pericytes may therefore be a novel therapeutic strategy to modify the BBB or BNB functions and promote brain or peripheral nerve regeneration.	f	\N
22010196	The eukaryotic cell is organized into membrane-covered compartments that are characterized by specific sets of proteins and biochemically distinct cellular processes. The appropriate subcellular localization of proteins is crucial because it provides the physiological context for their function. In this Commentary, we give a brief overview of the different mechanisms that are involved in protein trafficking and describe how aberrant localization of proteins contributes to the pathogenesis of many human diseases, such as metabolic, cardiovascular and neurodegenerative diseases, as well as cancer. Accordingly, modifying the disease-related subcellular mislocalization of proteins might be an attractive means of therapeutic intervention. In particular, cellular processes that link protein folding and cell signaling, as well as nuclear import and export, to the subcellular localization of proteins have been proposed as targets for therapeutic intervention. We discuss the concepts involved in the therapeutic restoration of disrupted physiological protein localization and therapeutic mislocalization as a strategy to inactivate disease-causing proteins.	f	\N
22011558	Although moderate alcohol drinkers have lower rates of incident coronary artery disease than abstainers, much less is known about the health effects of different patterns of alcohol use in women with established coronary artery disease. In the Determinants of Myocardial Infarction Onset Study, 1,253 women hospitalized for acute myocardial infarction (MI) at 64 centers nationwide from 1989 to 1996 were followed for mortality through December 31, 2007. Of the women, 761 (61%) reported abstention in the year before their MIs, 280 (22%) reported consumption of <1 serving/week, 75 (6%) reported consumption of 1 to 3 servings/week, and 137 (11%) reported consumption of ≥3 servings/week. Using Cox proportional-hazards models, the associations between total weekly volume of consumption, drinking days per week, drinks per drinking day, and beverage type with 10-year mortality were investigated, adjusting for clinical and socioeconomic potential confounders. Compared with abstention, adjusted hazard ratios were 0.66 (95% confidence interval 0.50 to 0.86) for <1 serving/week, 0.65 (95% confidence interval 0.38 to 1.11) for 1 to 3 servings/week, and 0.65 (95% confidence interval 0.38 to 1.11) for ≥3 servings/week (p for trend = 0.008). No differences were found by beverage type, and generally inverse associations of drinking frequency and quantity with mortality were found. In conclusion, in women who survive MI, moderate drinking is associated with a decreased risk for mortality, with no clear differences on the basis of pattern or beverage type. These results suggest that women who survive MI need not abstain from alcohol, but any derived benefit would appear to occur well below currently recommended limits in alcohol consumption.	f	\N
22015458	Cholangitis arising from biliary infection dominates the prognosis in Caroli's disease. To clarify the influences of bacterial infection on the biliary cystogenesis, in vivo and in vitro studies were performed using the polycystic kidney (PCK) rat as an animal model of Caroli's disease. Cholangitis became a frequent histological finding in aged PCK rats, and neovascularization around the bile ducts also increased in aged PCK rats. Immunohistochemistry revealed that expression of vascular endothelial growth factor (VEGF) was increased in PCK rat biliary epithelium. In vitro, PCK cholangiocytes overexpressed VEGF, and the supernatant of cultured PCK cholangiocytes significantly increased the proliferative activity, migration, and tube formation of cultured rat vascular endothelial cells. Stimulation with lipopolysaccharide (LPS) further induced VEGF expression in PCK cholangiocytes, which might be mediated by signaling pathways involving phosphatidylinositol 3-kinase (PI3K)-Akt and c-Jun N-terminal kinase (JNK). Both LPS and VEGF increased cell proliferative activity in PCK cholangiocytes, and siRNA against VEGF significantly reduced LPS-induced cell proliferation. Thus, LPS-induced overexpression of VEGF in the biliary epithelium may lead to hypervascularity around the bile ducts; concurrently, LPS and VEGF act as cell proliferation factors for cholangiocytes. Biliary infection may thus exacerbate biliary cystogenesis in PCK rats.	f	\N
22016594	We investigated the clinical characteristics and prognosis of elderly patients with acute lymphoblastic leukemia (ALL). We reviewed the clinical data, laboratory findings, bone marrow findings, and cytogenetic analysis of elderly patients (≥ 60 years) with ALL, and data of an additional 101 younger adult patients (< 60 years) with ALL were reviewed for comparison. Twenty-six elderly patients (≥ 60 years) and 101 younger adult patients (< 60 years) with ALL were retrospectively enrolled. The median follow-up duration was 6.0 months (range, 0.4 to 113.2) in the elderly patients and 21.7 months (range, 1.0 to 122.7) in the adult patients. In total, 34.6% (9 patients) of the elderly patients and 24.8% (25 patients) of the adult patients had Philadelphia chromosome positive ALL. The overall complete remission (CR) rate was much higher in the younger than in the elderly patients (94.1% vs. 57.7%, p < 0.001). The median overall survival (OS) of the younger patients (< 60 years) was 26.3 months, whereas that of the elderly patients (≥ 60 years) was 10.3 months (p = 0.003). In the elderly patients with ALL, T cell lineage and the presence of lymphadenopathy were significant prognostic factors for OS in a univariate analysis (p = 0.033 and 0.041, respectively). The outcomes of Korean elderly patients with ALL were poor, and the shorter OS was mainly due to the low CR rate. T-cell lineage and the presence of lymphadenopathy were significant prognostic factors in Korean elderly patients with ALL.	f	\N
22017219	Several genetic loci have been suggested to be associated with bipolar disorder but results have been inconsistent. Studying associations between bipolar symptoms and candidate genes may better expose this relationship. Here we investigate the association between bipolar key symptoms and the P2RX7 gene. Key symptoms of mania were rated in two sets of medicated bipolar disorder patients (n=171 and n=475) at two specialized outpatient clinics for affective disorders and three regular psychiatric outpatient units in Sweden. The relationships between all manic symptoms according to DSM-IV were entered in a principal component analysis. We used a case-case model to reduce the genetic heterogeneity and tested associations between four factors related to manic symptoms and their association to four single nucleotide polymorphisms in the P2RX7 gene. The combination of the cognitive symptoms, distractibility, talkativeness, and thought disorder was significantly associated with rs1718119 in the P2RX7 gene in Set 1 [odds ratio (OR) = 1.78; p=0.011]. The association was re-tested in the second set (OR = 1.42; p=0.009). In the total sample, the association was even stronger (OR = 1.49; p<0.001). None of the other factors was associated with the P2RX7 gene. Within the first factor, the distractibility symptom accounted for a significant portion of the association to rs1718119 (p=0.016). There is an association between specific symptoms of bipolar disorder and the P2RX7 gene. This finding may open up new approaches to elucidating the neurobiology behind bipolar symptoms.	f	\N
22018216	Although endoscopy and angiography have changed the management of lower gastrointestinal bleeding and the majority of patients respond to conservative treatment 10-20% of cases have no recognizable site of hemorrhage. About 10-30% of all patients will require operative intervation. A very rare case of massive lower gastrointestinal bleeding in a young patient who was found to suffer from two causes of gastrointestinal hemorrhage in the same time is reported. The patient had to undergo surgery for the control of bleeding. A 23 years old male Greek patient presented to the emergency department of our hospital because of three episodes of hematochezia during the last 10 hours. He was admitted to the surgical department for monitoring of his condition. In the next 10 hours the hematochezia continued and the patient although being transfused with three units of packed red blood cells, started to become unstable with his vital signs affected, having also a syncoptic episode. Emergent colonoscopy could not recognize the site of hemorrhage or any other pathology in the colon, but revealed an intestinal lumen full of blood from the anus to the cecum. It was decided that the patient should undergo operation to stop bleeding. An extensive right hemicolectomy was performed. After that the patient remained stable and showed no signs of hemorrage. The histopathological examination of the specimen showed an arteriovenous malformation but also lesions of the mucosa compatible with early inflammatory bowel disease. In young patients with massive lower gastrointestinal bleeding of unknown origin, extensive right hemicolectomy provides a good and safe therapeutic choice that will control hemorrhage in most cases with the advantage of lower mortality and morbidity rates compared to subtotal colectomy. Close monitoring of the patient postoperatively is essential.	f	\N
22023956	Atherosclerotic carotid artery disease remains an important cause of cerebrovascular ischemic disease. We present a patient with residual stenosis of the distal internal carotid artery following carotid endarterectomy that was treated with stenting. The case highlights the potential complimentary benefits of carotid endarterectomy and carotid stenting.	f	\N
22026553	Evidence suggests that occult adenoma remnants are responsible for persistent Cushing's disease (CD) following transsphenoidal surgery (TSS). To optimize the outcome, we have adapted our microsurgical concept. The influence of our surgical strategy on remission rate and pituitary function is presented. 83 patients undergoing TSS for newly diagnosed CD. An enlarged resection was performed in 36 patients. A modified exploration technique with radial incisions was performed in 19 patients in whom an adenoma was not readily detectable. The overall remission rate of primary surgery was 84·3% (70/83). A remission rate of 87·5% (63/72) was achieved in microadenomas. Six patients with microadenomas were re-operated for persistence, and hypercortisolism was corrected in five of them. With re-operation included, the overall remission rate for microadenomas was 94·4%. No procedure-related complications occurred in primary surgery. Of the patients in remission, 72·5% had early postoperative random cortisol levels below 2 μg/dl, 17·4% had cortisol levels between 2 and 5 μg/dl, and 10·1% had cortisol levels >5 μg/dl. 15·2% of the patients with microadenomas developed postoperative partial hypopituitarism and 3% diabetes insipidus. No increased rate of hypopituitarism was found with enlarged adenomectomy compared to selective adenomectomy. Only a slightly higher rate of partial hypopituitarism (23·1%) was found if extensive exploration was required. With our microsurgical concept, a high initial cure rate is achievable with minimal surgical morbidity. Enlarged adenomectomy has no adverse effect on the rate of postoperative hypopituitarism. Early repeat surgery is a successful option if CD persists.	f	\N
22034985	Earlier, we identified proteins connecting different disease proteins in the human protein-protein interaction network and quantified their mediator role. An analysis of the networks of these mediators shows that proteins connecting heart disease and diabetes largely overlap with the ones connecting heart disease and obesity. We quantified their overlap, and based on the identified topological patterns, we inferred the structural disease-relatedness of several proteins. Literature data provide a functional look of them, well supporting our findings. For example, the inferred structurally important role of the PDZ domain-containing protein GIPC1 in diabetes is supported despite the lack of this information in the Online Mendelian Inheritance in Man database. Several key mediator proteins identified here clearly has pleiotropic effects, supported by ample evidence for their general but always of only secondary importance. We suggest that studying central nodes in mediator networks may contribute to better understanding and quantifying pleiotropy. Network analysis provides potentially useful tools here, as well as helps in improving databases.	f	\N
22040839	Coronary artery disease (CAD) is the major cause of morbidity and mortality in type 2 diabetic patients. Severe vitamin D deficiency has been shown to predict cardiovascular mortality in type 2 diabetic patients. We investigated the association among severe vitamin D deficiency, coronary calcium score (CCS), and asymptomatic CAD in type 2 diabetic patients with elevated urinary albumin excretion rate (UAER) >30 mg/24 h. This was a cross-sectional study including 200 type 2 diabetic patients without a history of CAD. Severe vitamin D deficiency was defined as plasma 25-hydroxyvitamin D (p-25[OH]D3) <12.5 nmol/L. Patients with plasma N-terminal pro-brain natriuretic peptide >45.2 ng/L or CCS ≥400 were stratified as being high risk for CAD (n= 133). High-risk patients were examined by myocardial perfusion imaging (MPI; n = 109), computed tomography angiography (n = 20), or coronary angiography (CAG; n = 86). Patients' p-25(OH)D3 levels were determined by high-performance liquid chromatography/tandem mass spectrometry. The median (range) vitamin D level was 36.9 (3.8-118.6) nmol/L. The prevalence of severe vitamin D deficiency was 9.5% (19/200). MPI or CAG demonstrated significant CAD in 70 patients (35%). The prevalence of CCS ≥400 was 34% (68/200). Severe vitamin D deficiency was associated with CCS ≥400 (odds ratio [OR] 4.3, 95% CI [1.5-12.1], P = 0.005). This association persisted after adjusting for risk factors (4.6, 1.5-13.9, P = 0.007). Furthermore, severe vitamin D deficiency was associated with asymptomatic CAD (adjusted OR 2.9, 1.02-7.66, P = 0.047). In high-risk type 2 diabetic patients with elevated UAER, low levels of vitamin D are associated with asymptomatic CAD.	f	\N
22047508	Hypertension is a common major risk factor for stroke and coronary heart disease. Little is known about how achievement of financially incentivised and non-incentivised indicators of quality of care varies with deprivation, or about the effect of financial incentives on health inequalities in hypertension. General practices in the UK have received financial incentives for high quality care since 2004. This study set out to assess the variations in achievement of incentivised and non-incentivised quality indicators for hypertension by patient area deprivation, before and after the introduction of financial incentives. Achievement of 14 quality indicators for hypertension in 304 patient participants in 18 general practices in Norfolk, England was assessed one year before (2003) and one year after (2005) the introduction of financial incentives. Four indicators were incentivised and 10 were non-incentivised. Each participant's postcode was linked to an index of multiple deprivation score. The range of achievement of incentivised quality indicators was 65-94% in the least deprived third of participants, and 77-94% in the most deprived third in 2003 and 2005 combined. For non-incentivised indicators, the range was 7-85% in the least deprived and 24-93% in the most deprived third.Achievement of incentivised quality indicators in 2003 and 2005 combined did not vary significantly by area deprivation. Achievement of three of 10 non-incentivised indicators was higher in participants from more deprived postcode areas: providing lifestyle advice (odds ratio 1.34, 95% confidence interval 1.00-1.79), assessment of peripheral vascular disease (1.54, 1.02-2.35) and electrocardiography (1.38, 1.04-1.82). Participants from more deprived areas received at least the same, and sometimes better, quality of care than those from less deprived areas. Quality of care for hypertension in general practice may not follow the inequitable distribution seen with some other conditions.	f	\N
22050270	Vitiligo is a common acquired depigmentation disorder caused by the loss of melanocytes. Despite the numerous treatment modalities available for vitiligo, responses to treatment are still unsatisfactory. For this reason, new treatment modalities and approaches are needed. To investigate the effects of fractional carbon dioxide (CO(2) ) laser therapy followed by systemic narrowband ultraviolet B (NB-UVB) phototherapy on nonsegmental vitiligo (NSV) as a prospective and randomized left-right comparative study. Ten patients with NSV who presented symmetrical vitiligo lesions with no further improvement despite more than 1 year of conventional treatment were enrolled. Two sessions of half-body fractional CO(2) laser therapy were performed at a 2-month interval. NB-UVB phototherapy was then administered to the entire body 5 days after each fractional laser treatment twice a week, increasing the dose incrementally by 15% at each session. Objective clinical assessments were made by two blinded dermatologists using a quartile grading scale, and the patients' overall satisfaction was evaluated using a 10-point visual analogue scale. Two months after the last treatment, mean improvement scores, assessed by physicians, were significantly higher for those treated with half-body fractional CO(2) laser therapy followed by NB-UVB phototherapy, compared with those treated with NB-UVB alone (P=0·034). In addition, according to subjective assessment, the half-body laser treatment followed by NB-UVB showed significantly higher improvements compared with NB-UVB treatment alone (P=0·023). Noticeable adverse events, such as infection, scarring and Koebner phenomenon, were not found in any patient. This study suggests that fractional CO(2) laser therapy followed by NB-UVB phototherapy could be used effectively and safely as an alternative modality for the treatment of refractory vitiligo.	f	\N
22054870	Age-related cognitive decline is likely promoted by accumulated brain injury due to chronic conditions of aging, including neurodegenerative and vascular disease. Because common neuronal mechanisms may mediate the adaptation to diverse cerebral insults, we hypothesized that susceptibility for age-related cognitive decline may be due in part to a shared genetic network. We have therefore performed a genome-wide association study using a quantitative measure of global cognitive decline slope, based on repeated measures of 17 cognitive tests in 749 subjects from the Religious Orders Study. Top results were evaluated in 3 independent replication cohorts, consisting of 2279 additional subjects with repeated cognitive testing. As expected, we find that the Alzheimer's disease (AD) susceptibility locus, APOE, is strongly associated with rate of cognitive decline (P(DISC) = 5.6 × 10(-9); P(JOINT)= 3.7 × 10(-27)). We additionally discover a variant, rs10808746, which shows consistent effects in the replication cohorts and modestly improved evidence of association in the joint analysis (P(DISC) = 6.7 × 10(-5); P(REP) = 9.4 × 10(-3); P(JOINT) = 2.3 × 10(-5)). This variant influences the expression of 2 adjacent genes, PDE7A and MTFR1, which are potential regulators of inflammation and oxidative injury, respectively. Using aggregate measures of genetic risk, we find that known susceptibility loci for cardiovascular disease, type 2 diabetes, and inflammatory diseases are not significantly associated with cognitive decline in our cohort. Our results suggest that intermediate phenotypes, when coupled with larger sample sizes, may be a useful tool to dissect susceptibility loci for age-related cognitive decline and uncover shared molecular pathways with a role in neuronal injury.	f	\N
22054881	Lung cancer is a heterogeneous disease clinically, biologically, histologically, and molecularly. Understanding the molecular causes of this heterogeneity, which might reflect changes occurring in different classes of epithelial cells or different molecular changes occurring in the same target lung epithelial cells, is the focus of current research. Identifying the genes and pathways involved, determining how they relate to the biological behavior of lung cancer, and their utility as diagnostic and therapeutic targets are important basic and translational research issues. This article reviews current information on the key molecular steps in lung cancer pathogenesis, their timing, and clinical implications.	f	\N
22067963	Lewy pathology in Parkinson disease (PD) extends well beyond the CNS, also affecting peripheral autonomic neuronal circuits, especially the enteric nervous system (ENS). The ENS is an integrative neuronal network also referred to as "the brain in the gut" because of its similarities to the CNS. We have recently shown that the ENS can be readily analyzed using routine colonic biopsies. This led us to propose that the ENS could represent a unique window to assess the neuropathology in living patients with PD. In this perspective, we discuss current evidence which indicates that the presence of ENS pathology may by exploited to improve our understanding and management of PD and likely other neurodegenerative disorders.	f	\N
22068070	Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare adrenergically mediated arrhythmogenic disorder classically induced by exercise or emotional stress and found in structurally normal hearts. It is an important cause of cardiac syncope and sudden death in childhood. Catecholaminergic polymorphic ventricular tachycardia is a genetic cardiac channelopathy with known mutations involving genes affecting intracellular calcium regulation. We present a case of a 14-year-old boy who had cardiopulmonary arrest after an emotionally induced episode of CPVT while attempting to invite a girl to the school dance. Review of his presenting cardiac rhythm, induction of concerning ventricular arrhythmias during an exercise stress test, and genetic testing confirmed the diagnosis of CPVT. He recovered fully and was treated with β-blocker therapy and placement of an implantable cardioverter-defibrillator. In this report, we discuss this rare but important entity, including its molecular foundation, clinical presentation, basics of diagnosis, therapeutic options, and implications of genetic testing for family members. We also compare CPVT to other notable cardiomyopathic and channelopathic causes of sudden death in youth including hypertrophic cardiomyopathy, arrhythmogenic right ventricular dysplasia, long QT syndrome, short QT syndrome, and Brugada syndrome.	f	\N
22072024	Systemic lupus erythematosus (SLE) can be a severe and potentially life-threatening disease that often represents a therapeutic challenge because of its heterogeneous organ manifestations. Only glucocorticoids, chloroquine and hydroxychloroquine, azathioprine, cyclophosphamide and very recently belimumab have been approved for SLE therapy in Germany, Austria and Switzerland. Dependence on glucocorticoids and resistance to the approved therapeutic agents, as well as substantial toxicity, are frequent. Therefore, treatment considerations will include 'off-label' use of medication approved for other indications. In this consensus approach, an effort has been undertaken to delineate the limits of the current evidence on therapeutic options for SLE organ disease, and to agree on common practice. This has been based on the best available evidence obtained by a rigorous literature review and the authors' own experience with available drugs derived under very similar health care conditions. Preparation of this consensus document included an initial meeting to agree upon the core agenda, a systematic literature review with subsequent formulation of a consensus and determination of the evidence level followed by collecting the level of agreement from the panel members. In addition to overarching principles, the panel have focused on the treatment of major SLE organ manifestations (lupus nephritis, arthritis, lung disease, neuropsychiatric and haematological manifestations, antiphospholipid syndrome and serositis). This consensus report is intended to support clinicians involved in the care of patients with difficult courses of SLE not responding to standard therapies by providing up-to-date information on the best available evidence.	f	\N
22072546	Recent genome wide association studies have identified susceptibility loci for adult testicular germ cell tumors (GCT) near KITLG, SPRY4, BAK1, and DMRT1. We evaluated variants in these four genes to determine whether these are also susceptibility loci for pediatric GCTs. DNA was isolated from 52 pediatric GCTs (ages 0-21 years) obtained from the Cooperative Human Tissue Network. Control DNA was isolated from de-identified dried blood spots from 141 white newborns. Genotyping was conducted using TaqMan assays (rs4474514) or by PCR and sequencing (rs4324715, rs210138, and rs755383). Associations between variants and GCT were evaluated using logistic regression with adjustment for sex. We also evaluated whether the associations differed by age at GCT diagnosis (0-9 years, 10-21 years), sex, and tumor location (gonadal, non-gonadal). We observed a significant association for rs210138 (BAK1) and pediatric GCT overall (odds ratio (OR) = 1.80, 95% confidence interval (CI) 1.10-2.95, P = 0.02) with non-significant associations similar in magnitude in both the pediatric (P = 0.09) and adolescent (P = 0.06) age groups. The KITLG (rs4474514) and SPRY4 (rs4324715) variants were significantly associated with GCT only in the adolescent age group (rs4474514: OR = 2.28, 95% CI 1.09-4.79, P = 0.03 and rs4324715: OR = 2.40, 95% CI 1.19-4.83, P = 0.01). Associations were mostly similar when stratified by sex. This is the first study to suggest that these loci may also be important in susceptibility to GCTs in the adolescent (KITLG, SPRY4, and BAK1) and pediatric (BAK1) age groups.	f	\N
22078109	The aim of the present study was to examine abnormalities in the ankle-brachial index (ABI) and related risk factors in patients with type 2 diabetes. Between September 2003 and June 2010, the ABI was determined in 3924 outpatients attending the Diabetes Center of the People's Liberation Army 306th Hospital. In addition, demographic and laboratory data were collected. The risk factors for an abnormal ABI were determined using univariate and stepwise logistic regression analysis. The ABI was normal (0.91-1.3) in 93.1% of patients, low (<0.9) in 5.2%, and high (>1.3) in 1.7%. The prevalence of abnormal lower ABI was greater in elderly (≥ 65 years) patients (12.2%) than in younger (< 65 years) patients (3.6%). Using normal ABI as the reference, low ABI in younger patients was found to be independently associated with HbA1c, the urinary albumin:creatinine ratio, diabetic peripheral neuropathy, diabetic retinopathy, and cerebrovascular disease. A low ABI in elderly patients was found to be independently associated with age, smoking, HbA1c, uric acid, total cholesterol, diabetic peripheral neuropathy, diabetic retinopathy, diabetic nephropathy and cerebrovascular disease. A high ABI in younger patients was associated with being male. The prevalence of an abnormal ABI was high in patients with type 2 diabetes, especially elderly patients. Early identification and intensive treatment are needed to improve the quality of life and overall prognosis of patients with type 2 diabetes.	f	\N
22079056	Cancer represents a complex group of heterogeneous diseases. While many cancers share fundamental biological processes (hallmarks of cancer) necessary for their development and progression, cancers also distinguish themselves by their dependence on distinct oncogenic pathways. Over the last decade, targeted therapies have been introduced to the clinic with variable success. In truth, single targeted therapies may be successful in only a subset of malignancies but insufficient to address malignancies that often rely on multiple pathways, thus evading single targeted agents. Investigators have recently identified potentially functional components of the human genome that were previously thought to have no biological function. This discovery has added to the already established complexity of gene regulation in the pathogenesis of cancer. Non-coding RNAs represent key regulators of gene expression. Improved knowledge of their biogenesis and function may in turn lead to a better understanding of the heterogeneity of malignancies and eventually be leveraged as diagnostic, prognostic and therapeutic targets. MicroRNAs (miRNAs or miRs) for example, have the capacity for the regulation of multiple genes and thus redirection or reprogramming of biological pathways. However, several other members of the non-coding RNA family may be of equal biological relevance. In this review, we provide a perspective on emerging concepts in the clinical application of miRNA and other non-coding RNAs as biomarkers in cancer with an eye on the eventual integration of both miRNA and other non-coding RNA biology into our understanding of cancer pathogenesis and treatment.	f	\N
22082049	A growing number of prognostic indices for chronic obstructive pulmonary disease (COPD) is developed for clinical use. Our aim is to identify, summarize and compare all published prognostic COPD indices, and to discuss their performance, usefulness and implementation in daily practice. We performed a systematic literature search in both Pubmed and Embase up to September 2010. Selection criteria included primary publications of indices developed for stable COPD patients, that predict future outcome by a multidimensional scoring system, developed for and validated with COPD patients only. Two reviewers independently assessed the index quality using a structured screening form for systematically scoring prognostic studies. Of 7,028 articles screened, 13 studies comprising 15 indices were included. Only 1 index had been explored for its application in daily practice. We observed 21 different predictors and 7 prognostic outcomes, the latter reflecting mortality, hospitalization and exacerbation. Consistent strong predictors were FEV1 percentage predicted, age and dyspnoea. The quality of the studies underlying the indices varied between fairly poor and good. Statistical methods to assess the predictive abilities of the indices were heterogenic. They generally revealed moderate to good discrimination, when measured. We focused on prognostic indices for stable disease only and, inevitably, quality judgment was prone to subjectivity. We identified 15 prognostic COPD indices. Although the prognostic performance of some of the indices has been validated, they all lack sufficient evidence for implementation. Whether or not the use of prognostic indices improves COPD disease management or patients' health is currently unknown; impact studies are required to establish this.	f	\N
22082649	INTRODUCTION The identification of novel prognostic markers may help to better assess survival probability in different subgroups of patients with non-small-cell lung cancer (NSCLC) and to tailor treatment according to the molecular profile of the tumour. AIM We sought to examine whether the immunohistochemical expression of excision repair cross-complementing 1 (ERCC1), an essential component of the nucleotide excision repair pathway, may predict prognosis in NSCLC. MATERIAL AND METHOD Formalin-fixed paraffin-embedded tumour samples from 44 Turkish patients with NSCLC treated by adjuvant platinum-based chemotherapy were included in the study. Immunohistochemical expression levels of ERCC1 were correlated with clinical outcomes by Kaplan-Meier curves and multivariable Cox proportional hazards regression analysis. RESULTS A total of 29 patients had ERCC1-negative tumours while 15 had ERCC1-positive tumours. The mean progression- free survival (PFS) was significantly lower in patients with ERCC1-positive tumours (13±2 months) than in those with ERCC1-negative tumours (27±5 months, p<0.05). Similarly, the mean overall survival (OS) was significantly lower in patients with ERCC1-positive tumours (20±3 months) than in those with ERCC1-negative tumours (33±5 months, p<0.05). After allowance for potential confounders, Cox regression analysis demonstrated that ERCC1 expression was significantly associated with both PFS and OS (both p<0.05). CONCLUSION This study provides support for the prognostic value of ERCC1 immunohistochemical expression in patients with NSCLC treated by adjuvant platinum-based chemotherapy. If independently confirmed, these findings may improve prognostic stratification in this group of patients.	f	\N
22092655	Immunomodulatory T cells are thought to influence development of allergy and asthma, but early life longitudinal data on their phenotype and function are lacking. As part of the Urban Environment and Childhood Asthma (URECA) study, we investigated the development of immunomodulatory T cell phenotype and function, and characterized their relation to allergic disease progression from birth through to 2 years of age. Immunomodulatory T cell phenotype and function in cord blood mononuclear cells (CBMC) and peripheral blood mononuclear cells (PBMC) at 1 and 2 years of age were characterized by analysing CD25(bright) and FoxP3(+) expression, proliferative responses and cytokine production. The relation of immunomodulatory T cell characteristics to allergic sensitization and disease at 1- and 2-years of age was investigated. The proportion of CD4(+)CD25(bright) and CD4(+)CD25(+)FoxP3(+)T cells (n = 114, 83, 82 at birth, 1- and 2-years respectively) increased significantly, whereas there were no significant changes in the suppressive function of CD25(+)T cells (n = 78, 71, 81 at birth, 1- and 2-years respectively). Birth immunomodulatory T cell characteristics were not related to subsequent allergic sensitization or disease. However, increases in the numbers of CD4(+)CD25(bright) cells and their ability to suppress lymphoproliferative responses at 1 year of age were associated with reduced allergic sensitization at 1 (P = 0.03) and 2 (P = 0.02) years of age. Production of the anti-inflammatory cytokine IL-10 by CD25(+)T cells appeared to mediate this protective suppressive function. In contrast, by 2 years of age, we observed the emergence of a positive association of CD4(+)CD25(+) FoxP3(+) T cell numbers with allergic sensitization (P = 0.05) and eczema (P = 0.02). These findings suggest that the relationship between immunomodulatory T cell subsets, allergic sensitization and eczema is developmentally regulated. In the first year of life, CD4(+)CD25(+) IL-10 producing T cells are associated with a reduced incidence of allergic sensitization. Once allergic sensitization or eczema is established, CD4(+)CD25(+)FoxP3(+)T-reg cells expand to potentially counteract the allergic inflammatory response. Understanding the relationship between development of immunoregulatory T cells and early onset atopy could lead to new preventive strategies for allergic diseases.	f	\N
22104022	Bronchiolitis is the most common respiratory disease in children under 2 years-old and a major cause of hospitalization in young children, especially during the winter. To determine the prevalence and etiology of bronchiolitis in south-east of Spain. A prospective study was conducted during the bronchiolitis season (December-April). Children below 18 months-old admitted to the hospital for a first bronchiolitis episode were included. Nasopharyngeal aspirates were analysed by reverse transcription polymerase chain reaction (RT-PCR) respiratory syncytial virus. A total of 235 children were included during this period, and 235 RT-PCR were performed. A total of 287 viruses were detected in nasopharyngeal aspirates from 204 infants. Respiratory syncytial virus was the virus detected more frequently, followed by rhinovirus. Co-infections were found in the 36% of children. Respiratory viruses were detected in most of the children below 18 months-old hospitalised with bronchiolitis, and 36% of them showed a mixed infection.	f	\N
22106694	HLA-DQA1, -DQB1, and -DRB1 gene polymorphism were analyzed to study type 1 DM susceptibility in Malay patients from Southeast Asia (Malaysia and Singapore). Patients showed significant increases in the occurrence of DQA1*0501 (50.7% vs. 20.4%; RR = 3.97; Pc < 0.01), DQB1*0201 (48% vs. 19.1%; RR = 3.86; Pc < 0.05), and DRB1*0301 (38.7 vs. 6.8%; RR = 8.36; 95% Pc < 0.05). Conversely, significant decreases were noted in the occurrence of DQA1*0601 (14.7% vs. 35.2%; RR = 0.33; Pc = 0.008) and DQB1*0601 (4% vs. 23.5%; RR = 0.16; Pc < 0.05) in type 1 DM patients. Using a logistic regression model, we derived a risk prediction model for type 1 DM in our indigenous Malay population based on the identified HLA genotypes. The RR for type 1 DM increases by a factor of 5.68 for every unit increase in the number of DRB1*0301 allele (P < 0.001), and decreases by a factor of 0.18 per unit increase in the number of DQB1*0601 allele (P < 0.001). After adjusting for these two HLA genotypes, DQA1*0501, DQB1*0201 and DQA1*0601 were not statistically significant as risk predictors. The lower incidence of type 1 DM in the Malay population may be contributed by the genotypic combinations of DR and DQ genes as well as the linkage disequilibria between susceptible and protective alleles.	f	\N
22110167	A primary function of B lymphocytes is immunoglobulin production; however, the therapeutic benefit of B cell depletion in autoimmune diseases previously thought to be T cell mediated suggests that some B cells fulfill other roles in autoimmunity. We examined the recently identified human B1 cell population for T cell stimulatory activity. We found two kinds of B1 cells that are distinguished by multiple surface markers and distinct transcriptomic profiles. In both umbilical cord and adult peripheral blood, a CD11b(+) subset constitutes ~1 out of every 8-10 B1 cells, whereas a CD11b(-) subset constitutes the remaining B1 cells. These B1 cell populations differ functionally. CD11b(-) B1 cells spontaneously secrete much more IgM than CD11b(+) B1 cells. In contrast, CD11b(+) B1 cells express more CD86, and more efficiently stimulate allogeneic CD4(+) T cell expansion, than CD11b(-) B1 cells. The frequency of these CD11b(+) B1 cells is markedly elevated in lupus patients. CD11b(+) B1 cells in lupus patients express more CD86 and have increased T cell-stimulating activity in disease. This work distinguishes a novel, T cell-interacting B1 cell population whose abundance and activity may be a reflection of, and a therapeutic target in, autoimmune disease.	f	\N
22112193	Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and is one of the most common causes of chronic liver disease, worldwide. Lipoprotein-associated phospholipase A2 (Lp-PLA2) was recently characterized as a novel inflammatory biomarker that is correlated with several components constituting the metabolic syndrome. In this study, we determined the serum levels of Lp-PLA2 in patients with definite nonalcoholic steatohepatitis (NASH, n=25), borderline NASH (n=22), simple fatty liver (n=10), and healthy controls without evidence of liver disease (n=38). The levels of Lp-PLA2 were measured by enzyme-linked immunosorbent assay and compared in the four study groups. Moreover, concentrations of Lp-PLA2 were assessed in relation to the general characteristics of the study participants and the results of liver biopsy. Concentrations of Lp-PLA2 were significantly higher in patients with definite NASH (161.8±0.9 μg/L, P<0.001), borderline NASH (135.4±47.7 μg/L, P=0.001), and simple fatty liver (132.4±46.2 μg/L, P=0.042) compared with healthy controls (86.2±40.7 μg/L). Furthermore, the serum Lp-PLA2 level was strongly associated to histological steatosis scores in patients with NAFLD (β=0.32, t=2.50, P=0.016). Although subject to future confirmation, our data suggest that Lp-PLA2 levels are elevated in NAFLD.	f	\N
22122455	PPAR agonists represent a heterogeneous group of compounds that have been used in the treatment of cardiovascular and metabolic diseases for over thirty years. While the primary indications for PPAR agonist therapy focus on hyperlipidemia and diabetes, there is a growing body of pre-clinical data that suggests they may be beneficial in the treatment of heart failure; a disease marked by abnormal myocardial metabolism, fibrosis and insulin insensitivity. PPAR agonist treatment in numerous animal models of systolic heart failure have demonstrated improvement in cardiac function with decreased fibrosis, improved contractility and endothelial function. However, considerable controversy exists on the cardiac safety profile of PPAR agonists, particularly concern for inducing lipotoxicty and precipitating or worsening heart failure. In addition during pre-clinical testing, many compounds have been associated with increased death and adverse cardiovascular outcomes casting a pall over their future use for treating disorders of myocardial function. This article will review cardiac pathways involved in PPAR activation and their potential regulation of maladaptive pathways involved in heart failure and highlight molecular mechanisms that may contribute to adverse events and raise safety concerns. Specific attention will be focused on PPAR alpha and gamma, subtypes for which commercially available PPAR agonists are currently available.	f	\N
22122790	Atopic dermatitis (AD) is a kind of eczema with an inflammatory, relapsing, non-contagious, and pruritic skin disorder. It is associated with the local infiltration of T helper type 2 (Th2) cells that secrete interleukin (IL)-4 and IL-5. IL-21 is a member of IL-2 family cytokine mainly expressed by activated CD4+ T lymphocytes. Until now, there is no clinical research in the expression of IL-21 in patients with AD. We analyzed serum levels of total immunoglobulin E (IgE), allergen-specific IgE, and cytokines IL-4, IL-5, IFN-γ, IL-17, and IL-21 in AD cases and controls. In addition, cytokine levels in the culture supernatants of peripheral blood mononuclear cells stimulated with anti-CD3 and anti-CD28 Abs, phytohemagglutin (PHA), or pokeweed mitogen (PWM) were measured. We also assessed clinical skin severity by Scoring of Atopic Dermatitis (SCORAD) index. Our results showed that serum total IgE in the case group was significantly higher than that of control group (365.449 ± 52.945 and 39.243 ± 7.605 IU/ml, respectively). Logistic regression analysis system reveals serum levels of IL-21 and IFN-γ are significantly correlated. However, IL-21 and IL-4, IL-21 and IL-5, as well as IL-21 and IL-17 showed no correlation. A significantly decreased level of IL-21 was observed in children suffering with severe AD compared with controls, suggesting that IL-21 may play a role in AD.	f	\N
22124677	Colonic ischemia following colorectal surgery is an unusual and serious complication. As it has been reported that the incidence of colonic ischemia was higher after laparoscopic surgery, the aim of this report was to document the clinical features of postoperative colonic ischemia following colorectal surgery. Among 1,201 surgeries for sigmoid colon and rectal cancer by a single surgeon from 2006 to 2010, 10 cases of postoperative colonic ischemia were retrospectively identified (0.83%). IMA high ligation was routinely made in all surgeries. The clinical findings and laboratory data of these 10 cases were evaluated. Of the 10 patients, 9 were male and 1 was female. The mean age was 66.9 years old. The mean BMI was 23.3. Three patients (30%) had a cardiovascular disease other than hypertension. Eight patients (80%) underwent laparoscopic surgery and two patients (20%) underwent open surgery. Intraoperative bleeding occurred in five patients (50%, mean 435 ml). The average day for occurrence of postoperative colonic ischemia was on the 5th day (range 2nd-10th day). A consistent postoperative fever was found in eight patients (80%). Mortality due to postoperative colonic ischemia was 10%. Postoperative colonic ischemia may be considered one of the more important complications of colorectal resection.	f	\N
22129916	To evaluate the long-term safety and efficacy of etanercept treatment in Polish patients with juvenile idiopathic arthritis (JIA). The study involved patients, fulfilling the JIA criteria of the International League of Associations of Rheumatology (ILAR), who were started on etanercept therapy after methotrexate and other synthetic disease-modifying antirheumatic drugs (DMARDs) had proven ineffective. Patient data were collected in an electronic registry. Disease improvement was assessed based on Giannini's criteria. The statistical analysis involved 188 patients. Significant improvement was observed in all clinical and laboratory parameters after the first month of therapy and was maintained in the following months. ACR Pediatric 30, 50, 70, 90, and 100 improvement was observed in 81.4%, 65.9%, 27.5%, 16.2%, and 15%, respectively, of patients after 3 months and in 94.7%, 88.4%, 62.1%, 34.7%, and 26.3%, respectively, after 24 months of treatment. Throughout the 72-month safety observation period, 1162 adverse events were reported; the exposure-adjusted AE rate was 2.96 per patient per year. In patients with various subtypes of JIA resistant to conventional DMARD treatment, etanercept resulted in significant and long-lasting improvements in disease activity. Combination treatment with etanercept and a DMARD was well tolerated.	f	\N
22133826	The purpose of clinical assessment of atherosclerosis in aorta is to detect early lesions that are associated with a substantial risk of cardiovascular disease, such as stroke, aortic aneurysm and dissection, and to develop a treatment strategy for reduction of the cardiovascular risk. The pulse wave velocity (PWV) and pulse wave analysis (augmentation index : AI) can reveal atherosclerotic functional vascular abnormalities. On the contrary, plain X-rays, ultrasound examination, computed tomography (CT) , and magnetic resonance imaging (MRI) can be employed to easily assess the severity of atherosclerotic vascular damage morphologically. In these examinations, only PWV, as an index of arterial stiffness, can detect early atherosclerotic change in aorta before organic change. So, considering the importance of detecting early lesion, PWV is the most useful examination of atherosclerosis in aorta.	f	\N
22134016	In this review, the pitfalls that still exist with the surgical treatment of endometriosisassociatedpelvic pain have been discussed and the best evidence regarding various aspects of surgical techniques have been reviewed. When laparoscopy is performed to evaluate a woman with pelvic pain symptoms, it is important she be counseled that the primary function of the surgery is to confirm the presence (and allow surgical treatment) of endometriosis, and that it is not the penultimate diagnostic modality for her pelvic pain. There are many etiologies of pelvic pain that present with symptoms resembling those of endometriosis-associated pelvic pain that are not diagnosable with laparoscopy, such as interstitial cystitis and irritable bowel syndrome. It is unfortunate that many women are left with the belief that if a laparoscopy fails to provide a diagnosis of a pain generator, then it means there are no diagnoses other than that the “pain is in her head,” often disparagingly termed “supratentorial” byclinicians. In fact, the pain-related diagnoses that are amenable to and possibly require a laparoscopy are quite limited, a group of diagnoses that this author terms the “dirty dozen” because there are just 12, and only the first 4 have good evidence to clearly associate them with chronic pelvic pain:1. Endometriosis 2. Ovarian remnant syndrome 3. Pelvic inflammatory disease 4. Tuberculous salpingitis 5. Adhesions 6. Benign cystic mesothelioma 7. Postoperative peritoneal cysts 8. Adnexal cysts (nonendometriotic)9. Chronic ectopic pregnancy 10. Endosalpingiosis 11. Residual accessory ovary 12. Hernias: ventral, inguinal, femoral, spigelian.I would argue that diagnostic laparoscopy in modern gynecology has a limited, if any role, and that when laparoscopy is planned for women with chronic pelvic pain, it should be with a very high suspicion of a diagnosis and with plans to treat the disease operatively. In this era, a negative diagnostic laparoscopy should be a rare event.	f	\N
22139583	Omics is the study of proteins, peptides, genes, and metabolites in living organisms. Systems biology aims to understand the system through the study of the relationship between elements such as genes and proteins in biological system. Recently, systems biology emerged as the result of the advanced development of high-throughput analysis technologies such as DNA sequencers, DNA arrays, and mass spectrometry for omics studies. Among a number of analytical tools and technologies, CE and CE coupled to MS are promising and relatively rapidly developing tools with the potential to provide qualitative and quantitative analyses of biological molecules. With an emphasis on CE for systems biology, this review summarizes the method developments and applications of CE for the genomic, transcriptomic, proteomic, and metabolomic studies focusing on the drug discovery and disease diagnosis and therapies since 2009.	f	\N
22145272	The prognosis of multiple myeloma patients has significantly improved since the introduction of the novel agents thalidomide, bortezomib and lenalidomide. We report the data of a medical need programme with lenalidomide plus dexamethasone, conducted in Belgium between August 2007 and March 2008, and including 98 relapsed refractory multiple myeloma patients. In addition to chemotherapy and steroids, all patients had received prior treatment with bortezomib, and 84% of them had been exposed to thalidomide. In 52 patients response data could be retrieved by post-hoc analysis. A partial remission or better was achieved in 52% (49% partial and 3% complete response) of patients, despite a median of 5 previous anti-myeloma treatment lines. Responses were rapid while the majority of patients received lenalidomide with once weekly (also called low-dose) dexamethasone. Treatment with lenalidomide plus dexamethasone did prolong overall survival by nearly half a year in this population with end-stage myeloma. Overall response and quality of response were independent of previous response to thalidomide and bortezomib, although the time to progression tended to be shorter in thalidomide- and bortezomib-refractory patients. It can be concluded that lenalidomide plus dexamethasone is an effective and safe treatment regimen in highly refractory multiple myeloma patients, and that these responses are irrespective of previous exposure or sensitivity to thalidomide and bortezomib.	f	\N
22153142	As important members of the health care team, patients and caregivers must be empowered to recognize their asthma status and to act accordingly. Education about asthma, complications, and successful management of asthma provide the best way to empower children and their caregivers. A Shared Medical Appointment (SMA) is a unique health care delivery approach that integrates disease management and patient education. The SMA described here is a 90-minute group appointment for four to nine patients who share a diagnosis of asthma, bronchospasm, or wheeze and their caregivers. The appointment includes a brief individual examination, health education delivered to the group, and the opportunity for interaction between group members. Because a supporting theoretic framework is not identified in the original design proposals for the SMA model or in the literature on its use, for the purposes of this project, Social Cognitive Theory is identified as the theoretical framework that best explains and reinforces the benefits of the SMA. The theoretic framework is important to direct the development and continued success of this treatment model. This project report describes the first nurse practitioner-led SMA as a tool for improving quality of care and service for children with asthma and their caregivers.	f	\N
22153317	Oral ulcer is the cardinal clinical sign and increased neutrophilic activity is a part of the pathogenesis in Behcet's disease (BD). Saliva, as a part of the innate immune response, contains antimicrobial peptides (AMPs) that are derived from both oral epithelial cells and neutrophils. The aim of this study was to investigate the associations between salivary levels of AMPs HNP 1-3, LL-37 and S100 and disease course in patients with Behcet's disease (BD). Fifty-three patients with BD and 44 healthy controls (HC) were included in the study. Disease severity score reflecting organ involvement was calculated. Salivary HNP 1-3, LL-37 and S100 levels were measured in unstimulated saliva samples by ELISA. Salivary HNP 1-3 and S100 levels in BD patients (2715.2 ± 1333.4 μg/ml and 430.6 ± 203.9 ng/ml) were significantly higher compared to HC (1780.6 ± 933.2 μg/ml and 365.3 ± 84.7 ng/ml) (p = 0.000 and p = 0.004, respectively). Although LL-37 levels were also higher in BD than HC (190.9 ± 189.1 vs 143.1 ± 128.9 ng/ml), no significant difference was observed (p = 0.53). Salivary HNP 1-3 and LL-37 levels were associated with the severity of BD (mild disease: 1975.1 ± 1174.2 μg/ml and 115.9 ± 109.4 ng/ml vs severe disease: 2955.7 ± 1305.6 μg/ml and 215.3 ± 203.8 ng/ml, p=0.020 and p=0.031, respectively). Salivary LL-37 levels also correlated with the number of monthly oral ulcers (r = 0.5 p = 0.000). An increase in salivary HNP 1-3 and S100 levels might be associated with enhanced local and systemic innate responses in BD.	f	\N
22156557	statin drugs may induce skeletal myopathy, but might also have the potential to improve rehabilitation outcomes by improving sarcopenia or by preventing intercurrent illness. We examined the association between statin use and functional outcomes in the rehabilitation of older people. retrospective cohort study using routinely collected clinical data. Admissions to Royal Victoria Hospital, Dundee for inpatient rehabilitation over a 10-year period were identified. Data were available regarding demographics, statin therapy, antiplatelet therapy, admission and discharge Barthel scores, length of stay and comorbid disease. Multivariate analyses were performed to examine the difference between admission and discharge Barthel score in patients taking statins compared with those not taking statins. a total of 3,422 patients were included. Mean age was 81.4 years; 40% were male. Baseline Barthel scores were similar in the statin/non-statin groups, respectively (10.4/20 versus 10.3/20, P = 0.57). Improvement in the Barthel score between admission and discharge was greater in the statin than non-statin group (3.59 versus 4.30 points, P < 0.001) after adjustment for age, sex, baseline Barthel score and comorbid disease. statin use was associated with improved Barthel scores on discharge from rehabilitation. This gain could contribute to improved outcomes as part of the rehabilitation package and requires further prospective investigation.	f	\N
22156787	Spinal muscular atrophy is a relatively stable chronic disease. Patients may gradually experience declines in muscle strength and motor function over time. However, functional progression is difficult to document, and the mechanism remains poorly understood. An 11-year-old girl was diagnosed at 19 months and took a few steps without assistance at 25 months. She was evaluated for 54 months in a prospective multicenter natural history study. Outcome measures were performed serially. From 6 to 7.5 years, motor function improved. From 7.5 to 11 years, motor function declined with increasing growth. Manual muscle testing scores minimally decreased. Motor unit number estimation studies gradually increased over 4.5 years. Compared to the published natural history of spinal muscular atrophy type III, our patient lost motor function over time. However, she walked with assistance 2 years longer than expected. Our report highlights possible precipitating factors that could affect the natural history of spinal muscular atrophy type III.	f	\N
22157156	Rhinitis is a common condition associated with significant under-recognized morbidity and impaired quality of life. The natural history of rhinitis is poorly characterized. Better understanding of its natural history and associated risk factors would improve the ability to effectively manage rhinitis in clinical practice. This review focuses on the current research findings on the natural history of rhinitis and how that is influenced by atopy and sex. Recent work from the Isle of Wight Birth Cohort Study has demonstrated that the prevalence of atopic rhinitis increases steadily in the first 18 years of life in both sexes. However, nonatopic rhinitis behaves differently during adolescence. Its prevalence decreases in boys but continues to increase in girls resulting in a female predominance after puberty. Numerous recent studies have proposed potential roles for sex-related and adipose-related hormonal changes in influencing the course of allergic disease. Further research is needed to establish mechanisms that could underlie such findings. Rhinitis becomes increasingly common through childhood, with prevalence during adolescence being mediated by differential effects of sex and atopy. Mechanisms to explain these findings await elucidation.	f	\N
22174195	Early rheumatoid arthritis (RA) and very early RA are major targets of research and clinical practice. Remission has become a realistic goal in the management of RA, particularly in early disease. The 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) RA classification criteria, the EULAR treatment recommendations for RA, and the EULAR recommendations for the management of early arthritis focus on early disease and translate the knowledge related to early RA into classification and management. Nevertheless, there is a need for further improvement and progress. Results from 6 recent studies are summarized, evaluating the performance of the 2010 ACR/EULAR RA classification criteria. The data show a significant risk of misclassification, and highlight that overdiagnosis and underdiagnosis may become important issues if the criteria recommend synthetic and biological disease-modifying antirheumatic drugs. Therefore, some considerations are presented on how the current problems and limitations could be overcome in clinical practice and future research. A consensus is needed to better define the early phase of RA and differentiate from other early arthritis. The possible effect of misclassification on spontaneous and drug-induced remission of early and very early RA awaits further elucidation. Such research will eventually lead to more reliable diagnostic and classification criteria for new-onset RA.	f	\N
22174210	To compare clinical features of patients with remitting seronegative symmetrical synovitis with pitting edema (RS3PE) and patients with polymyalgia rheumatica (PMR) and to explore the purported association between RS3PE and malignancy. We did a retrospective chart review of patients with RS3PE and PMR treated in a community-based hospital between January 2000 and December 2009. Outcomes assessed were clinical course of disease and associated malignancies. We identified 28 patients with RS3PE and 123 with pure PMR. All patients with RS3PE fulfilled PMR criteria as well. Age, comorbidity, erythrocyte sedimentation rate, duration and progression of symptoms, treatment response to initial low-dose steroids, and steroid complication rates were similar in both groups. Patients with RS3PE were more likely to be male (79% vs 41%; p = 0.001) and to have a history of smoking (39% vs 15%; p = 0.008) and a higher rate of depression (11% vs 2%; p = 0.044) at diagnosis. Among those with RS3PE, hip pain was less common (39% vs 74%; p = 0.001) than in the PMR group. No patients with RS3PE and 6 patients with pure PMR (4.9%) developed another rheumatological disease during followup. Seven of 9 patients (78%) with concurrent cancer presented slightly more frequently with systemic symptoms compared to patients without cancer (48%; p = 0.098), especially with fatigue (56% vs 22%; p = 0.037) and anorexia (33% vs 9.0%; p = 0.047). Despite rigorous cancer screening in patients with RS3PE, however, the rate of associated malignancy was not statistically different from that of patients with pure PMR [2 (7%) vs 7 (6%), respectively; p = 0.673]. Despite evidence that RS3PE is clinically distinct from PMR, we observed characteristics, treatment response, and outcomes like those expected in pure PMR. Compared to patients with pure PMR, patients with RS3PE are more likely to be male, to be depressed, and to smoke. Contrary to earlier studies, no clear association of RS3PE with malignancy was found despite rigorous cancer screening, although clinicians should be aware that patients with concurrent cancer may manifest more systemic signs and symptoms, as well as steroid resistance.	f	\N
22179327	Population allele frequencies of apolipoprotein E (APOE) vary by geographic region. The purpose of this study is to summarize and evaluate published estimates for the prevalence of APOE e4 carrier status among the population diagnosed with Alzheimer's disease (AD) by geographic region and country. A systematic review of English-language publications from January 1, 1985, through May 31, 2010, was conducted. Studies reporting APOE e4 status for patients diagnosed with AD were included in the analysis; trials and autopsies were excluded. APOE e4 data were pooled, and prevalence and 95% confidence intervals (CIs) were calculated. Pooled estimates for APOE e4 carrier prevalence data were derived from 142 independent samples: 48.7% (95% CI: 46.5-51.0), and from 73 samples for e4/4 (homozygotes): 9.6% (95% CI: 8.4-10.8). The highest estimates were in Northern Europe: 61.3% (95% CI: 55.9-66.7), e4/4 prevalence: 14.1% (95% CI: 12.2-16.0). The lowest estimates were in Asia and Southern Europe. Substantial heterogeneity of these prevalence estimates was observed. APOE e4 genotype prevalence varies among AD patients by region and within each country. Further exploration is warranted to better understand the substantial heterogeneity of these prevalence estimates.	f	\N
22183718	The gut epithelium is a barrier between the 'outside' and 'inside' world. The major function of the epithelium is to absorb nutrients, ions and water, yet it must balance these functions with that of protecting the 'inside' world from potentially harmful toxins, irritants, bacteria and other pathogens that also exist in the gut lumen. The health of an individual depends upon the efficient digestion and absorption of all required nutrients from the diet. This requires sensing of meal components by gut enteroendocrine cells, activation of neural and humoral pathways to regulate gastrointestinal motor, secretory and absorptive functions, and also to regulate food intake and plasma levels of glucose. In this way, there is a balance between the delivery of food and the digestive and absorptive capacity of the intestine. Maintenance of the mucosal barrier likewise requires sensory detection of pathogens, toxins and irritants; breakdown of the epithelial barrier is associated with gut inflammation and may ultimately lead to inflammatory bowel disease. However, disruption of the barrier alone is not sufficient to cause frank inflammatory bowel disease. Several recent studies have provided compelling new evidence to suggest that changes in epithelial barrier function and inflammation are associated with and may even lead to altered regulation of body weight and glucose homeostasis. This article provides a brief review of some recent evidence to support the hypothesis that changes in the gut microbiota and alteration of gut epithelial function will perturb the homeostatic humoral and neural pathways controlling food intake and body weight.	f	\N
22184604	Assessing the medical history of patients before any treatment is an essential aspect of the dentist's responsibility; however, many dental practitioners assume that their patients are systemically healthy so their medical history is often overlooked. The objective of this study was to determine the prevalence of self-reported medical conditions among a sample of dental school patients at the Institute of Dental Sciences, Bareilly (Uttar Pradesh), India. Detailed medical histories were taken from 3,786 new dental patients in an outpatient setting. The demographic data, medical status, and use of medications from the charts were analyzed. Thirty-eight percent of the total patients had a positive finding in their medical history for at least one systemic condition. The most commonly reported systemic condition was hypertension (15.2 percent) followed by diabetes (11.4 percent), and 26 percent of the patients were taking at least one medication daily. The results of this study reflect the medical complexity of the increasingly aging population.	f	\N
22185707	Acute pyelonephritis (APN) requires prompt diagnosis and immediate treatment. To develop a simple score to assist in diagnosing treatment deterioration in patients with serious APN. Using data from a retrospective cohort of 193 patients with APN, we developed scores based on multivariate logistic regression after the jackknife procedure. We validated the scores in a prospective cohort of 40 patients. Nine criteria were independently associated with our investigation: Abscess (adjusted odds ratio [OR], 19.8; 95% confidence interval [95% CI] 4.5-72.1), pyonephrosis with or without stone (18.3; 4.8-70.9), pelvicalyceal air (15.5; 3.2-26.9), poor global excretion of contrast (12.3; 2.9-68.5), tachycardia or hypotension (10.1; 2.5-28.0), obliteration of the renal sinus (9.6; 2.5-45.2), persistent fever or pyuria (9.8; 1.9-25.8), diabetes (9.4; 2.0-31.8), and global renal enlargement (7.5; 2.1-35.8). The APN score was based on these nine criteria. Low-risk and high-risk groups were derived from the score (probability, 3.5% [95% CI 0-7.5] and 67% [51-83]). Application of these criteria to the prospective cohort confirmed the diagnostic accuracy of the score (probability 0% [0-15] and 71% [25-100] in the low-risk and high-risk groups, respectively). This easy-to-calculate score may prove useful for diagnosing patients with serious APN who deteriorate with treatment.	f	\N
22195084	There is increasing interest in leveraging electronic health data across disparate sources for a variety of uses. A fallacy often held by data consumers is that clinical data quality is homogeneous across sources. We examined one attribute of data quality, completeness, in the context of electronic laboratory reporting of notifiable disease information. We evaluated 7.5 million laboratory reports from clinical information systems for their completeness with respect to data needed for public health reporting processes. We also examined the impact of health information exchange (HIE) enhancement methods that attempt to improve completeness. The laboratory data were heterogeneous in their completeness. Fields identifying the patient and test results were usually complete. Fields containing patient demographics, patient contact information, and provider contact information were suboptimal. Data processed by the HIE were often more complete, suggesting that HIEs can support improvements to existing public health reporting processes.	f	\N
22199325	There have been reports suggesting that continuous administration of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is advantageous for patients in which disease progression was observed after the establishment of clinical benefit from EGFR-TKIs. We retrospectively evaluated the clinical course of patients who received continuous administration of EGFR-TKIs after disease progression was detected solely in bone lesions. The medical records of patients administered gefitinib or erlotinib between 2002 and 2010 were reviewed. We evaluated the progression-free survival (PFS) and overall survival (OS) in patients who had bone metastases after the establishment of clinical benefit from EGFR-TKI and who received radiation therapy for the bone lesion and continuous treatment with EGFR-TKI. Ten patients were enrolled in this study. The median PFS and OS were 88 days and 330 days, respectively. Furthermore, a longer duration from the start of first EGFR-TKI to detection of bone metastases (p=0.0049) was identified as being significantly associated with a longer PFS. Our data suggest that continuous administration of EGFR-TKI is a treatment option for patients with bone metastases who previously benefited from therapy with EGFR-TKI.	f	\N
22200856	Caveolin-1 (cav-1) has been implicated in the development of human cancers. However, the distribution of cav-1 in non-small cell lung cancer (NSCLC) and its signiﬁcance require further study. Real-time PCR and Western blot assays were performed to detect cav-1 mRNA and protein levels in tumor tissues (TT) and matched tumor-free tissues (TF). The protein expression in 115 paraffin-embedded blocks was examined by immunohistochemical staining (IHC). Correlations between cav-1 mRNA and protein expression by IHC and clinicopathological features were statistically evaluated. For the 136 patients examined, the levels of cav-1 mRNA and protein expression were significantly lower in lung TT compared to matched TF (P<0.05). High cav-1 expression was detected in 60 of 115 (52.2%) NSCLC tissues and this level was significantly lower than cav-1 expression in non-cancerous lung tissues (15 of 19, 78.9%, P<0.05). Up-regulation of cav-1 mRNA expression in lung adenocarcinoma (AC) (29.7%) was higher than that observed in lung squamous cell carcinoma (SCC) (15.8%). Statistical analysis of the correlation between cav-1 protein expression and clinical features showed a statistical association with poorer N-stage (P=0.032) and higher pathological TNM stage (P=0.012) in lung AC patients, that was not found in lung SCC patients. Moreover, lung AC patients with higher cav-1 expression showed significantly shorter life-spans than those with lower cav-1 expression (P=0.032, log-rank test). The levels of cav-1 mRNA and protein expression were significantly lower in lung cancers when compared to matched TF or non-cancerous lung tissues. The higher protein expression correlated with the advanced pathological stage and shorter survival rates in lung AC patients.	f	\N
22201290	Integrins play myriad and vital roles in development and disease. They connect a cell with its surroundings and transmit chemical and mechanical signals across the plasma membrane to the cell's interior. Dissecting their roles in cell behavior is complicated by their overlapping ligand specificity and shared downstream signaling components. In principle, immobilized synthetic peptides can mimic extracellular matrix proteins by supporting integrin-mediated adhesion, but most short peptide sequences lack selectivity for one integrin over others. In contrast, synthetic integrin antagonists can be highly selective. We hypothesized that this selectivity could be exploited if antagonists, when immobilized, could support cellular adhesion and activate signaling by engaging specific cell-surface integrins. To investigate this possibility, we designed a bifunctional (RGD)-based peptidomimetic for surface presentation. Our conjugate combines a high affinity integrin ligand with a biotin moiety; the former engages the α(v)β(3) integrin, and the latter allows for presentation on streptavidin-coated surfaces. Surfaces decorated with this ligand promote both cellular adhesion and integrin activation. Moreover, the selectivity of these surfaces for the α(v)β(3) integrin can be exploited to capture a subset of cells from a mixed population. We anticipate that surfaces displaying highly selective small molecule ligands can reveal the contributions of specific integrin heterodimers to cell adhesion and signaling.	f	\N
22211766	Retinol binding protein-4 (RBP-4) is a member of adipocytokines, which is potentially associated with fibrosis, vasodilation, and angiogenesis in addition to insulin resistance. To investigate the clinical significance of serum RBP4 levels in patients with systemic sclerosis (SSc), which is a systemic autoimmune disease characterized by fibrosis and vasculopathy. Serum RBP4 levels were determined by enzyme-linked immunosorbent assay in 62 SSc patients and 19 healthy controls. Similar to patients with chronic kidney disease, serum RBP4 levels inversely correlated with estimated glomerular filtration rate in SSc patients with renal dysfunction. Therefore, analyses were carried out by excluding SSc patients with estimated glomerular filtration rate <60 mL/min/1.73 m(2) . Serum RBP4 levels were significantly lower in diffuse cutaneous SSc (dcSSc) than in control subjects [median (25-75 percentile); 25.8 μg/mL (19.6-47.0) vs. 43.1 μg/mL (31.7-53.4), P < 0.05], while there was no significant difference between limited cutaneous SSc (lcSSc) [28.0 μg/mL (25.4-43.3)] and control subjects. In both of dcSSc and lcSSc, patients with Raynaud's phenomenon had RBP4 levels significantly lower than those without. Furthermore, serum RBP4 levels inversely correlated with pulmonary function test results in dcSSc and with right ventricular systolic pressure in lcSSc. CONCLUSION  Decreased RBP4 levels are associated with the prevalence of Raynaud's phenomenon in dcSSc and lcSSc, with the severity of interstitial lung disease in dcSSc, and with the degree of pulmonary vascular involvement in lcSSc, suggesting the possible contribution of RBP4 to the pathological events in this disorder.	f	\N
22215125	Primary hyperoxaluria type I is a rare inherited disease that presents a disturbed metabolism of glyoxylate. Consequently, patients suffer from hyperoxaluria, leading to renal failure and subsequent skeletal calcium oxalate deposition. Areas with high concentrations of calcium oxalate, so-called dense metaphyseal bands, are at risk for pathological fracturing. The primary disease is treated by combined liver-kidney transplantation, although pathological fracturing also occurs in the posttransplant period. In the current case, we present a 3-year-old boy with a pathological fracture of his right femur, 2 years after liver-kidney transplantation. We opted for a conservative regime, leading to good fracture healing. As there are limited data in the literature regarding treatment of fractures in these patients, it is important to notify the outcome of conservative treatment of pathological fractures in patients with primary hyperoxaluria type I.	f	\N
22226887	Cystic fibrosis is a lethal autosomal recessive condition caused by a defect of the transmembrane conductance regulator gene that has a key role in cell homeostasis. A dysfunctional cystic fibrosis transmembrane conductance regulator impairs the efflux of cell anions such as chloride and bicarbonate, and also that of other solutes such as reduced glutathione. This defect produces an increased viscosity of secretions together with other metabolic defects of epithelia that ultimately promote the obstruction and fibrosis of organs. Recurrent pulmonary infections and respiratory dysfunction are main clinical consequences of these pathogenetic events, followed by pancreatic and liver insufficiency, diabetes, protein-energy malnutrition, etc. This complex comorbidity is associated with the extensive injury of different biomolecular targets by reactive oxygen species, which is the biochemical hallmark of oxidative stress. These biological lesions are particularly pronounced in the lung, in which the extent of oxidative markers parallels that of inflammatory markers between chronic events and acute exacerbations along the progression of the disease. Herein, an abnormal flux of reactive oxygen species is present by the sustained activation of neutrophils and other cystic fibrosis-derived defects in the homeostatic processes of pulmonary epithelia and lining fluids. A sub-optimal antioxidant protection is believed to represent a main contributor to oxidative stress and to the poor control of immuno-inflammatory pathways in these patients. Observed defects include an impaired reduced glutathione metabolism and lowered intake and absorption of fat-soluble antioxidants (vitamin E, carotenoids, coenzyme Q-10, some polyunsaturated fatty acids, etc.) and oligoelements (such as Se, Cu and Zn) that are involved in reactive oxygen species detoxification by means of enzymatic defenses. Oral supplements and aerosolized formulations of thiols have been used in the antioxidant therapy of this inherited disease with the main aim of reducing the extent of oxidative lesions and the rate of lung deterioration. Despite positive effects on laboratory end points, poor evidence was obtained on the side of clinical outcome so far. These aspects examined in this critical review of the literature clearly suggest that further and more rigorous trials are needed together with new generations of pharmacological tools to a more effective antioxidant and anti-inflammatory therapy of cystic fibrosis patients. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease.	f	\N
22237046	PTPN22 is involved in T-cell activation and its R620W single-nucleotide polymorphism (SNP) has been shown to predispose to different autoimmune diseases. The aims of this study were to investigate the role of the PTPN22 R620W SNP in conferring susceptibility to the ANCA-associated vasculitides (AAVs), and to explore potential associations between the PTPN22 genotype and the disease manifestations. PTPN22 R620W SNP was genotyped in a cohort of 344 AAV patients [143 with granulomatosis with polyangiitis (Wegener's) (GPA), 102 with microscopic polyangiitis (MPA) and 99 with Churg-Strauss syndrome (CSS)] and in 945 healthy controls. The frequency of the minor allele (620W) was significantly higher in GPA patients than in controls [P = 0.005, χ(2 )= 7.858, odds ratio (OR) = 1.91], while no statistically significant association was found with MPA or CSS. Among GPA patients, the 620W allele was particularly enriched in ANCA-positive patients as compared with controls (P = 0.00012, χ(2 )= 14.73, OR = 2.31); a particularly marked association was also found with ENT involvement (P = 0.0071, χ(2 )= 7.258, OR = 1.98), lung involvement (P = 0.0060, χ(2 )= 7.541, OR = 2.07) and skin manifestations of all kinds (P = 0.000047, χ(2 )= 16.567, OR = 3.73). The PTPN22 620W allele confers susceptibility to the development of GPA (but not of MPA or CSS), and particularly of its ANCA-positive subset.	f	\N
22237792	Substantia nigra hyperechogenicity assessed by transcranial sonography is a typical finding in up to 90% of patients with idiopathic Parkinson's disease, although its value as a surrogate marker for disease progression in Parkinson's disease is controversial. (123) I-FP-CIT-single photon emission computed tomography (SPECT) represents an established paraclinical surrogate marker to quantify the nigrostriatal dopaminergic deficit in Parkinson's disease. Whereas most studies found no correlation between extent of substantia nigra echogenicity and the putaminal FP-CIT binding ratio, a more recent analysis reported opposite results. In 92 patients with Parkinson's disease the substantia nigra echogenicity was compared with the putaminal FP-CIT binding ratio using an investigator-independent SPECT analysis protocol and with several clinical parameters. No correlation was found between the substantia nigra hyperechogenicity and the FP-CIT binding ratio or the disease severity. Substantia nigra hyperechogenicity does not reflect the degree of the nigrostriatal degeneration or the clinical state of the disease progression.	f	\N
22239875	Dual-energy x-ray absorptiometry (DEXA) is a safe, noninvasive, inexpensive tool for managing patients with neuromuscular diseases. Regional and whole-body DEXA can be used to guide clinical treatments, such as determining body composition to guide nutritional recommendations, as well as to monitor disease progression by assessing regional and whole-body lean tissue mass. DEXA can also be used as an outcome measure for clinical trials.	f	\N
22239959	An inadequate level of bowel preparation can affect the efficacy and safety of colonoscopy. Although some factors have been associated with outcome, there is no strategy to identify patients at high risk for inadequate preparation. We searched for factors associated with an inadequate level of preparation and tested the validity of a predictive clinical rule based on these factors. We performed a prospective study of 2811 consecutive patients who underwent colonoscopy examinations at 18 medical centers; clinical and demographic data were collected before the colonoscopy. Bowel preparation was classified as adequate or inadequate; 925 patients (33%) were found to have inadequate preparation. Multivariate analysis was used to identify factors associated with inadequate preparation, which were expressed as odds ratio (OR) and used to build a predictive model. Factors associated with inadequate bowel preparation included being overweight (OR, 1.5), male sex (OR, 1.2), a high body mass index (OR, 1.1), older age (OR, 1.01), previous colorectal surgery (OR, 1.6), cirrhosis (OR, 5), Parkinson disease (OR, 3.2), diabetes (OR, 1.8), and positive results in a fecal occult test (OR, 0.6). These factors predicted which patients would have inadequate cleansing with 60% sensitivity, 59% specificity, 41% positive predictive value, and 76% negative predictive value; they had an under the receiver operating characteristic curve value of 0.63. Assuming 100% efficacy of a hypothetical regimen to address patients predicted to be at risk of inadequate preparation, the rate would decrease from 33% to 13%. We identified factors associated with inadequate bowel preparation for colonoscopy and used these to build an accurate predictive model.	f	\N
22241793	Neointimal hyperplasia causes a high rate of hemodialysis synthetic graft failure. Thus, therapies that inhibit neointimal hyperplasia are urgently needed. The Coll-R is a sirolimus-eluting collagen matrix designed for intra-operative perivascular implantation around the graft-venous anastomosis. Sirolimus is an anti-proliferative drug that has proven clinical utility in suppressing neointimal tissue growth in coronary artery disease when delivered locally to the vascular wall by an endovascular drug eluting stent. A cohort of 12 chronic hemodialysis patients underwent surgical placement of 13 polytetrafluoroethylene grafts + Coll-R and were followed for up to 24 months. The primary endpoint was safety (freedom from device related adverse events). Secondary endpoints were pharmacokinetics of sirolimus release, success of Coll-R implantation and primary unassisted graft patency. There were no technical failures, infections, vascular anastomotic or wound-healing problems. Whole blood sirolimus levels rose to a mean peak of 4.8 ng/mL at 6 h and fell to <1 ng/mL at 1 week (n = 5). Twelve and 24-month primary unassisted patencies were 76 and 38%, respectively, and the thrombosis rate was 0.37/patient-year. Perivascular implantation of the Coll-R during graft surgery safely delivered sirolimus to the vascular wall. Systemic sirolimus levels were sub-therapeutic for immunosuppression. This small first-in-human study supports the concept that the Coll-R can safely deliver sirolimus to the graft-venous anastomosis. Safety and patency in this small study were sufficiently encouraging to justify randomized controlled trials to further test the efficacy of the Coll-R.	f	\N
22248333	We assessed HIV prevalence and associated behaviors and risk factors among men who have sex with men (MSM) in Beijing, China. Five hundred MSM were recruited for a biological and behavioral survey using respondent-driven sampling (RDS) in 2009. Serologic specimens were tested for markers of HIV and syphilis infection. A computer-assisted personal interview (CAPI) administered questionnaire gathered information including demographic characteristics, sexual behaviors, HIV testing, and social norms concerning condom use. The adjusted HIV prevalence was 8.0%, syphilis 22.0%. HIV testing and disclosure was low; only 39.3% had HIV tested in the past 12 months, 49.7% knew their own HIV status and 22.8% knew their last male partner's HIV status. HIV infection was associated with syphilis, ever having sex with a woman, not knowing the HIV status of the most recent male partner, and never buying condoms in the past 12 months. Stronger endorsement of positive social norms around condom use strongly and predicted lower prevalence of HIV infection. Compared to surveys of similar design in the recent past, HIV continues to spread rapidly among Beijing's MSM. Our results identify points of intervention that, if addressed in time, may still alter the course of the epidemic including the promotion of HIV testing and partner disclosure, syphilis control and particularly changing social norms around condom use.	f	\N
22249461	Kuru was the first human transmissible spongiform encephalopathy (TSE) or prion disease identified, occurring in the Fore linguistic group of Papua New Guinea. Kuru was a uniformly fatal cerebellar ataxic syndrome, usually followed by choreiform and athetoid movements. Kuru imposed a strong balancing selection on the Fore population, with individuals homozygous for the 129 Met allele of the gene (PRNP) encoding for prion protein (PrP) being the most susceptible. The decline in the incidence of kuru in the Fore has been attributed to the exhaustion of the susceptible genotype and ultimately by discontinuation of exposure via cannibalism. Neuropathologically, kuru-affected brains were characterized by widespread degeneration of neurons, astroglial and microglial proliferation, and the presence of amyloid plaques. These early findings have been confirmed and extended by recent immunohistochemical studies for the detection of the TSE-specific PrP (PrP). Confocal laser microscopy also showed the concentration of glial fibrillary acidic protein-positive astrocytic processes at the plaque periphery. The fine structure of plaques corresponds to that described earlier by light microscopy. The successful experimental transmission of kuru led to the awareness of its similarity to Creutzfeldt-Jakob disease and Gerstmann-Sträussler-Scheinker disease and formed a background against which the recent epidemics of iatrogenic and variant Creutzfeldt-Jakob disease could be studied.	f	\N
22252480	The objective is to evaluate the relationship between cholesterolemia, serum apolipoprotein B (apoB) level and blood pressure in a large sample of general population. The Brisighella Heart Study (BHS) is a prospective, population-based longitudinal epidemiological investigation. For this study, we analysed the data sampled in the 2008 BHS population survey, excluding those participants treated with antihypertensive and/or lipid lowering drugs (N: 2473). In a sex, BMI, smoking habit, physical activity level and serum creatinine adjusted model, low-density lipoprotein-cholesterol (LDL-C) appears to be significantly related to SBP (P < 0.001), DBP (P = 0.026), and pulse pressure (PP) (P < 0.001). In individuals aged less than 52 years, LDL-C was significantly associated to SBP and DBP (P < 0.001), but not PP. In the same model, apoB appears to be mildly but significantly related to SBP (P < 0.001), DBP (P < 0.001), and PP (P < 0.001). In individuals aged less than 52 years, apoB was significantly associated to SBP (P < 0.001), DBP (P < 0.001), and PP (P < 0.001). In individuals aged 52 or more, nor LDL-C neither apoB were significantly associated to blood pressure. Including in the same model LDL-C and apoB, apoB excluded the predicting role of LDL-C as it regards the blood pressure either in the whole population sample and in the younger individuals. On the basis of our observation, either serum LDL-C and apoB are significantly related to the blood pressure level in a large sample of individuals untreated with antihypertensive and lipid-lowering drugs. This association is stronger in younger individuals than in elderly. ApoB seems to be a stronger predictor of either SBP, DBP and PP than LDL-C.	f	\N
22253312	During past decades, twin studies have played an important role in genetic epidemiology studies of complex traits. The strength of twin studies lies in the ability to disentangle genetic and environmental factors that contribute to a phenotype, by comparing genetically identical monozygotic twins to dizygotic twins, who share on average 50% of genetic variants. Twin studies now offer the opportunity to study epigenetic variation across the genome with two aims. First, twin studies can improve our understanding of the factors regulating epigenetic variability by assessing the heritability of epigenetic variants. Secondly, the use of twins in epigenetic research is increasingly recognized as an important approach to help unravel the complexities associated with human development and disease. The strategic use of identical twins discordant for complex disease has revealed the importance of linking epigenetic disruption to the disease-associated risk in humans. Lastly, we also discuss the possibility that epigenetic effects on disease may in part explain some of the missing heritability in genome-wide association studies. The study of human epigenetic factors in twins can inform the role of genetics, as well as in utero and postnatal environments to the establishment, maintenance and functional consequences of human epigenome variation.	f	\N
22257051	Extracellular matrix metalloproteinases (MMPs) are a family of zinc-dependent neutral endopeptidases involved in physiological and pathological processes, through the cleavage of extracellular matrix. MMPs are capable of degrading essentially all matrix components, which is crucial for malignant tumor growth, invasion, metastasis and angiogenesis. The vertebrates MMP family includes at least 26 enzymes (23 have been known in humans) with only MMP-1, 2, and 7 experimentally validated as targets for antitumoral drug design. However, inhibition of MMP-1 has been hypothesized to be the cause of the clinically observed musculoskeletal syndrome when broad spectrum inhibitors are used. On the other hand, MMP-9 is a tricky enzyme, since its inhibition might be useful in treating patients with early-stage cancers, but MMP-9 is an anti-target in patients with advanced disease. So, MMP-9 inhibition should also be prevented. Therefore, selective MMP-2 inhibition arises as a pursued profile for MMP binders. Among them, hydroxamates have been extensively studied as small molecule drug candidates characterized by an effective zinc-binding group plus additional side chains responsible for the selectivity. This article pays particular attention to MMP-2 selectivity on hydroxamate-type inhibitors, especially against MMP-9, and their chemical structure, SAR, general synthetic methods, and molecular modelling studies are here reviewed in order to inspire further design of new effective anticancer agents.	f	\N
22266119	The apicomplexan parasite Plasmodium vivax is responsible for causing more than 70% of human malaria cases in Central and South America, Southeastern Asia and the Indian subcontinent. The rising severity of the disease and the increasing incidences of resistance shown by this parasite towards usual therapeutic regimens have necessitated investigation of putative novel drug targets to combat this disease. The apicoplast, an organelle of procaryotic origin, and its circular genome carrying genes of possible functional importance, are being looked upon as potential drug targets. The genes on this circular genome are believed to be highly conserved among all Plasmodium species. Till date, the plastid genome of P. falciparum, P. berghei and P. chabaudi have been detailed while partial sequences of some genes from other parasites including P. vivax have been studied for identifying evolutionary positions of these parasites. The functional aspects and significance of most of these genes are still hypothetical. In one of our previous reports, we have detailed the complete sequence, as well as structural and functional characteristics of the Elongation factor encoding tufA gene from the plastid genome of P. vivax. We present here the sequences of large and small subunit rRNA (lsu and ssu rRNA) genes, sufB (ORF470) gene, RNA polymerase (rpo B, C) subunit genes and clpC (casienolytic protease) gene from the plastid genome of P. vivax. A comparative analysis of these genes between P. vivax and P. falciparum reveals approximately 5-16% differences. A codon usage analysis of major plastid genes has shown a high frequency of codons rich in A/T at any or all of the three positions in all the species. TTA, AAT, AAA, TAT, and ATA are the major preferred codons. The sequences, functional domains and structural analysis of respective proteins do not show any variations in the active sites. A comparative analysis of these Indian P. vivax plastid genome encoded genes has also been done to understand the evolutionary position of the Indian parasite in comparison to other Plasmodium species.	f	\N
22267663	Oral candidiasis is often accompanied by severe inflammation, resulting in a decline in the quality of life of immunosuppressed individuals and elderly people. To develop a new oral therapeutic option for candidiasis, a nonpathogenic commensal oral probiotic microorganism, Streptococcus salivarius K12, was evaluated for its ability to modulate Candida albicans growth in vitro, and its therapeutic activity in an experimental oral candidiasis model was tested. In vitro inhibition of mycelial growth of C. albicans was determined by plate assay and fluorescence microscopy. Addition of S. salivarius K12 to modified RPMI 1640 culture medium inhibited the adherence of C. albicans to the plastic petri dish in a dose-dependent manner. Preculture of S. salivarius K12 potentiated its inhibitory activity for adherence of C. albicans. Interestingly, S. salivarius K12 was not directly fungicidal but appeared to inhibit Candida adhesion to the substratum by preferentially binding to hyphae rather than yeast. To determine the potentially anti-infective attributes of S. salivarius K12 in oral candidiasis, the probiotic was administered to mice with orally induced candidiasis. Oral treatment with S. salivarius K12 significantly protected the mice from severe candidiasis. These findings suggest that S. salivarius K12 may inhibit the process of invasion of C. albicans into mucous surfaces or its adhesion to denture acrylic resins by mechanisms not associated with the antimicrobial activity of the bacteriocin. S. salivarius K12 may be useful as a probiotic as a protective tool for oral care, especially with regard to candidiasis.	f	\N
22270369	α-Dystroglycan (α-DG) is a membrane-associated glycoprotein that interacts with several extracellular matrix proteins, including laminin and agrin. Aberrant glycosylation of α-DG disrupts its interaction with ligands and causes a certain type of muscular dystrophy commonly referred to as dystroglycanopathy. It has been reported that a unique O-mannosyl tetrasaccharide (Neu5Ac-α2,3-Gal-β1,4-GlcNAc-β1,2-Man) and a phosphodiester-linked modification on O-mannose play important roles in the laminin binding activity of α-DG. In this study, we use several dystroglycanopathy mouse models to demonstrate that, in addition to fukutin and LARGE, FKRP (fukutin-related protein) is also involved in the post-phosphoryl modification of O-mannose on α-DG. Furthermore, we have found that the glycosylation status of α-DG in lung and testis is minimally affected by defects in fukutin, LARGE, or FKRP. α-DG prepared from wild-type lung- or testis-derived cells lacks the post-phosphoryl moiety and shows little laminin-binding activity. These results show that FKRP is involved in post-phosphoryl modification rather than in O-mannosyl tetrasaccharide synthesis. Our data also demonstrate that post-phosphoryl modification not only plays critical roles in the pathogenesis of dystroglycanopathy but also is a key determinant of α-DG functional expression as a laminin receptor in normal tissues and cells.	f	\N
22276367	Evaluation of the fitness of an accused person to participate in legal proceedings is a classic forensic activity. Before the trial, the forensic expert will already assess any preexisting somatic and psychological illnesses and give a written expert opinion describing the condition of the accused at the time of the examination and assessing whether he is fit to stand trial. Nevertheless, decompensation or aggravation of a disease may occur--especially in stress situations as they are to be expected for an accused in the courtroom--so that apart from the current evaluation of the state of health of the accused, emergency treatment may occasionally become necessary in the courtroom. The article tries to answer the question how the expert can meet this challenge.	f	\N
22280950	Endocardial lead-induced tricuspid regurgitation has not been well recognized, either clinically or echocardiographically, and yet it is likely a preventable iatrogenic disease. In severe cases, it can lead to right ventricular failure and require tricuspid valve surgery. This complication will become increasingly important, because the numbers of permanent pacemakers and implantable cardioverter-defibrillators are expected to increase because of the aging population and the expanding capabilities of these devices. Published studies are largely retrospective, and serial studies to assess the time course of the development of tricuspid regurgitation are lacking. The mechanisms and severity of tricuspid regurgitation may not be well evaluated by two-dimensional echocardiography. Real-time three-dimensional echocardiography appears to be a promising technique to evaluate the mechanism of tricuspid regurgitation and may allow the early detection of patients who will develop severe lead-induced tricuspid regurgitation. A better understanding of the mechanism of lead-induced tricuspid regurgitation will be essential to the development of preventive strategies, which can then be tested in future clinical trials.	f	\N
22281228	Progressive multifocal leukoencephalopathy (PML) is a subacute central nervous system infection due to reactivation of the JC virus. Most reported cases occurred in HIV-infected patients (80% of cases), patients with lymphoid malignancies (13%) and transplant recipients taking immunosuppressants (5%). Less often, PML has been described in patients with chronic inflammatory joint diseases associated with autoimmune disorders (lupus, rheumatoid arthritis [RA] and vasculitis) (2%). Magnetic resonance imaging of the brain shows suggestive changes and confirmation of the diagnosis is obtained by performing PCR tests to identify the JC virus in the cerebrospinal fluid or, when necessary, a brain biopsy. No treatments have been proven effective. Most patients experience progressive disease that is fatal within a few months or induces incapacitating neurological impairments. The risk of PML is 0.4/100,000 in patients with RA. In the few case-reports of PML in RA patients, the treatments used included methotrexate (five cases) combined with a biological agent such as infliximab (one case), rituximab (four cases), or leflunomide (two cases including one with concomitant rituximab). PML is an extremely rare but devastating complication. Rituximab therapy is associated with an increased prevalence of PML in RA patients (4/100,000), who should be informed of this risk. In patients with lupus, the risk of PML is higher than in RA (4/100,000) and 40% of cases of PML occur during low-dose glucocorticoid therapy without immunosuppressive therapy.	f	\N
22281918	Sporotrichosis is a subcutaneous fungal infection caused by Sporothrix schenckii and acquired by direct inoculation. Although the majority of cases consist of the classic lymphocutaneous presentation, the frequency of atypical and severe clinical forms of the disease has increased progressively. Systemic and disseminated cutaneous sporotrichosis constitute rare variants and such cases are generally associated with cellular immunodeficiency or debilitated states. The present paper describes the first published case of molluscum-like lesions in disseminated mucocutaneous sporotrichosis. Direct mycological examination and histopathology revealed numerous yeast cells.	f	\N
22283575	Inhaled dry powder mannitol is well established for use in bronchial provocation testing. Inhaled mannitol also increases mucociliary clearance, and therefore could have a role in treating chronic suppurative lung disease. There have been a number of studies in cystic fibrosis and bronchiectasis. An international Phase III trial has just been published that suggests the use of regular inhaled mannitol increases lung function and reduces exacerbation frequency in cystic fibrosis. Inhaled mannitol exerts its effects in a number of ways, most importantly like hypertonic saline, setting up an osmotic gradient so water flows into the airway lumen, increasing mucus hydration and mucociliary clearance. Its formulation as a dry powder makes it quick and convenient to take.	f	\N
22288822	Urinary schistosomiasis is caused by the digenetic trematode Schistosoma haematobium, characterized by accumulation of eggs in the genitourinary tract. Cytotoxic T-lymphocyte antigen 4 (CTLA-4) can play an important role in parasitic infection due to its major role as a negative regulator of T-cell activation and proliferation. This study was performed in patients with schistosomiasis and healthy controls to analyze the allele and genotype frequencies of four CTLA-4 gene polymorphisms. The CTLA-4 gene was amplified using Taqman real-time polymerase chain reaction, and allele and genotypes of 49 patients with schistosomiasis were analyzed using allelic discrimination analysis followed by subsequent direct sequencing. The results were compared with healthy control subjects. The frequencies of CTLA-4 rs733618 A allele at position -1722 (p=0.001), rs11571316 C allele at position -1577 (p<0.001), and rs231775 A allele at position +49 (p=0.002) in the patient group were significantly higher than the control group. The rs733618 AA genotype (p=0.001), rs11571316 CC genotype (p<0.001), and rs231775 AA genotype (p=0.007) were also significantly overrepresented. Meanwhile, rs733618 AG genotype (p=0.001), rs11571316 CT genotype (p=0.02), and rs231775 GG genotype (p=0.029) were significantly decreased in the patients with schistosomiasis, as compared with the controls. No significant difference was observed in both allele and genotype of rs16841252. The results of this study suggest that the rs733618, rs11571316, and rs231775 polymorphisms in the CTLA-4 gene may influence susceptibility to schistosomiasis infection in the Gabonese children.	f	\N
22289889	Accumulating evidence indicates that infiltrating stromal cells contribute directly and indirectly to tumor growth in a wide range of cancers. In follicular lymphoma (FL), malignant B cells are found admixed with heterogeneous lymphoid-like stromal cells within invaded lymph nodes and BM. In addition, mesenchymal stromal cells (MSCs) support in vitro FL B-cell survival, in particular after their engagement toward lymphoid differentiation. We show here that BM-MSCs obtained from patients with FL (FL-MSCs) display a specific gene expression profile compared with MSCs obtained from healthy age-matched donors (HD-MSCs). This FL-MSC signature is significantly enriched for genes associated with a lymphoid-like commitment. Interestingly, CCL2 could be detected at a high level within the FL-cell niche, is up-regulated in HD-MSCs by coculture with malignant B cells, and is overexpressed by FL-MSCs, in agreement with their capacity to recruit monocytes more efficiently than HD-MSCs. Moreover, FL-MSCs and macrophages cooperate to sustain malignant B-cell growth, whereas FL-MSCs drive monocyte differentiation toward a proangiogenic and lipopolysaccharide-unresponsive phenotype close to that of tumor-associated macrophages. Altogether, these results highlight the complex role of FL stromal cells that promote direct tumor B-cell growth and orchestrate FL-cell niche, thus emerging as a potential therapeutic target in this disease.	f	\N
22299123	Abuse of methamphetamine (meth), a potent central nervous system stimulant, has been associated with significant dental disease. Current descriptions of "meth mouth" are limited in their scope and fail to illuminate the potential pathogenic mechanisms of meth for oral disease. The purpose of this pilot study was to characterize the oral health of subjects with a history of meth abuse as compared to nonabusing control subjects. A total of 28 meth abusers and 16 control subjects were enrolled. Interviews and surveys regarding meth abuse, dental history, oral hygiene, and diet were collected. A comprehensive oral cavity examination including salivary characterization was completed. We observed significantly higher rates of decayed surfaces, missing teeth, tooth wear, plaque, and calculus among meth abusers. No significant difference in salivary flow rates were noted, yet results showed significant trends for lower pH and decreased buffering capacity. These findings suggest that salivary quality may play a more important role in meth mouth than previously considered. Salivary analysis may be useful when managing a dental patient with history of methamphetamine abuse.	f	\N
22299530	Traditional forms of treatment of the thyroid diseases: pharmacotherapy, radioiodine therapy and surgery can not always be applied. Intolerance, side effects of antithyroid drugs, low iodine uptake, high risk of surgery or disagreement with the proposed treatment was the reason for seeking alternative healing methods. With the development of interventional radiology, and gained experience in the use of arterial embolization, this method has become possible to use in treatment of thyroid diseases. The essence of this treatment is to shut down blood flow in major arteries of the thyroid by direct injection into the vessel's light of adequate size particles containing polyvinyl alcohol (PVA). The consequence of acute ischemia is septic necrosis of the glandular tissue in a field being supplied by this artery. Further repair processes and fibrosis lead to a reduction of active thyroid hormone synthesis and restriction of thyroid gland. Effects of embolization on angiogenesis, apoptosis and autoimmune reactions contribute to compensation thyroid function and significant reduction a goiter volume in course of Graves' disease. Preoperative selective embolization of a huge goiter or thyroid cancer improves surgery outcomes, reduces the risk of hemorrhage and damage to surrounding tissue. Palliative use of embolization in advanced stages of thyroid cancer reduces symptoms and improves quality of life. Little invasive nature of this procedure, the lack of serious undesirable coincidence makes embolization of thyroid arteries an attractive form of a therapy, which may become a therapeutic option in many difficult clinical situations and improve the clinical effectiveness of treatment of thyroid disease.	f	\N
22299533	Objectification assess the health status of COPD patients poses numerous problems arising from the complexity of both the disease and medical co-operation with the patient. So far, the methods adopted do not correlate with the quality of life. Also, the discrepancy in the evaluation of their symptoms by patients leads to an underestimation of obtained information. Recently proposed a test study of COPD has been validated in many countries and can be implemented into daily practice.	f	\N
22302706	Homozygous germline mutations of the PARK2 gene are responsible for the development of early-onset Parkinson's disease (PD). Homozygous PARK2 mutations have been also detected in lung adenocarcinoma (LADC). However, since heterozygous PARK2 germline mutations are present in a subset of non-PD individuals, the timing for the occurrence of two-hit PARK2 mutations in LADC progression is unclear. Therefore, we comprehensively analyzed mutations, expression and copy number variations of the PARK2 gene in 267 primary LADCs together with the corresponding noncancerous lung cells and 39 LADC cell lines. Heterozygous germline exonic deletions were detected in five patients with LADC, and loss of heterozygosity including the PARK2 locus was detected in 31/267 (11.6%) LADCs. However, homozygous PARK2 inactivation was not detected in any of them, including the five patients with germline mutations. Homozygous PARK2 inactivation was detected in 6/39 (15%) cell lines, two exonic deletions, one exonic duplication, and three point mutations, while heterozygous PARK2 inactivation was detected in two cell lines (both by exonic deletions). These results strongly indicate that somatic PARK2 mutations occur rarely (or do not occur) in LADC development and that germline PARK2 mutations could contribute to LADC progression but not to LADC development.	f	\N
22304951	Coronary computed tomography angiography (CTA) is a highly accurate noninvasive test that is increasingly used in symptomatic patients primarily for the diagnosis of coronary artery disease (CAD). Beyond its proven accuracy, data have now clearly demonstrated the incremental prognostic information available from coronary CTA related to the presence, extent, and severity of obstructive and nonobstructive CAD across a variety of clinical settings and patient populations. Current evidence supports the use of coronary CTA not only for the diagnosis of CAD in appropriately selected symptomatic patients but also to further refine their cardiovascular risk assessment following testing.	f	\N
22306387	Heart disease is one of the leading causes of death in the United States. With the increase in substance abuse, the incidence of acute myocardial infarction (MI) in younger population has been on the rise. Traditionally, cocaine has been blamed for acute MI; however, recently, there have been more incidences of marijuana as an inciting factor. We present a case of marijuana-induced acute MI and discuss the proposed mechanism.	f	\N
22309448	The aetiology of female pattern hair loss (FPHL) is largely unknown. However, it is hypothesized that FPHL and male pattern baldness (AGA) share common susceptibility alleles. The two major susceptibility loci for AGA are the androgen receptor (AR)/ectodysplasin A2 receptor (EDA2R) locus on the X-chromosome, and a locus on chromosome 20p11, for which no candidate gene has yet been identified. To examine the role of the AR/EDA2R and 20p11 loci in the development of FPHL using 145 U.K. and 85 German patients with FPHL, 179 U.K. supercontrols and 150 German blood donors. Patients and controls were genotyped for 25 single nucleotide polymorphisms (SNPs) at the AR/EDA2R locus and five SNPs at the 20p11 locus. Analysis of the AR/EDA2R locus revealed no significant association in the German sample. However, a nominally significant association for a single SNP (rs1397631) was found in the U.K. sample. Subgroup analysis of the U.K. patients revealed significant association for seven markers in patients with an early onset (P = 0·047 after adjustment for the testing of multiple SNPs by Monte Carlo simulation). No significant association was obtained for the five 20p11 variants, either in the overall samples or in the analysis of subgroups. The observed association suggests that the AR/EDA2R locus confers susceptibility to early-onset FHPL. Our results do not implicate the 20p11 locus in the aetiology of FPHL.	f	\N
22310615	Due to the severe shortage of deceased donors in Japan, ABO-incompatible living donor kidney transplantation has been performed since the late 1980s. Excellent long-term outcomes have been achieved; the rates of graft survival among these patients are currently similar to those of recipients of ABO-compatible grafts. Our single-center experience describing the immunosuppressive protocols, complications, and grafts survivals is documented in this study. Among 123 patients with end-stage renal disease who underwent living donor kidney transplantation between January 1999 and December 2010, 25 cases were ABO-incompatible grafts. All of these patients were followed until August 2011. Analyzing these patients, we focused on their immunosuppressive protocols, complications, and graft survivals. Patient and graft survival rates were 100%. One patient experienced antibody-mediated rejection and an intractable acute cellular rejection episode, 1 patient an antibody-mediated rejection, and 6 patients had acute cellular rejection episodes. However, there were no severe complications. Although ABO-incompatible kidney transplantation is a high-risk procedure, a short-term graft survival rate of 100% may be expected due to recent significant improvements in desensitization and recipient management.	f	\N
22312826	Combination anti-HIV therapies revolutionized patient life expectancy in the mid-1990's. Afterwards, in the early 2000's, research focused on the adverse effects caused by HIV drugs. Among these, the most serious ones are myocardial infarction at young age, disturbances of kidney function, liver disorders, pancreatitis and osteoporosis. The worsening of prognosis, for instance in respect of cardiac diseases, observed approximately five years ago in patients due to pauses in HIV medication, has changed perspective. Currently it is being discussed whether the overall prognosis will be improved with HIV medication started as early as possible.	f	\N
22318137	Herpes simplex virus 1 (HSV-1) and HSV-2 are medically significant pathogens. The development of an effective HSV vaccine remains a global public health priority. HSV-1 and HSV-2 immunodominant "asymptomatic" antigens (ID-A-Ags), which are strongly recognized by B and T cells from seropositive healthy asymptomatic individuals, may be critical to be included in an effective immunotherapeutic HSV vaccine. In contrast, immunodominant "symptomatic" antigens (ID-S-Ags) may exacerbate herpetic disease and therefore must be excluded from any HSV vaccine. In the present study, proteome microarrays of 88 HSV-1 and 84 HSV-2 open reading frames(ORFs) (ORFomes) were constructed and probed with sera from 32 HSV-1-, 6 HSV-2-, and 5 HSV-1/HSV-2-seropositive individuals and 47 seronegative healthy individuals (negative controls). The proteins detected in both HSV-1 and HSV-2 proteome microarrays were further classified according to their recognition by sera from HSV-seropositive clinically defined symptomatic (n = 10) and asymptomatic (n = 10) individuals. We found that (i) serum antibodies recognized an average of 6 ORFs per seropositive individual; (ii) the antibody responses to HSV antigens were diverse among HSV-1- and HSV-2-seropositive individuals; (iii) panels of 21 and 30 immunodominant antigens (ID-Ags) were identified from the HSV-1 and HSV-2 ORFomes, respectively, as being highly and frequently recognized by serum antibodies from seropositive individuals; and (iv) interestingly, four HSV-1 and HSV-2 cross-reactive asymptomatic ID-A-Ags, US4, US11, UL30, and UL42, were strongly and frequently recognized by sera from 10 of 10 asymptomatic patients but not by sera from 10 of 10 symptomatic patients (P < 0.001). In contrast, sera from symptomatic patients preferentially recognized the US10 ID-S-Ag (P < 0.001). We have identified previously unreported immunodominant HSV antigens, among which were 4 ID-A-Ags and 1 ID-S-Ag. These newly identified ID-A-Ags could lead to the development of an efficient "asymptomatic" vaccine against ocular, orofacial, and genital herpes.	f	\N
22319048	Consumption of high levels of fructose in humans and animals leads to metabolic and cardiovascular dysfunction. There are questions as to the role of the autonomic changes in the time course of fructose-induced dysfunction. C57/BL male mice were given tap water or fructose water (100 g/l) to drink for up to 2 mo. Groups were control (C), 15-day fructose (F15), and 60-day fructose (F60). Light-dark patterns of arterial pressure (AP) and heart rate (HR), and their respective variabilities were measured. Plasma glucose, lipids, insulin, leptin, resistin, adiponectin, and glucose tolerance were quantified. Fructose increased systolic AP (SAP) at 15 and 60 days during both light (F15: 123 ± 2 and F60: 118 ± 2 mmHg) and dark periods (F15: 136 ± 4 and F60: 136 ± 5 mmHg) compared with controls (light: 111 ± 2 and dark: 117 ± 2 mmHg). SAP variance (VAR) and the low-frequency component (LF) were increased in F15 (>60% and >80%) and F60 (>170% and >140%) compared with C. Cardiac sympatho-vagal balance was enhanced, while baroreflex function was attenuated in fructose groups. Metabolic parameters were unchanged in F15. However, F60 showed significant increases in plasma glucose (26%), cholesterol (44%), triglycerides (22%), insulin (95%), and leptin (63%), as well as glucose intolerance. LF of SAP was positively correlated with SAP. Plasma leptin was correlated with triglycerides, insulin, and glucose tolerance. Results show that increased sympathetic modulation of vessels and heart preceded metabolic dysfunction in fructose-consuming mice. Data suggest that changes in autonomic modulation may be an initiating mechanism underlying the cluster of symptoms associated with cardiometabolic disease.	f	\N
22326991	After age, the second largest risk factor for Alzheimer's disease (AD) is apolipoprotein E (APOE) genotype, where APOE4 is associated with lower apoE protein levels, more severer brain pathology, enhanced inflammation and disease. Small peptides corresponding to the receptor-binding region of apoE mimic the anti-inflammatory activity of the apoE holoprotein. These apoE mimetics greatly improve behavioral outcomes and neuronal survival in head trauma models that display AD pathology and neuronal loss. To determine whether apoE mimetics change behavior, inflammation and pathology in CVND-AD (SwDI-APP/NOS2(-/-)) transgenic mice. Starting at 9 months, apoE peptides were subcutaneously administered 3 times per week for 3 months followed by behavioral, histochemical and biochemical testing. Treatment with apoE mimetics significantly improved behavior while decreasing the inflammatory cytokine IL-6, neurofibrillary tangle-like and amyloid plaque-like structures. Biochemical measures matched the visible pathological results. Treatment with apoE mimetics significantly improved behavior, reduced inflammation and reduced pathology in CVND-AD mice. These improvements are associated with apoE-mimetic-mediated increases in protein phosphatase 2A activity. Testing in additional AD models showed similar benefits, reinforcing this novel mechanism of action of apoE mimetics. These data suggest that the combination of anti-inflammatory and neuroprotective activities of apoE mimetics represents a new generation of potential therapeutics for AD.	f	\N
22333444	To investigate the feasibility and safety of unilateral incision hybrid fixation using pedicle screws and a translaminar screw in minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF). From January to June 2010, 18 patients with single-level lumbar disc disease were treated with MIS-TLIF under METRx(TM) X-tube. After decompression and fixation using unilateral pedicle screws, a translaminar screw was inserted from the same incision to the other side. The results of perioperative parameters, radiographic images and clinical outcomes were assessed. All patients underwent MIS-TLIF were accomplished unilateral hybrid fixation without any neural complication. The average operative time was (107 ± 19) min, the average operative blood loss was (62 ± 21) ml, and the average postoperative ambulation time was (21 ± 5) h. The average length of translaminar facets screw was (52 ± 2) mm, and the postoperative images showed all screws penetrate through facets joint. During the follow-up the visual analogue scale and Oswestry disability index scores were significant improved compared with preoperative (F = 42.221 - 259.833, P < 0.01). Bilateral hybrid fixation could be completed through unilateral incision by pedicle screws and a translaminar screw in MIS-TLIF, and the advantage including less invasion, quickly recovery, short operative time, and saving fixation cost.	f	\N
22335481	Optical imaging has seen significant developments over the past decade as an investigational tool for in-vivo visualization of cellular and sub-cellular events. With the recent addition of optoacoustic (photoacoustic) methods, in particular multi-spectral opto-acoustic tomography (MSOT), to the already rich armamentarium of photonic methods the capacity of optical molecular imaging across scales has widened significantly. MSOT brings unique features into optical imaging, namely high resolution optical imaging over several millimeters to centimeters of tissue depth and the ability to simultaneously resolve multiple tissue molecules and extrinsically administered optical or optoacoustic agents with physiological or molecular specificity. Here, we discuss the implications of utilizing MSOT in the context of drug discovery and review suitable optoacoustic agents against disease and drug efficacy biomarkers. The combination of existing knowledge on generating optical targeted contrast, with the high resolution deep tissue visualization offered by MSOT, allows for the development of next-generation biological optical imaging and corresponding drug discovery applications.	f	\N
22337313	Rubella virus (RV) usually causes a mild disease. However, infection during the first trimester of pregnancy often leads to severe birth defects known as congenital rubella syndrome (CRS). Although wild-type RVs exist and circulate worldwide, their genotypes remain unknown in many countries. The aim of this study was to identify the molecular characteristics of RVs found in Vietnam during the years 2009-2010 and to provide the first data concerning RV genotypes in this country. Throat swab samples were collected between 2009 and 2010 from four CRS cases and nine rubella infection cases visiting one Children's Hospital and one outpatient clinic in Ho Chi Minh City. The 739-nucleotide coding region of the RV E1 gene recommended by the World Health Organization was amplified by reverse transcriptase PCR, and the resulting DNA fragments were then sequenced. Sequences were assigned to genotypes by phylogenetic analysis with RV reference strains. RV RNA was detected in 11 clinical specimens. Phylogenetic analysis of the sequences showed that all 11 strains belonged to 2B genotype. Several variations in amino acids were found, among which five changes were involved in the B and T cell epitopes. These data indicate that viruses of genotype 2B were circulating in Vietnam. The increasing information about RV genotype in Vietnam should aid in the control of rubella infection and CRS in this country.	f	\N
22339380	Acute pancreatitis is an acute inflammatory condition of the pancreas, which might extend to local and distant extrapancreatic tissues. The global incidence varies between 17.5 and 73.4 cases per 100,000 and the pathogenesis recognizes alcohol exposure and biliary tract disease as the leading causes, ahead of post-endoscopic retrograde cholangiopancreatography, drugs and abdominal trauma. The diagnosis of acute pancreatitis is substantially based on a combination of clinical signs and symptoms, imaging techniques and laboratory investigations. Contrast-enhanced computed tomography is the reference standard for the diagnosis, as well as for establishing disease severity. The assessment of pancreatic enzymes, early released from necrotic tissue, is the cornerstone of laboratory diagnosis in this clinical setting. Although there is no single test that shows optimal diagnostic accuracy, most current guidelines and recommendations indicate that lipase should be preferred over total and pancreatic amylase. Although a definitive diagnostic threshold cannot be identified, cut-offs comprised between ≥ 2 and ≥ 4 times the upper limit of the reference interval are preferable. The combination of amylase and lipase has been discouraged as although it marginally improves the diagnostic efficiency of either marker alone, it increases the cost of investigation. Some interesting biomarkers have been also suggested (e.g., serum and urinary trypsinogen-1, -2 and -3, phospholipase A2, pancreatic elastase, procalcitonin, trypsinogen activated protein, activation peptide of carboxypeptidase B, trypsin-2-alpha1 antitrypsin complex and circulating DNA), but none of them has found widespread application for a variety of reasons, including the inferior diagnostic accuracy when compared with the traditional enzymes, the use of cumbersome techniques, or their recent discovery. The promising results of recent proteomics studies showed that this innovative technique might allow the identification of changes characterizing pancreatic tissue injury, thus highlighting new potential biomarkers of acute pancreatitis.	f	\N
22353988	Several studies have reported that patients with essential tremor (ET) may also have mild cognitive impairment. Event-related potentials (ERPs) involve cognitive processes in the brain. No detailed investigation has been conducted into auditory ERPs (AERPs) to detect the subclinical cognitive dysfunction in patients with ET. Therefore, this study aimed to clarify the usefulness of AERPs in ET-related cognitive impairment. The AERPs were obtained by using an oddball paradigm in 27 patients with ET and 27 age-matched control subjects. The mean latency and amplitude of the ERPs were compared between the two groups. The correlation between disease duration and the mean values of all components of the potentials was assessed. The association between tremor severity and potentials was also evaluated. The patients with ET showed significant prolongation of all components of the ERP latencies at each electrode site. The N200 and P300 amplitudes were reduced in the ET group. Interestingly, the significant prolongation of N100 and N200 latencies correlated with disease duration, and N200 latencies appeared significantly longer in patients with severe tremor. Significant differences were found between the components of the AERPs and tremor severity and disease duration. This finding implies that ERPs may be useful in evaluating the cognitive functions in ET and that those AERP abnormalities may appear before clinical presentation.	f	\N
22356008	A 22 year old female with valvular heart disease, moderate mitral valve insufficiency, moderate aortic insufficiency, extensive aneurysmal dilatation of the entire ascending aorta and arch, and segmental dilatation of descending aorta underwent entire anterior aortic replacement. We performed aortic root and valve replacement with a composite graft, followed by coronary artery reimplantation using the Bentall and De Bono technique. Simultaneously, we carried out a graft replacement of the transverse arch and descending aortic aneurysms with a woven Dacron graft using the Elephant Trunk technique. The goal of this surgery was to correct or optimally treat the multiple sites of aortic disease. To the best of our knowledge, there is no reported case from Pakistan with extensive aortic grafting from root to descending aorta using the Bentall and Elephant Trunk technique simultaneously.	f	\N
22363380	The redox system is an important anti-oxidative system composed of thioredoxin, thioredoxin reductase, and peroxiredoxin (PRx). The fine details of PRx expression and its protective effects in various cells in cardiovascular tissue under oxidative stress created by hydrogen peroxide have not been fully elucidated. Oxidative stress was induced by adding hydrogen peroxide at 0.25 mM for 2 hours to rat neonatal cardiomyocytes (rCMCs), rat vascular smooth muscle cells (rVSMCs), and human umbilical vein endothelial cells (HUVECs). Apoptosis was quantified by flow cytometry and the expression patterns of the six PRx isoforms were evaluated by western blotting in the three cell lines after hydrogen peroxide stimulation. Apoptosis and the cell survival signal pathway were evaluated by PRx1 gene delivery using lentiviral vector in hydrogen peroxide stimulated rCMCs versus green fluorescence protein gene delivery. Hydrogen peroxide induced 25% apoptosis in rCMCs. Furthermore, the PRx1 and 5 isoforms were found to be overexpressed in hydrogen peroxide treated rCMCs, and PRx1 overexpression by gene delivery was found to reduce hydrogen peroxide induced rCMCs apoptosis significantly. In addition, this effect was found to originate from cell survival pathway modification. Hydrogen peroxide induced significant oxidative stress in rCMCs, rVSMCs, and HUVECs, and PRx1 overexpression using a lentiviral vector system significantly reduced hydrogen peroxide induced rCMCs apoptosis by upregulation of cell survival signals and downregulation of apoptotic signals. These findings suggest that PRx1 could be used as a treatment strategy for myocardial salvage in conditions of oxidative stress.	f	\N
22363739	Southeast Asia has been the focus of considerable investment in pandemic influenza preparedness. Given the wide variation in socio-economic conditions, health system capacity across the region is likely to impact to varying degrees on pandemic mitigation operations. We aimed to estimate and compare the resource gaps, and potential mortalities associated with those gaps, for responding to pandemic influenza within and between six territories in Asia. We collected health system resource data from Cambodia, Indonesia (Jakarta and Bali), Lao PDR, Taiwan, Thailand and Vietnam. We applied a mathematical transmission model to simulate a "mild-to-moderate" pandemic influenza scenario to estimate resource needs, gaps, and attributable mortalities at province level within each territory. The results show that wide variations exist in resource capacities between and within the six territories, with substantial mortalities predicted as a result of resource gaps (referred to here as "avoidable" mortalities), particularly in poorer areas. Severe nationwide shortages of mechanical ventilators were estimated to be a major cause of avoidable mortalities in all territories except Taiwan. Other resources (oseltamivir, hospital beds and human resources) are inequitably distributed within countries. Estimates of resource gaps and avoidable mortalities were highly sensitive to model parameters defining the transmissibility and clinical severity of the pandemic scenario. However, geographic patterns observed within and across territories remained similar for the range of parameter values explored. The findings have important implications for where (both geographically and in terms of which resource types) investment is most needed, and the potential impact of resource mobilization for mitigating the disease burden of an influenza pandemic. Effective mobilization of resources across administrative boundaries could go some way towards minimizing avoidable deaths.	f	\N
22365640	For an evaluation of the progress achieved in the field of kidney cancer care in the Netherlands in the last decades, we described trends in incidence, treatment, mortality and relative survival. All adult patients newly diagnosed with kidney cancer between 1989 and 2009 (N=32,545) were selected from the Netherlands Cancer Registry. Age-standardised incidence and mortality rates were calculated. Follow-up was completed until January 2010. In order to assess trends estimated annual percentages of change (EAPC) were estimated. The incidence of kidney cancer has been fairly stable between 1989 and 2001 with a European Standardised Rate of approximately 11 per 100,000 person years (PY). Since 2001 the incidence increased to 13 per 100,000 PY in 2009 (EAPC: 2.4%; 95%confidence interval (CI): 1.5 to 3.4%). The mortality rate decreased slightly over time, from 6.2 per 100,000 PY in 1989 to 5.6 in 2010. No changes in treatment were observed, except for the introduction of targeted therapies for stage IV disease, since 2005. The 5-year relative survival improved from 51% in 1989-1994 to 58% in 2005-2009 (EAPC: 0.9%; 95%CI 0.7 to 1.2%). Improvement in survival was especially seen in males, younger age groups and low stages. The incidence of kidney cancer has increased slightly, and survival improved modestly, resulting in a decreasing mortality. A positive effect of the introduction of targeted therapies for metastatic kidney cancer was observed in 1-year relative survival. For progress in kidney cancer care, effective prevention strategies and new therapies remain warranted.	f	\N
22370242	This review describes the features of modern infrared imaging technology and the standardization protocols for thermal imaging in medicine. The technique essentially uses naturally emitted infrared radiation from the skin surface. Recent studies have investigated the influence of equipment and the methods of image recording. The credibility and acceptance of thermal imaging in medicine is subject to critical use of the technology and proper understanding of thermal physiology. Finally, we review established and evolving medical applications for thermal imaging, including inflammatory diseases, complex regional pain syndrome and Raynaud's phenomenon. Recent interest in the potential applications for fever screening is described, and some other areas of medicine where some research papers have included thermal imaging as an assessment modality. In certain applications thermal imaging is shown to provide objective measurement of temperature changes that are clinically significant.	f	\N
22383586	To report the annual incidence of occupational diseases (ODs) in economic sectors in The Netherlands. In a 5-year prospective cohort study (2009-2013), occupational physicians were asked to participate in a sentinel surveillance system for OD notification. The inclusion criteria for participation were (1) covering a population of employees, (2) reporting the economic sectors and the size of their employee population and (3) willingness to report all diagnosed ODs. In this study, an OD was defined as a disease with a specific clinical diagnosis that was predominantly caused by work-related factors. The economic sectors (n=21) were defined according the NACE (Nomenclature des Activités Économiques dans la Communauté Européenne) classification. In a total working population of 514,590 employees, 1782 ODs were reported over 12 months in 2009. The estimated annual incidence for any OD was 346 (95% CI 330 to 362) per 100,000 worker-years. Of all the ODs, mental diseases were reported most frequently (41%), followed by musculoskeletal (39%), hearing (11%), infectious (4%), skin (3%), neurological (2%) and respiratory (2%) diseases. The four economic sectors with the highest annual incidences per 100,000 workers were construction (1127; 95% CI 1002 to 1253), mining and quarrying (888; 95% CI 110 to 1667), water and waste processing (832; 95% CI 518 to 1146) and transport and storage (608; 95% CI 526 to 690). ODs are reported in all economic sectors in The Netherlands. Up to 91% of all ODs are mental, musculoskeletal and hearing diseases. Efforts to increase the effective assessment of ODs and compliance in reporting activities enhance the usability of incidence figures for the government, employers and workers.	f	\N
22394620	The longitudinal degradation mechanism of extracellular matrix (ECM) in the interbertebral disc remains unclear. Our objective was to elucidate catabolic and anabolic gene expression profiles and their balances in intervertebral disc degeneration using a static compression model. Forty-eight 12-week-old male Sprague-Dawley rat tails were instrumented with an Ilizarov-type device with springs and loaded statically at 1.3 MPa for up to 56 days. Experimental loaded and distal-unloaded control discs were harvested and analyzed by real-time reverse transcription-polymerase chain reaction (PCR) messenger RNA quantification for catabolic genes [matrix metalloproteinase (MMP)-1a, MMP-2, MMP-3, MMP-7, MMP-9, MMP-13, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4, and ADAMTS-5], anti-catabolic genes [tissue inhibitor of metalloproteinases (TIMP)-1, TIMP-2, and TIMP-3], ECM genes [aggrecan-1, collagen type 1-α1, and collagen type 2-α1], and pro-inflammatory cytokine genes [tumor necrosis factor (TNF)-α, interleukin (IL)-1α, IL-1β, and IL-6]. Immunohistochemistry for MMP-3, ADAMTS-4, ADAMTS-5, TIMP-1, TIMP-2, and TIMP-3 was performed to assess their protein expression level and distribution. The presence of MMP- and aggrecanase-cleaved aggrecan neoepitopes was similarly investigated to evaluate aggrecanolytic activity. Quantitative PCR demonstrated up-regulation of all MMPs and ADAMTS-4 but not ADAMTS-5. TIMP-1 and TIMP-2 were almost unchanged while TIMP-3 was down-regulated. Down-regulation of aggrecan-1 and collagen type 2-α1 and up-regulation of collagen type 1-α1 were observed. Despite TNF-α elevation, ILs developed little to no up-regulation. Immunohistochemistry showed, in the nucleus pulposus, the percentage of immunopositive cells of MMP-cleaved aggrecan neoepitope increased from 7 through 56 days with increased MMP-3 and decreased TIMP-1 and TIMP-2 immunopositivity. The percentage of immunopositive cells of aggrecanase-cleaved aggrecan neoepitope increased at 7 and 28 days only with decreased TIMP-3 immunopositivity. In the annulus fibrosus, MMP-cleaved aggrecan neoepitope presented much the same expression pattern. Aggrecanase-cleaved aggrecan neoepitope increased at 7 and 28 days only with increased ADAMTS-4 and ADAMTS-5 immunopositivity. This rat tail sustained static compression model mimics ECM metabolic imbalances of MMPs, aggrecanases, and TIMPs in human degenerative discs. A dominant imbalance of MMP-3/TIMP-1 and TIMP-2 relative to ADAMTS-4 and ADAMTS-5/TIMP-3 signifies an advanced stage of intervertebral disc degeneration.	f	\N
22407767	Cryptic subtelomeric chromosomal aberrations are responsible for 5-10% of moderate/severe and 1% of mild intellectual disability. Unbalanced subtelomeric chromosomal rearrangements result in variable phenotypes which seem to be highly influenced by both the size of the duplication/deletion and the chromosomes involved in the translocation. We report on three related patients with moderate intellectual disability, language delay, hypotonia, facial dysmorphism, cardiac anomalies, scoliosis, and kyphosis in whom a familial (maternal) unbalanced submicroscopic translocation was found by subtelomeric fluorescence in situ hybridization (FISH). This rearrangement resulted in a partial trisomy 10pter and partial monosomy 21qter. The karyotype was 46,XY.ish der(21)t(10;21)(p14;q22.2). Confirmation of a 6.7 Mb size distal duplication of the p15.3-14 region of chromosome 10 and a 5.6 Mb distal deletion of the q22.2-22.3 region of chromosome 21 was obtained by array-CGH. To our best knowledge, such a composition of subtelomeric unbalanced translocations has not yet been published. Detection of this aberration in successive pregnancies of carrier members of the family by prenatal FISH could prevent the recurrence of the disease. Furthermore, detection of the rearrangements and identification of genes located in the chromosomal regions involved might be of interest.	f	\N
22412958	This study identified sex differences in progression of cutaneous melanoma. Of 7,338 patients who were diagnosed as an invasive primary CM without clinically detectable metastases from 1976 to 2008 at the University of Tuebingen in Germany, 1,078 developed subsequent metastases during follow up. The metastatic pathways were defined in these patients and analyzed using the Kaplan-Meier method. Multivariate survival analysis was performed using Cox modeling. In 18.7% of men and 29.2% of women (P<0.001) the first metastasis following diagnosis of primary tumor was locoregional as satellite/in-transit metastasis. The majority of men (54.0%) and women (47.6%, P = 0.035) exhibited direct regional lymph node metastasis. Direct distant metastasis from the stage of the primary tumor was observed in 27.3% of men and 23.2% of women (P = 0.13). Site of first metastasis was the most important prognostic factor of survival after recurrence in multivariate analysis (HR:1.3; 95% CI: 1.0-1.6 for metastasis to the regional lymph nodes vs. satellite/in-transit recurrence, and HR:5.5; 95% CI: 4.2-7.1 for distant metastasis vs. satellite/in-transit recurrence, P<0.001). Median time to distant metastasis was 40.5 months (IQR, 58.75) in women and 33 months (IQR, 44.25) in men (P = 0.002). Five-year survival after distant recurrence probability was 5.2% (95% CI: 1.4-2.5) for men compared with 15.3% (95% CI: 11.1-19.5; P = 0.008) for women. Both, the pattern of metastatic spread with more locoregional metastasis in women, and the time course with retracted metastasis in women contributed to the more favorable outcome of women. Furthermore, the total rate of metastasis is increased in men. Interestingly, there is also a much more favorable long term survival of women after development of distant metastasis. It remains a matter of debate and of future research, whether hormonal or immunologic factors may be responsible for these sex differences.	f	\N
22417127	In approximately 5-8% patients with primary ovarian insufficiency (POI), the disease is caused by an autoimmune process made evident by the appearance of autoantibodies against steroidogenic enzymes (SCA-POI). Anti-müllerian hormone (AMH) is the best marker of the residual follicular pool. To evaluate the rate of loss of the residual follicle pool in women with SCA-POI after clinical diagnosis. One hundred and thirty-two women with POI were tested for 21-hydroxylase autoantibodies, 17α-hydroxylase autoantibodies and P450scc autoantibodies, and 35 patients with SCA-POI were identified. AMH was analysed at the time of the first visit in all women with POI, and in follow-up, serum samples were taken 1-3 years after in 11 women with SCA-POI and detectable AMH. 12/35 (35%) women with SCA-POI had AMH levels within the normal range at the time of first sampling, as compared to 6/97 (6%) with idiopathic POI (P < 0·001). 11/17 (65%) women with SCA-POI with <6 years disease duration had normal serum AMH concentration. A progressive decline in AMH concentration was observed at longitudinal follow-up in all 11 AMH-positive women with SCA-POI, at an estimated average rate of 1·6 μg/l AMH/year (corresponding to an average 57% of preserved follicle pool/previous year) (R(2)  = 0·219, P = 0·028). After 6 years of disease duration, only 1/18 (6%) women with SCA-POI had detectable levels of AMH, similar to women with idiopathic POI (5/78, 6%). Most women with SCA-POI present at clinical diagnosis with a preserved follicle pool that is progressively lost within a few years.	f	\N
22426166	Natural killer (NK) cells are the effector cells of innate immunity that respond to infection and tumor. Interactions between killer cell immunoglobulin like receptors (KIR) and human leukocyte antigen (HLA) class I molecules regulate NK cells responses to eliminate infected and transformed cells. To investigate the impact of KIR genes, HLA ligand genes, and KIR-HLA combinations on susceptibility to tuberculosis (TB) in Lur population of Iran. The genomic DNA of 50 patients with TB from Lorestan province of Iran was genotyped for sixteen KIR genes and their five major HLA class I ligands were determined by a polymerase chain reaction-sequence-specific primers (PCR-SSP) assay. The results were compared with those of 200 healthy unrelated Iranian individuals. In Lur population of Iran, a significant decrease in frequency of KIR3DS1 was found in TB patients compared to control group (24% vs. 44.5%, OR=0.394, CI=0.194-0.798, p=0.013). Also, among the three activating genes that may use HLA class I molecules as their ligands, a significant decrease was shown in frequency of KIR3DS1 with HLA-B Bw4Ile80 ligand in TB patients compared to control group (4% vs. 23%, OR=0.14, CI=0.033-0.596, p=0.004). These findings imply a genetic imbalance between activating and inhibitory KIR genes and KIR-HLA combinations in Lur TB patients. Low level of activating KIR3DS1 and its combination with HLA-B Bw4Ile80 ligand might have an influence on the susceptibility to TB in Lur population of Iran.	f	\N
22433620	The aim of this study was to define body fat percentiles for German children and adolescents aged 3-16 years using the largest German database. The study population included 11,632 girls and 11,604 boys. Data were pooled from: i) Kiel Obesity Prevention Study (KOPS), acquisition period: 1996-2008, n = 12,237; ii) 'Better diet. More exercise. KINDERLEICHT-REGIONS', acquisition period: 2007, n = 9,405; and iii) examination of Jena schoolchildren, acquisition period: 2005, n = 1,594. Body fat mass was measured by bioelectrical impedance analysis using a population-specific algorithm. Data were weighted to achieve a representative sample for Germany. Percentile curves were constructed by the LMS method and proved by Worm plots and Q-statistic. In both genders, the higher body fat percentile curves sloped downwards to age 7 years, whereas the lower percentiles declined up to 8.5 years. Thereafter fat mass remained nearly constant with age in boys and increased in girls. The 10th percentile achieved a minimum of 10-11% body fat in both genders, whereas the 90th percentile curve fluctuated between 29 and 44% in boys or 30-43% in girls. The association between fat mass and blood pressure was too weak to define disease-related cut-offs. These body fat percentiles are suitable reference values for German children and adolescents.	f	\N
22434759	The aim of our study was to evaluate the physical and sedentary activities and energy expenditure (EE) in a group of children affected by non-alcoholic fatty liver disease (NAFLD), compared with normal and obese subjects, using a physical activity questionnaire (PAQ) and a SenseWear armband (SWA). Forty NAFLD (10 females), 41 lean (NRM; 11 females) and 30 obese (OB; 10 females), age- and pubertal stage-matched, children were included. Sedentary activity (PAQ) was similar in NAFLD and NRM but less in OB, while SWA showed that NAFLD spent less time in physical activity and more in sedentary activities compared with NRM, but not with OB. Insulin sensitivity index result is related to active EE (cal kg(-1)  d(-1) ) in NAFLD, while homeostatic model assessment index result was negatively related to total EE in OB. Regular physical activity must be encouraged in all obese children affected by NAFLD or not, and SWA might be a possible valid tool for evaluating actual EE.	f	\N
22458506	The roles of cysteine protease (CP) enzymes in the biochemistry and infectivity of the three trypanosomal parasitic infections, Chagas' disease, leishmaniasis and human African trypanosomiasis, which have been elucidated over the last three decades are summarized. Inhibitors of these enzymes, which act through trapping the active site cysteine with an electrophilic warhead, hold huge potential as therapeutic agents but the promise of these has yet to be realized in clinical studies. The article addresses aspects that ought to be considered in order to develop orally active CP inhibitors that are safe and effective therapies for trypanosomiasis. This article reviews learnings from CP research in the trypanosomal field and recent advances in developing cysteine protease inhibitors (CPIs) of human cathepsin K, a related enzyme. Considerations such as intra- and extracellular localization of the CPs, off-target activities against human cathepsin enzymes, basic versus neutral and potential pro-drug inhibitors are reviewed. A description of odanacatib, a cathepsin K inhibitor currently in late stage development, is made to illustrate the attributes of a clinically viable CPI. The emerging role of CPs in a wide array of parasitic diseases is highlighted with the vision that CP inhibitors could become the 'β-lactams' of anti-parasitic treatments in the coming decades. New CPI research will see the optimization of intra- and extracellular enzyme targeting, reduction of off-target activities and better understanding of pharmacokinetic-pharmacodynamic interactions which will all lead to compounds with much improved efficacy and viability as clinical therapies.	f	\N
22458804	Over the past few years, there has been a rapid rise in the older segments of the world population, which has brought along with it a major health concern: dementia. Alzheimer's disease, considered to be the most common cause of dementia, has become a prospect feared by the elderly. Inflammation of the brain is strongly implicated in Alzheimer's disease which could be enhanced by systemic inflammation. Periodontitis being a chronic inflammatory condition, which can cause systemic inflammation, the question is whether chronic periodontitis can initiate or hasten the rate of progression of Alzheimer's disease in susceptible individuals. In this article, the authors outline the proposed oral systemic link between periodontitis and Alzheimer's disease.	f	\N
22463746	Evaluation of peritoneal involvement in colonic cancer (CC) can be difficult. We studied pT4N0 cancers and their association with pathological prognostic markers, including tumour budding. Tumours were classified as (i) at the peritoneal surface or free in the peritoneal cavity (pT4a subgroup n = 44); (ii) directly invading adjacent organ (pT4b subgroup n = 8); or (iii) showing inflammatory involvement of the peritoneum (pT4I subgroup n = 25). A published pT3N0 cohort was used to compare Stage II subgroups. Standard pathological markers including tumour budding were assessed. Elastin staining was performed in the pT4I subgroup. Seventy-seven Stage II CCs met inclusion criteria. There was no significant difference in survival across subgroups. pT4b tumours were larger than pT4a tumours (P < 0.001). Over-represented features in pT4a versus pT4b tumours were tumour budding (P = 0.02) and infiltrative margin (P = 0.02). Tumour budding did not predict survival. Using multivariate analysis, neural invasion was the only parameter predictive of survival (hazard ratio = 2.8; 95% CI 1.2-6.4; P = 0.02). Stage II pT4I CCs have a similar outcome to T4a/b tumours. Elastin staining is useful in defining this group. Tumour budding may facilitate peritoneal invasion in pT4a tumours, but does not predict outcome in pT4N0 disease. Only neural invasion independently predicted poor outcome.	f	\N
22466542	Most common type of head and neck malignant tumors is squamous cell carcinoma reaching 3% of all human cancers. Oral squamous cell carcinoma (OSCC) has tendency of increasing incidence and mortality worldwide with an overall 5 year survival rate of <60%. In order to explore this disease, different in vivo mouse models have been introduced. In this study we analyzed clinical and morphological characteristics of OSCC in vivo nude mouse model. 80% of mice which were injected with human oral squamous cancer cells developed orthotopic tumors with the mean volume of 146 mm(3), from which 62% exhibited metastatic spread. Morphology of the cancer tissue was characterized with invasive phenotype and inflammation. Proliferation activity rate of orthotopicly grown tumors were 55,7 ± 4,7 mitotic cells/optical field and displayed weakly developed vascular network. OSCC in vivo orthotopic nude mouse model can mimic pathological and clinical picture of the malignant disease and may be effectively used in oncology research.	f	\N
22472026	Patients with Crohn's disease (CD) may need anti-inflammatory drugs for decades. Anti-TNF-α agents have good efficacy and adverse events similar to placebo in randomized controlled trials (RCTs), but there are still questions about long-term safety and efficacy. In this respect, reports from clinical practice may be useful. We currently report on the clinical experience with infliximab and adalimumab in a single-center cohort of patients with CD. Patients with CD treated with infliximab or adalimumab from 2000 to 2010 were reviewed. Patient and disease characteristics at start, reason for discontinuation, and adverse events were recorded retrospectively. Corticosteroid use, the need for hospitalization, and surgeries before and during anti-TNF-α therapy were recorded. Eighty-three patients had received anti-TNF-α treatment against CD, median treatment duration was 11.4 months (0.2-99.5), and follow-up time 59 months (8-135). Eighteen of 43 patients using corticosteroids at treatment start discontinued corticosteroids during TNF-α therapy. Need for hospitalizations (6.13 vs. 3.28 days/year, p < 0.001) and surgeries (0.56 vs. 0.16 operations/year, p < 0.001) were lower during anti-TNF-α therapy than before treatment. Twenty-six percent discontinued therapy due to adverse events and 26% due to lack or loss of response. Two of four deaths observed during follow-up were believed to be related to anti-TNF-α treatment. Anti-TNF-α therapy was beneficial in many patients with CD, but the majority of patients discontinued treatment during follow-up. Reports from clinical experience with anti-TNF-α treatment may be valuable for clinicians treating patients with CD.	f	\N
22483567	Anti tumor necrosis factor alpha (TNFα) agents have become widely used in pediatric inflammatory bowel disease (IBD). So far, only few studies examined the long-term results of anti-TNFα treatment in children with IBD. The long-term outcome of pediatric patients with IBD was assessed retrospectively in a multicenter cohort of children treated with anti-TNFα beyond induction treatment. Short- and long-term response rates, predictors for loss of response, data on growth and laboratory parameters were assessed. 120 patients [101 crohn's disease (CD), 19 ulcerative colitis (UC) or indeterminate colitis (IC)] received either infliximab or adalimumab. The mean age at initiation of anti-TNFα was 13.4 ± 3.9 years and the median duration of anti-TNFα treatment was 15 months (range: 2-90). Overall, 89% of the cohort experienced short-term response following induction. Response was associated with improvement in weight and BMI Z-scores (p<0.001) but not with linear growth. Responders experienced a significant decrease in erythrocyte sedimentation rate (ESR) and C reactive protein (CRP) during treatment (p<0.001). Albumin and hemoglobin both improved but only albumin increased significantly (p<0.001). The cumulative probability of losing response to anti-TNFα treatment was 17%, 38%, and 49% after 1, 3, and 5 years, respectively. Responders had a significantly lower weight and BMI Z-scores at initiation of anti-TNFα treatment in compared to non-responders (p=0.04 and 0.02 respectively). Our long term cohort supports the current evidence on the effectiveness and safety of anti-TNFα treatment in children with IBD. Response to treatment was interestingly associated with lower weight and BMI.	f	\N
22484574	To determine the incidence of radiographic lumbar spondylosis (LS)and lower back pain, and their risk factors in Japan using a large-scale population from the nationwide cohort Research on Osteoarthritis/osteoporosis Against Disability (ROAD) Study. Participants in the ROAD study who had been recruited between 2005 and 2007 were followed up with lumbar spine radiography for 3 years. A total of 2,282 paired radiographs (75% of the original sample) were scored using Kellgren and Lawrence (KL) grades, and the incidence and progression rate of radiographic LS was analyzed. The incidence of lower back pain was also examined. In addition, associations between risk factors and incident and progressive radiographic LS as well as incident lower back pain were tested. Given a 3.3-year follow-up, the incidence of KL≥2 radiographic LS was 50.0% and 34.4% (15.3% and 10.5% per year), while that of KL≥3 LS was 15.3% and 23.7% (4.6% and 7.2% per year) in men and women, respectively. The progression rate of LS was 20.5% and 27.4% (6.2% and 8.3% per year) in men and in women, respectively. In addition, the incidence of lower back pain was 28.3% and 31.2% (8.6% and 9.5% per year) in men and women. Lower back pain was not significantly associated with incident radiographic LS, while a more severe KL grade at baseline was associated with incident lower back pain. The present longitudinal study revealed a high incidence of radiographic LS in Japan.	f	\N
22484921	Sarcoidosis is a multi-systemic disease. A 21-year-old female patient was admitted to our department with lymphadenopathy, B symptoms, erythema nodosum and joint pain. Sarcoidosis showed a very atypical course, lacking any pulmonary symptoms or typical laboratory values. The diagnosis was finally confirmed histologically and thus various differential diagnoses such as microbiological and malignant diseases could be excluded. Oral steroid medication led to remission.	f	\N
22484998	Populations living in poverty in the developing world suffer a heavy burden caused by infectious diseases, most of them zoonoses. The poorer populations also tend to be marginalised from the health sector and so are many of the diseases that affect them. The poor in every society, and particularly in developing countries, bear a disproportionately high share of the disease burden. There is a broad range of viral, bacterial, mycotic, chlamydial, rickettsial and parasitic diseases of global and regional importance given their major impact on the health and socio-economic development of many populations. Endemic infectious diseases, including zoonoses, together with emerging and re-emerging diseases, are mostly shouldered by poor and vulnerable populations. Livestock are important in supporting the livelihoods of poor farmers, consumers and traders throughout the developing world. The animals of poor people are particularly vulnerable to disease because of costs, absence or unsuitability of the animal health sector, etc. The impact of endemic animal diseases are mainly felt at the farm level, while a broader economic impact can occur with these diseases through the restriction of trade in livestock and their products. Addressing comprehensive and sustainable solutions to public health problems created by endemic infections cannot be achieved solely by the public health sector alone. Partnerships with other sectors, particularly agriculture, environment, education, local administration, will be necessary to contain and effectively control zoonotic and foodborne diseases that affect mainly the poor. International organisations could support developing countries by coordinating national intersectoral activities, promoting appropriate technology and public health education, community participation and encouraging decision-makers to commit themselves. This is the only perspective for improved quality of life of poor and marginalised populations.	f	\N
22485050	Immunogenicity and safety of ACWY-TT compared with licensed ACWY polysaccharide vaccine (MenPS) in healthy adults, and lot-to-lot consistency of three ACWY-TT lots were evaluated in a phase 3, open, controlled study. Adults aged 18-55 y were randomized to receive ACWY-TT (one of three lots) or MenPS. Serum bactericidal antibodies (rSBA) were measured pre- and 1 mo post-vaccination. Adverse events (AEs) were assessed 4 d (solicited symptoms) and 31 d (unsolicited symptoms) post-vaccination. Serious AEs were reported up to 6 mo after vaccination. The number of vaccinated subjects was 1247 (ACWY-TT, n = 935; MenPS, n = 312). ACWY-TT lot-to-lot consistency and non-inferiority of ACWY-TT as compared with MenPS groups were demonstrated according to pre-specified criteria. The percentages of subjects with a vaccine response (VR = rSBA titer ≥ 1:32 in initially seronegative; ≥ 4-fold increase in initially seropositive) to ACWY-TT vs. MenPS were 80.1%/69.8% (serogroup A), 91.5%/ 92.0% (C), 90.2%/85.5% (W-135), 87.0%/78.8% (Y). Exploratory analyses showed that for serogroups A, W-135 and Y, VR rates and GMTs were significantly higher for ACWY-TT compared with MenPS. For each serogroup, ≥ 98.0% of subjects had rSBA titers ≥ 1:128. Grade 3 solicited AEs were reported in ≤ 1.6% of subjects in any group. The immunogenicity of ACWY-TT vaccine was non-inferior to MenPS for all four serogroups in adults, with significantly higher VR rates to serogroups A, W-135 and Y and an acceptable safety profile. Consistency of 3 ACWY-TT production lots was demonstrated. These data suggest that, if licensed, ACWY-TT conjugate vaccine may be used for protection against invasive meningococcal disease in healthy adults.   This study is registered at clinicaltrials.gov NCT00453986.	f	\N
22486286	Patients with chronic kidney disease are exposed to oxidative stress (OS) that contributes to deterioration of health. Decrease in renal excretory capacity contributes to the accumulation of pro-oxidative substances that are detrimental not only to kidney but to the whole organism including the cardiovascular system. Components of antioxidant system play an important role in the elimination of the OS. The monitoring of antioxidant levels and products of oxidative damage in these patients and the correct interpretation of relationship between these markers and the function of kidney and other organs may contribute to the more effective treatment and health improvement of the patients.	f	\N
22494938	The whipworms Trichuris trichiura and Trichuris suis in humans and pigs, respectively, are believed to be two different species yet closely related. Morphologically, adult worms, eggs and larvae of the two species are indistinguishable. The aim of this study was to examine the genetic variation of Trichuris sp. mainly recovered from natural infected pigs and humans. Worm material isolated from humans and pigs living in the same geographical region in Uganda were analyzed by PCR, cloning and sequencing. Measurements of morphometric characters were also performed. The analysis of the ITS-2 (internal transcribed spacer) region showed a high genetic variation in the human-derived worms with two sequence types, designated type 1 and type 2, differing with up to 45%, the type 2 being identical to the sequence found in pig-derived worms. A single human-derived worm showed exclusively the type 2-genotype (T. suis-type) and three cases of 'heterozygote' worms in humans were identified. However, the analysis showed that sympatric Trichuris primarily assorted with host origin. Sequence analysis of a part of the genetically conserved β-tubulin gene confirmed two separate populations/species but also showed that the 'heterozygote' worms had a T. suis-like β-tubulin gene. A PCR-RFLP on the ITS-2 region was developed, that could distinguish between worms of the pig, human and 'heterozygote' type. The data suggest that Trichuris in pigs and humans belong to two different populations (i.e. are two different species). However, the data presented also suggest that cross-infections of humans with T. suis takes place. Further studies on sympatric Trichuris populations are highly warranted in order to explore transmission dynamics and unravel the zoonotic potential of T. suis.	f	\N
22498694	Although many of the effects of estrogens on the brain are mediated through estrogen receptors (ERs), there is evidence that neuroprotective activity of estrogens can be mediated by non-ER mechanisms. Herein, we review the substantial evidence that estrogens neuroprotection is in large part non-ER mediated and describe in vitro and in vivo studies that support this conclusion. Also, we described our drug discovery strategy for capitalizing on enhancement in neuroprotection while at the same time, reducing ER binding of a group of synthetic non-feminizing estrogens. Finally, we offer evidence that part of the neuroprotection of these non-feminizing estrogens is due to enhancement in redox potential of the synthesized compounds.	f	\N
22503230	To investigate whether single nucleotide polymorphisms (SNPs) in interleukin (IL)-1β, IL-6, and IL-12β are associated with the susceptibility and severity of contact lens-related keratitis. Retrospective, case control study. One hundred twelve cases of keratitis and 225 controls were recruited from studies conducted at Moorfields Eye Hospital and in Australia during 2003 through 2005. Buccal swab samples were collected on Whatman FTA cards and were mailed by post for analysis. IL-1β (-31), IL-6 (-174, -572, -597), and IL-12B (3'+1158) genotypes were analyzed with pyrosequencing and analyzed using a regression model for susceptibility (sterile, microbial keratitis, controls) and severity. Statistical significance was set at 0.05. The relative risk of developing contact lens-related keratitis and more severe forms of the disease based on allele, genotype, and haplotype associations. Carriers of IL-6 SNPs were more likely to experience moderate and severe events compared with those with nonmutated genotypes (-174 heterozygous: odds ratio [OR], 3.1; 95% confidence interval [CI], 1.1-8.3; homozygous: OR, 6.4; 95% CI, 1.4-28.4; -174/-597: OR, 4.1; 95% CI, 1.6-11.0). More severe keratitis and microbial keratitis were less likely to occur in wearers with the nonmutated IL-6 haplotype (severity OR, 0.4 [95% CI, 0.2-0.7]; microbial OR, 0.6 [95% CI, 0.4-0.9]). Wearers carrying an IL-12B SNP had an increased risk of sterile keratitis (OR, 9.7; 95% CI, 1.2-76.9) compared with controls. The IL-6 SNPs are known to reduce protein expression of this cytokine and thus ocular immune defense, and carriers of these SNPs were more likely to experience more severe and microbial keratitis, suggesting that IL-6 decreases the severity and susceptibility of contact lens-related keratitis. Carriers of a functional SNP of IL-12B that is known to increase IL-12 expression and stability are more likely to experience sterile keratitis, suggesting that this is associated with the intense inflammatory reaction that occurs in this condition.	f	\N
22505009	To evaluate inhibin-A immunoreactivity and its utility in the differential diagnosis of nervous system neoplasms and non-neoplastic lesions. An immunohistochemical study of 252 central and peripheral nervous system tumors and 40 non-neoplastic lesions was undertaken. Brain lesions included the basic spectrum of astrocytic, oligodendroglial, and ependymal neoplasms, as well as glioneuronal, pineal parenchymal, choroid plexus, and embryonal. Meningeal neoplasms, basic peripheral nerve tumors, and uncommon sellar lesions were also assessed. Non-neoplastic lesions included demyelinating disease, progressive multifocal leukoencephalopathy, organizing infarct, and reactive gliosis. Diffuse cytoplasmic, membranous, and perinuclear cytoplasmic staining patterns were observed. Significant immunoreactivity was noted in glioblastoma (12 of 20), pleomorphic xanthoastrocytoma (6 of 10), ganglioglioma (8 of 10), meningioma (14 of 20), and hemangioblastoma (10 of 10). Peripheral nerve and sellar tumors as well as non-neoplastic lesions were entirely immunonegative. In our study that investigated the inhibin-A immunoreactivity in a broad spectrum of nervous system lesions, inhibin-A positivity was established in various low-grade and high-grade central nervous system tumors. Thus, inhibin-A is not a specific marker of hemangioblastoma and may be of limited utility in the differential diagnosis of astrocytic and meningothelial neoplasms. Its pathophysiologic role in these various tumors remains to be determined. Further evaluation of the possible significance of staining patterns and degrees of reactivity relative to pathobiology and/or prognosis significance is required.	f	\N
22507833	Osteoporosis, a major health problem among postmenopausal women, is influenced by dietary factors. The purpose of the present study was to evaluate the hypothesis that erythrocyte levels of n-3 polyunsaturated fatty acid (PUFA) and the dietary intake of fish are associated with risk of osteoporosis and correlate with bone mass in postmenopausal Korean women with the disease. Fifty cases and 100 controls were recruited. Osteoporosis was defined according to the International Society for Clinical Densitometry guideline as a score lower than -2.5 SD below the T-score for lumbar vertebrae L₁-L₄, femoral neck or femoral total. The T-score of the femoral neck was positively correlated with erythrocyte levels of n-3 PUFA, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and the intake of fish, and was negatively correlated with the ratio of n-6/n-3 PUFA after adjusting for age, years after menopause and height. In addition, the risk of osteoporosis was positively associated with erythrocyte levels of saturated fatty acids but negatively associated with EPA + DHA. Erythrocyte levels of n-3 PUFA and the intake of fish were positively correlated with bone mass. In particular, erythrocyte levels of EPA + DHA reduced the risk of osteoporosis in postmenopausal Korean women.	f	\N
22509749	Mast cells are tissue-resident immune cells that participate in a variety of allergic and inflammatory conditions. Limited attention has been given to the role of mast cells in periodontal diseases, and the effects of mast cell degranulation on the chronic stages of non-allergic inflammation, particularly in periodontitis, are not known. The present study analyzes the relationship between the mast cell degranulation and human periodontal disease progression. A total of 50 clinical specimens including moderate periodontitis (n = 17), advanced periodontitis (n = 18), and healthy control tissues (n = 15) were used in this study. All specimens were fixed in 10% buffered formalin and stained with hematoxylin and eosin for histopathology, with toluidine blue for identifying mast cells, and by immunohistochemistry for the expressions of mast cell tryptase in periodontal tissues. The total and degranulated mast cell densities (per high-power field) were quantified in the specimens. Compared with healthy controls, there were significantly increased both total and degranulated mast cell densities in human moderate (P <0.01) and advanced (P <0.01) periodontitis groups by toluidine blue staining, and there were significantly higher densities of both total and degranulated tryptase-positive mast cell subpopulation in the moderate periodontitis group (P <0.01) and even significantly higher subpopulation densities in the advanced periodontitis group by immunohistochemical staining, in which both total and degranulated mast cell densities were significantly higher in the advanced periodontitis group than those in the moderate periodontitis group (P <0.01) by both toluidine blue staining and immunohistochemical staining. There was significantly more severe periodontal inflammatory pathology in the advanced periodontitis group than in the moderate periodontitis group (P <0.01). These findings indicate a significant correlation among tryptase-positive mast cell density, the degree of their degranulation, and the human periodontitis severity, and the results of this study further indicate that mast cell degranulation appears to be associated with human periodontal disease.	f	\N
22511575	We sought to examine the contemporary use of thrombectomy during primary percutaneous coronary intervention (PCI) in the United States. Adjunctive thrombectomy during primary PCI for patients with ST-segment elevation myocardial infarction (STEMI) has demonstrated mixed results. While earlier studies showed either unfavorable or neutral effects with rheolytic thrombectomy, recent clinical trials have shown benefits with manual or rheolytic thrombectomy when compared to PCI alone. We analyzed data from 122,449 patients undergoing primary PCI for STEMI from 1,181 centers reported to the CathPCI Registry® between July 2009 and December 2010. We used logistic regression analysis to examine factors associated with the use of manual and rheolytic thrombectomy. Thrombectomy was performed in 23,195 patients (18.9%): 22,404 (18.3%) had manual thrombectomy and 791 (0.6%) had rheolytic thrombectomy. The use of manual thrombectomy increased over time (P < 0.05). The use of rheolytic thrombectomy did not change. There was significant variation in the use of thrombectomy across hospitals. The strongest predictors of manual versus no thrombectomy included TIMI 0/1 flow (odds ratio 1.69), younger age (OR 0.90 per 10 year increase), saphenous vein graft (OR 2.22), glycoprotein IIb/IIIa inhibitor (OR 1.34), single-vessel disease (OR 1.13), and year of admission (OR 1.20 per year; all P < 0.001). The strongest predictor of manual versus rheolytic thrombectomy was year of admission (OR 1.23, P < 0.001). Our data show that thrombectomy is performed infrequently in the US during primary PCI for STEMI. There is significant variation in the use of thrombectomy across US hospitals.	f	\N
22515999	Myocarditis is defined as inflammation of the myocardium accompanied by myocellular necrosis. Acute myocarditis must be considered in patients who present with recent-onset of cardiac failure or arrhythmia. Fulminant myocarditis is a distinct entity characterized by sudden onset of severe congestive heart failure or cardiogenic shock, usually following a flu-like illness, parvovirus B19, human herpesvirus 6, coxsackievirus and adenovirus being the most frequently viruses responsible for the disease. Treatment of myocarditis remains largely supportive, since immunosuppression has not been proven to be beneficial for acute lymphocytic myocarditis. Trials of antiviral therapies, or immunostimulants such as interferons, suggest a potential therapeutic role but require further investigation. Lastly, early recognition of patients rapidly progressing to refractory cardiac failure and their immediate transfer to a medical-surgical center experienced in mechanical circulatory support is warranted. In this setting, ECMO should be the first-line mechanical assistance. For highly unstable patients, a Mobile Cardiac Assistance Unit, that rapidly travels to primary care hospitals with a portable ECMO system and hooks it up before refractory multiorgan failure takes hold, is the preferred option.	f	\N
22523117	Podocyturia, i.e. urinary loss of viable podocytes, may serve as a diagnostic tool for pre-eclampsia and as a marker of active renal disease. The current method to detect podocyturia is technically complex, lengthy and requires a high level of expertise for interpretation. The aim of this study was to develop a new technique for the identification of urinary podocytes, based on the detection of podocyte-specific tryptic peptides by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS), which will provide an operator-independent and highly reproducible method. The diagnosis of pre-eclampsia was confirmed in the presence of hypertension (>140/90 mmHg) and proteinuria >0.3 g/24 h urine. The diagnosis of HELLP was confirmed based on the accepted clinical criteria of hemolysis, elevated liver enzymes and low platelet count. Random urine samples within 24 h prior to delivery were collected and centrifuged. One half of the sediment was cultured for 24 h to select for viable cells and then stained with a podocin antibody, followed by a secondary fluorescein isothiocyanate-labeled antibody to identify podocytes. The second half of the pellet was solubilized, digested and analyzed by LC-MS/MS using an internal standard. We have recruited 13 patients with pre-eclampsia and 6 patients with pre-eclampsia/HELLP syndrome. The presence of podocytes was confirmed in all patients by the podocyte culture method. In the respective samples, the presence of a podocin-specific tryptic peptide was confirmed with LC-MS/MS technology. The LC-MS/MS method is a reliable technology for the identification of urinary podocytes, based on the presence of podocyte-specific proteins in the urine.	f	\N
22525341	Epoxyeicosatrienoic acids (EETs) are natural angiogenic mediators regulated by soluble epoxide hydrolase (sEH). Inhibitors of sEH can stabilize EETs levels and were reported to reduce atherosclerosis and inhibit myocardial infarction in animal models. In this work, we investigated whether increasing EETs with the sEH inhibitor t-AUCB would increase angiogenesis related function in endothelial progenitor cells (EPCs) from patients with acute myocardial infarction (AMI). EPCs were isolated from 50 AMI patients and 50 healthy subjects (control). EPCs were treated with different concentrations of t-AUCB for 24h with or without peroxisome proliferator activated receptor γ (PPARγ) inhibitor GW9662. Migration of EPCs was assayed in trans-well chambers. Angiogenesis assays were performed using a Matrigel-Matrix in vitro model. The expression of vascular endothelial growth factor (VEGF), hypoxia-inducible factor 1α (HIF-1α) mRNA and protein in EPCs was measured by real-time PCR or Western blot, respectively. Also, the concentration of EETs in the culture supernatant was detected by ELISA. The activity of EPCs in the AMI patient group was reduced compared to healthy controls. Whereas increasing EET levels with t-AUCB promoted a dose dependent angiogenesis and migration in EPCs from AMI patients. Additionally, the t-AUCB dose dependently increased the expression of the angiogenic factors VEGF and HIF-α. Lastly, we provide evidence that these effects were PPARγ dependent. The results demonstrate that the sEH inhibitor positively modulated the functions of EPCs in patients with AMI through the EETs-PPARγ pathway. The present study suggests the potential utility of sEHi in the therapy of ischemic heart disease.	f	\N
22527997	Early life stress, such as maternal separation, causes adaptive changes in neural mechanisms that have adverse effects on the neuroplasticity of the brain in adulthood. As a consequence, children who are exposed to stress during development may be predisposed to neurodegenerative disorders in adulthood. A possible mechanism for increased vulnerability to neurodegeneration may be dysfunctional mitochondria. Protection from neurotoxins, such as 6-hydroxydopamine (6-OHDA), has been observed following voluntary exercise. The mechanism of this neuroprotection is not understood and mitochondria may play a role. The purpose of this study was to determine the effects of maternal separation and exercise on mitochondrial function in a rat model of Parkinson's disease. Maternally separated (pups separated from the dam for 3 h per day from postnatal day (P) 2-14) and non-separated rats were placed in individual cages with or without attached running wheels for 1 week prior to unilateral infusion of 6-OHDA (5 μg/4 μl, 0.5 μl/min) into the left medial forebrain bundle at P60. After 2 h recovery, rats were returned to their cages and wheel revolutions recorded for a further 2 weeks. On P72, the rats' motor function was assessed using the forelimb akinesia test. On P74, rats were sacrificed for measurement of mitochondrial function. Exercise increased the respiratory control index (RCI) in the non-lesioned hemisphere of 6-OHDA-lesioned rats. This effect was evident in the striatum of non-separated rats and the prefrontal cortex of maternally separated rats. These results suggest that early life stress may reduce the adaptive response to exercise in the striatum, a major target of dopamine neurons, but not the prefrontal cortex in this model of Parkinson's disease.	f	\N
22531706	To identify the underlying mutation and describe the phenotype in a consanguineous Kurdish family with Leber's congenital amaurosis (LCA)/early onset severe retinal dystrophy (EOSRD). Members of the index family were followed up to 22 years by ophthalmological examinations, including best corrected visual acuity (BCVA), Goldmann visual field (GVF), two-color-threshold perimetry (2CTP) and Ganzfeld electroretinogram (ERG), fundus photographs, fundus autofluorescence (FAF), and optical coherence tomography (OCT). After excluding seven of nine known LCA/EOSRD genes in the index patient, linkage analysis was performed in the family using a microarray followed by microsatellite fine mapping and direct sequencing of candidate genes. RD3 was screened by direct sequencing of 85 independent patients with LCA/EOSRD presenting with a BCVA ≥ 1.0 LogMAR before the age of 2 years to assess the prevalence of RD3 mutations in LCA/EOSRD. Since RD3 and RetGC1 have a functional relation, study authors screened for a modifying effect of RD3 mutations in 17 independent patients with mutations in GUCY2D. BCVA was severely reduced from the earliest examinations (as early as 3 months), never exceeding 1.3 LogMAR. The disease presented as cone-rod dystrophy with dystrophic changes in the macula and bone spicules in the periphery on progression. Linkage analysis narrowed the region of interest towards the LCA12 locus. Direct sequencing of RD3 revealed a homozygous nonsense mutation (c.180C > A) in all affected members tested. Screening of additional unrelated LCA/EOSRD patients revealed only polymorphisms in RD3. This is the second family reported so far with mutations in RD3. Mutations in RD3 are a very rare cause of LCA associated with an extremely severe form of retinal dystrophy.	f	\N
22533114	Although the number of tuberculosis cases in the US is at an all-time low, with progressive declines seen for the past 17 years, many goals in the tuberculosis elimination process remain unrealized. This report describes a cluster of four tuberculosis cases in a family, including one case of acquired multidrug resistant tuberculosis. It also underscores some important issues in tuberculosis control today, including significant disparities in the foreign-born population with multidrug resistant tuberculosis as a looming problem, as well as utilization of therapeutic drug level monitoring in complicated cases.	f	\N
22533233	Hen's egg is one of the main causes of food allergy in children. Accidental exposure is common in food-allergic patients. However, the few studies that analyze this problem focus mainly on peanut allergy. We sought to calculate the frequency of accidental exposure reactions in children allergic to hen's egg during a 12-month period, to analyze the clinical characteristics and circumstances surrounding the reactions, and to identify risk factors for the most severe reactions. Ninety-two egg-allergic children (55 boys; median age, 52 months) were included in the study. A systematic questionnaire about accidental exposure was administered. Reactions were classified as mild, moderate, and severe. Egg white-specific immunoglobulin (Ig) E antibody titers were determined. Nineteen (21%) children had 24 reactions in the previous year (42% mild, 50% moderate, and 8% severe). Most reactions took place at home (50%) under routine circumstances (83%). Children with severe or moderate reactions had higher specific IgE levels to egg white (adjusted odds ratio for every 0.1-unit increase in the decimal logarithm, 1.15; 95% CI, 1.03-1.28; P = .008) and lower serum total IgE (adjusted odds ratio for every 1-unit increase in the decimal logarithm, 0.16; 95% CI, 0.05-0.54; P = .001) than those children with mild or no reactions. Reactions to accidental exposure are frequent in children with egg allergy. The proportion of severe or moderate reactions was 58%. The risk factors for such reactions included high titers of specific IgE to egg white and low titers of serum total IgE.	f	\N
22545160	Successful and sustainable intervention against human helminthiases depends on optimal utilisation of available control measures and development of new tools and strategies, as well as an understanding of the evolutionary implications of prolonged intervention on parasite populations and those of their hosts and vectors. This will depend largely on updated knowledge of relevant and fundamental parasite biology. There is a need, therefore, to exploit and apply new knowledge and techniques in order to make significant and novel gains in combating helminthiases and supporting the sustainability of current and successful mass drug administration (MDA) programmes. Among the fields of basic research that are likely to yield improved control tools, the Disease Reference Group on Helminth Infections (DRG4) has identified four broad areas that stand out as central to the development of the next generation of helminth control measures: 1) parasite genetics, genomics, and functional genomics; 2) parasite immunology; 3) (vertebrate) host-parasite interactions and immunopathology; and 4) (invertebrate) host-parasite interactions and transmission biology. The DRG4 was established in 2009 by the Special Programme for Research and Training in Tropical Diseases (TDR). The Group was given the mandate to undertake a comprehensive review of recent advances in helminthiases research in order to identify notable gaps and highlight priority areas. This paper summarises recent advances and discusses challenges in the investigation of the fundamental biology of those helminth parasites under the DRG4 Group's remit according to the identified priorities, and presents a research and development agenda for basic parasite research and enabling technologies that will help support control and elimination efforts against human helminthiases.	f	\N
22547770	Crizotinib (PF02341066, Xalkori; Pfizer) was recently approved by the U.S. Food and Drug Administration for treatment of ALK-positive non-small cell lung cancer (NSCLC) as defined by a jointly approved diagnostic test using a break-apart fluorescence in situ hybridization assay. The approval was based on dramatic response rates in ALK-positive NSCLC patients of 54% to 61% in phase I and II trials. To date, the overall disease control rates in these trials are close to 90%. Progression-free survival approaches 10 months. This review focuses on the ALK-inhibitory activity of crizotinib in preclinical and clinical trials that led to approval, as well as the diagnostic methods to classify patients with ALK-positive NSCLC. Although these patients represent a small subset of all patients with NSCLC, the rapid time course from identification of this unique target to an approved targeted therapy with striking benefit serves as a paradigm for the development of targeted therapeutics in an era of personalized medicine.	f	\N
22548237	Ochroconis spp. are dematiaceous fungi and have recently become recognized as the cause of human disease. Infections due to members of this genus have primarily occurred in patients with impaired immunity following organ transplantation or chemotherapy for hematologic malignancies. There is no universally agreed upon therapy or duration of treatment, but amphotericin B and/or triazoles are typically employed. We present a case of Ochroconis gallopava infection in a patient with chronic granulomatous disease (CGD). The organism exhibited elevated minimal inhibitory concentrations against itraconazole (0.5 μg/ml) and voriconazole (2 μg/ml) in comparison with results from other studies reported in the literature. This case illustrates the complexities associated with antibiotic susceptibility testing, selection of appropriate drugs, and management in patients with Ochroconis infections. We also review the literature of human infections with Ochroconis to date, and discuss its microbiology to apprise both clinicians and laboratory personnel of this infrequently encountered but potentially aggressive pathogen.	f	\N
22559253	Polyphenols, a ubiquitous group of secondary plant metabolites sharing at least one aromatic ring structure with one or more hydroxyl groups, represent a large group of natural antioxidants abundant in fruits, vegetables, and beverages, such as grape juice, wine, and tea, and are widely considered to contribute to health benefits in humans. However, little is yet known concerning their bioactive forms in vivo and the mechanisms by which they may alter our metabolome, which ultimately contribute toward disease prevention. Here we report a study to determine the metabolic fate of polyphenolic components in a Chinese tea (Pu-erh) in human subjects using a metabonomic profiling approach coupled with multivariate and univariate statistical analysis. Urine samples were collected at 0 h, 1 h, 3 h, 6 h, 9 h, 12 h, and 24 h within the first 24 h and once a day during a 6 week period including a 2 week baseline phase, a 2 week daily Pu-erh tea ingestion phase, and a 2 week "wash-out" phase, and they were analyzed by gas chromatography mass spectrometry and liquid chromatography mass spectrometry. The dynamic concentration profile of bioavailable plant molecules (due to in vivo absorption and the hepatic and gut bacterial metabolism) and the human metabolic response profile were measured and correlated with each other. This study demonstrates that the metabonomic strategy will enable us to integrate the overwhelming amount of metabolic end points as a systems' response to the absorption, metabolism, and disposition of a multicomponent botanical intervention system, leading to a direct elucidation of their mechanisms of action.	f	\N
22571342	In carcinogenesis, methylation of DNA promoter regions results in inactivation of tumor-suppressing genes. MG98 was designed to inhibit DNA methyltransferases enzyme 1 production. This multicenter study explored two schedules of MG98 with Interferon-α-2β to identify schedule and dose for patients with metastatic RCC. Doses of IFN 9 MIU/MG98 125 mg/m(2) for a continuous schedule and IFN 9 MIU/MG98 200 mg/m(2) for an intermittent schedule were considered the MTDs. Treatment resulted in one PR and eight SD. MG98 combined with IFN was safe and resulted in clinical activity.	f	\N
22573749	The increase of severe cases of acute tonsillitis (AT) is presently marked. Severe cases of AT disturb immune and metabolic homoeostasis initiating the development of disease. Therapy optimization is required to select the best treatment. In patients with severe cases of AT of mixed viral/bacterial etiology before the treatment it is revealed the increase of general activity of lactatedehydrigenase (LDH) and increase of the level of cathode "anaerobic" factions LDH4+5 and the decline of concentration ATP in the blood. There was a compensatory rise of level of ADP and АМP. The substantial decline of serum interferon (CIF) activity and diminishing maintenance of α-interferon (α-IFN) and γ-interferon (γ-IFN) in the blood of the patients, that testified to oppressing of interferonogenesis. Treatment of severe cases of AT of mixed viral/bacterial etiology of modern detoxic preparation reamberin and immunoactive preparation cycloferon combination positively influences the studied laboratory indexes. The improvement of power metabolism is marked, that was characterized by normalization of level adenine nucleotides (ATP, АDP, АМP) and general activity of LDH and its izoenzimes spectrum. At the same time the increase of CIF level is set, maintenances α-IFN and γ-IFN in the blood, that testified to the improvement of interferonogenesis. The results demonstrate the therapeutic potential of reamberin and cycloferon combination for treatment of patients with AT of mixed viral/bacterial etiology.	f	\N
22582962	Infants with viral bronchiolitis are often hospitalised with a proportion requiring respiratory support. The aim of this review was to examine the use of nasal prong continuous positive airway pressure (CPAP) as a management strategy for infants with a diagnosis of bronchiolitis, who required stabilisation and transport to a tertiary centre. A retrospective audit of infants with bronchiolitis requiring CPAP during transport between January 2003 and June 2007. Nasal CPAP was initiated in 54 infants with 51 of these (34 ex-preterm, 17 term) subsequently continuing on CPAP during retrieval. Mean CPAP pressure was 7 cmH(2)O. Oxygenation improved between stabilisation and the end of retrieval (P < 0.01). During retrieval, there was no significant increase in transcutaneous CO(2), no infant required endotracheal ventilation and no adverse events were noted. Five infants were intubated within the first 24 h of admission at the receiving hospital. This review demonstrated that use of nasal prong CPAP to transport infants with bronchiolitis was a safe management strategy in those with moderate to severe disease severity.	f	\N
22595407	The authors used multidetector computed tomography (MDCT) to study the relation between culprit plaque characteristics and cardiac troponin T (cTnT) elevation after percutaneous coronary intervention (PCI). Percutaneous coronary intervention is often complicated by post-procedural myocardial necrosis manifested by elevated cardiac biomarkers. Stable angina patients (n = 107) with normal pre-PCI cTnT levels underwent 64-slice MDCT before PCI to evaluate plaque characteristics of culprit lesions. Patients were divided into 2 groups according to presence (group I, n = 36) or absence (group II, n = 71) of post-PCI cTnT elevation ≥3 times the upper limit of normal (0.010 ng/ml) at 24 h after PCI. Computed tomography attenuation values were significantly lower in group I than in group II (43.0 [26.5 to 75.7] HU vs. 94.0 [65.0 to 109.0] HU, p < 0.001). Remodeling index was significantly greater in group I than in group II (1.20 ± 0.18 vs. 1.04 ± 0.15, p < 0.001). Spotty calcification was observed significantly more frequently in group I than in group II (50% vs. 11%, p < 0.001). Multivariate analysis showed presence of positive remodeling (remodeling index >1.05; odds ratio: 4.54; 95% confidence interval: 1.36 to 15.9; p = 0.014) and spotty calcification (odds ratio: 4.27; 95% confidence interval: 1.30 to 14.8; p = 0.016) were statistically significant independent predictors for cTnT elevation. For prediction of cTnT elevation, the presence of all 3 variables (CT attenuation value <55 HU; remodeling index >1.05, and spotty calcification) showed a high positive predictive value of 94%, and their absence showed a high negative predictive value of 90%. MDCT may be useful in detecting which lesions are at high risk for myocardial necrosis after PCI.	f	\N
22610716	A 320-row multidetector CT provides the capability for prospective electrocardiogram (ECG)-gated coronary CT angiography (CTA) and tube current modulated cardiac function assessment (CFA). We assessed and compared the effective radiation dose of these two modes. On a prospective basis, we performed ECG-gated cardiac CT on 119 patients (87 were males). For heart rates (HRs) </=65 beats/min (bpm), we used one-heartbeat acquisition and half-scan reconstruction. HRs from 66 to 79 bpm and >/=80 bpm were scanned with either two or three heartbeats acquisitions, respectively. We used two types of scans. One type was based on a prospective ECG-gated CTA mode and the other using a tube current modulated CFA mode covering an entire R-R interval. The mean BMI of patients was 25.4 (range 18.8-49.3). Fifty-one patients (42.9 %) underwent CFA scanning, while the remaining 68 (57.1 %) had CTA. The majority of patients completed the scan in a single heartbeat (59.7 %). The mean dose of CTA mode at 65-85 % phase window for one and two heartbeats was 3.68 mSv (2.40-7.23) and 8.61 mSv (6.76-10.60), respectively. The mean dose of CFA mode for a single heartbeat measurement with dose modulation (25 % dose for CFA, and 100 % dose during 65-85 % phase window for CTA) was 6.32 mSv (4.69-8.89). CTA with prospective ECG-gating allows for acceptable image quality and radiation dose. HR reduction is mandatory to minimize radiation exposure. Global left ventricle function can be assessed with a single heartbeat within an acceptable radiation dose.	f	\N
22616529	Global climate warming for the last 10 years actualized the problem of mortality rise in some European countries in anomalous summer heat. Russia faced this problem in July-August 2010 when extreme heat entailed a significant elevation of mortality in 31 regions of the country primarily due to coronary heart disease and cerebrovascular diseases. The analysis of foreign researches has shown that old age and living in cities are leading risk factors of deat in anomalous heat. Experience of the European countries and USA evidences that stay in conditioned apartments and early referral for medical assistance are most effective death preventive measures in heat.	f	\N
22621617	Graves' disease (GD) is one of the most common autoimmune thyroid disorders and has a striking characteristic of female preponderance. The main objective of this study was to investigate whether IL12B gene polymorphisms were associated with either GD itself or with gender bias in GD. GD patients (151 males, 97 females) and 211 healthy control subjects without antithyroid autoantibodies or a family history of autoimmune disorders were recruited for this study. The G/C polymorphism (rs6887695) of the IL12B gene was analyzed using the polymerase chain reaction-restriction fragment length polymorphism, and the deletion and insertion polymorphism (rs41292470) in the IL12B promoter was detected after polyacrylamide gel electrophoresis-silver staining method. There was no significant difference between GD patients and normal subjects, and no differences in frequencies of genotypes or alleles of either polymorphism between male and female GD subjects. We conclude that these IL12B gene polymorphisms were not associated with sex bias in GD and do not confer susceptibility to Graves' disease (GD) in the Chinese population.	f	\N
22626277	Inflammation in the ovary, including ovulation and pelvic inflammatory disease, has been proposed to play a role in the pathogenesis of ovarian cancer. Endometriotic lesions trigger a local inflammatory reaction and have been reported to be associated with an increased risk of epithelial ovarian cancer. However, the precise molecular mechanisms of ovarian cancer arising from endometriosis are still to be elucidated. To clarify the involvement of mismatch repair (MMR) abnormalities in the inflammation-associated malignant transformation of endometriosis, the immunohistochemical expression of mismatch repair proteins (human mutL homolog 1 [hMLH1] and human mutS homolog 2 [hMSH2]) was examined in 27 cases of ovarian endometriosis, 25 cases of ovarian carcinoma accompanied by endometriosis, and 39 cases of solitary ovarian carcinoma. In addition, the relationship between mismatch repair abnormalities including the microsatellite instability, PTEN (phosphatase and tensin homolog) mutation, and clinicopathologic parameters was analyzed. The expression of mismatch repair proteins was stepwisely decreased in endometriosis, ovarian carcinoma accompanied by endometriosis, and ovarian carcinoma. Tumors harboring multiple microsatellite instability (high-frequency microsatellite instability [MSI-H]) were detected in 4 (14.8%) of 27 cases of endometriosis and 7 (30.4%) of 23 cases of ovarian carcinomas. The frequency of PTEN mutations was higher in MSI-H cases than in microsatellite instability-stable (MSI-S) cases. In 2 cases of ovarian carcinoma accompanied by endometriosis, the decreased expression of mismatch repair proteins and MSI-H was observed in both the endometriosis and carcinoma lesions. Clinicopathologically, the MSI-H cases were associated with elevated serum levels of C-reactive protein and higher white blood cell counts. These findings suggest that mismatch repair abnormalities might be involved in the malignant transformation of ovarian endometriosis and that inflammation induces mismatch repair abnormalities during ovarian carcinogenesis arising from endometriosis.	f	\N
22639889	Neuronal protein α-synuclein (α-syn) is an essential player in the development of neurodegenerative diseases called synucleinopathies. A spontaneous autosomal recessive rat model for neurodegeneration was developed in our laboratory. These rats demonstrate progressive increases in α-syn in the brain mesencephalon followed by loss of dopaminergic terminals in the basal ganglia (BG) and motor impairments. The severity of pathology is directly related to the overexpression of α-syn and parallel decrease in dopamine (DA) level in the striatum (ST) of affected rats. The neurodegeneration in this model is characterized by the presence of perikarya and neurites Lewis bodies (LB) and diffuse marked accumulation of perikaryal α-syn in the substantia nigra (SN), brain stem (BS), and striatum (ST) along with neuronal loss. Light and ultrastructural analyses revealed that the process of neuronal degeneration is a 'dying back' type. The disease process is accompanied by gliosis and release of inflammatory cytokines. This neurodegeneration is a multisystemic disease and implicate α-syn as a major factor in the pathogenesis of this inherited autosomal recessive animal model. Decrease dopamine (DA) and overexpression of α-syn in the brain mesencephalon may provide a naturally occurring animal model for Parkinson's disease (PD) and other synucleinopathies that reproduces significant pathological, neurochemical, and behavioral features of the human disease.	f	\N
22644412	To evaluate retrospectively whether technical factors of hepatic arterial embolization affect the prognosis of patients with hepatocellular carcinoma (HCC). Inclusion criteria of this study were the following: (1) patients received embolization as the initial treatment during 2003-2004, (2) Child A or B liver profile, (3) five or fewer HCCs with maximum diameter of 7 cm or smaller, and (4) no extrahepatic metastasis. Patient data were gathered from 43 centers. Prognostic factors were evaluated using univariate and multivariate analyses. Eight hundred fifteen patients were enrolled. The 1-, 3-, 5-, and 7-year overall survival rates were 92.0 % (95 % CI 90.1-93.9), 62.9 % (95 % CI 59.3-66.6), 39.0 % (95 % CI 35.1-43.0), and 26.7 % (95 % CI 22.6-30.8) in all patients. Univariate analysis showed a Child-Pugh class-A, alpha-fetoprotein level lower than 100 ng/ml, tumor size of 3 cm or smaller, tumor number of 3 or fewer, one-lobe tumor distribution, nodular tumor type, within the Milan criteria, stage I or II, no portal venous invasion, use of iodized oil, and selective embolization were significantly better prognostic factors. In the multivariate Cox model, the benefit to survival of selective embolization remained significant (hazard ratio 0.68; 95 % CI 0.48-0.97; p = 0.033). Selective embolization contributes to survival in patients with HCCs.	f	\N
22652723	Anemia is a significant cause of morbidity and lowers the quality of life of patients suffering from chronic kidney disease (CKD). Iron deficiency is the most important cause of erythropoietin (EPO) hyporesponsiveness in CKD. EPO administration significantly increases the costs of CKD management. It follows that paramount importance must be given to enhancing responsiveness to EPO thereby ensuring that the patient derives maximum benefit. Intravenous iron (IVI) administration has been used for decades to replenish body iron stores. Multiple preparations of Iron are available in the market. However, IVI administration is fraught with dangers like adverse drug reactions, susceptibility to infection, and, as recently postulated, direct cellular toxicity. Traditional approaches to IVI administration have focused on multiple administrations of lower doses for fear of adverse reactions. However, recent studies have demonstrated that higher doses can be safely administered in a single infusion, thereby reducing hospitalization costs and patient inconvenience. Newer preparations of IVI are relatively safer, easier to administer and efficacious. Preparations like Iron sucrose, ferumoxytol, ferric carboxymaltose and iron isomaltoside do not require test doses and allow higher doses to be administered at a time with cost and effect benefits.	f	\N
22655515	Recently we reported a cytoplasmic sodium overload to cause a severe osmotic oedema in Duchenne muscular dystrophy (DMD). Our results suggested that this dual overload of sodium ions and water precedes the dystrophic process and persists until fatty muscle degeneration is complete. The present paper addresses the questions as to whether these overloads are important for the pathogenesis of the disease, and if so, whether they can be treated. As a first step, we investigated the effects of various diuretic drugs on a cell model of DMD, i.e. rat diaphragm strips previously exposed to amphotericin B. We found that both carbonic anhydrase inhibitors and aldosterone antagonists were able to repolarise depolarised muscle fibres. Since carbonic anhydrase inhibitors are known to have acidifying effects and this might be detrimental to the ventilation of DMD patients, we mainly concentrated on the modern spironolactone derivative, eplerenone. This drug had a very high repolarizing power, the parameter considered by us as being most relevant for a beneficial effect. In a pilot study we administered this drug to a 22-yr-old female DMD patient who was bound to an electric wheelchair and has had no corticosteroid therapy before. Eplerenone decreased both cytoplasmic sodium and water overload and increased muscle strength and mobility. We conclude that eplerenone has beneficial effects on DMD muscle. In our opinion the cytoplasmic oedema is cytotoxic and should be treated before fatty degeneration takes place.	f	\N
22658853	Pulmonary complications associated with Sjögren syndrome (SS) have attracted attention in recent years. Sjögren syndrome has been associated with small cyst formation in salivary glands, thymus, and lungs and has been recently brought to the forefront by radiologists due to high-resolution techniques. However, pathologists are less aware of this finding unless clinico-radiologic-pathologic correlation is sought. Formation of large bullae in SS is a rare complication with potential for confusion with other diseases. Here, we present the clinical, radiologic, and pathologic findings in 3 patients with SS associated with multiple pulmonary cystic lesions. All 3 patients had a variable mixed restrictive and obstructive component of the disease. There was good correlation with the pulmonary function tests (PFTs), high-resolution computed tomographic scan, and morphology with regard to the restrictive component. The small cysts appear to correlate with the extent of obstructive changes on the PFTs. However, the large bullae do not, implying noncommunication with the conducting airways. This noncorrelation between the PFTs and extent of bullous disease with predominant involvement of lower lobes in SS enables distinction from bullous emphysema. The mechanism of bulla formation in SS appears to be different from bullous emphysema. A check valve mechanism has been proposed previously in SS, which does not explain cyst formation in the thymus. Alternately, inflammation may play a role with the key suspects being CD4 T-helper cells and perhaps NK cells. This is the first report of a clinico-radiologic-pathologic correlation with analysis of lymphocyte subsets.	f	\N
22669091	Aim of the study was to analyze outcome in patients who underwent surgery following type A aortic dissections and to evaluate the long-term survival rates in patients 70 years of age and older and those under 70 years of age, and in males as compared to females. Between September 1997 and October 2008, 154 patients were retrospectively enrolled. There were 102 males (66.2%) and 52 females (33.8%) with a mean age of 63.5±12; seven patients (4.5%) were over 80 years of age, 46 (29.8%) were between 70 and 80 years of age and 101 were under 70 years of age at the time of surgery. We compared patients 70 years of age and older with those under 70 years of age, analyzing the early and long-term survival results and postoperative complications. Overall in-hospital mortality was 17.5% and permanent neurological dysfunction occurred in 10 patients (6.5%). Twenty patients (12.9%) died during follow-up. Among the males, the long-term survival rate was 80%, 68% and 51% at 1, 5 and 10 years, respectively. Among the females, survival rate was 84.6%, 72.3% and 47.5% at 1, 5 and 10 years, respectively. Five- and 10-year survival rates were 78.1% and 59.4%, respectively, for patients under 70 years of age, and 50.8% at 5 years and 26.1% at 10 years for those over 70. Patients might not be excluded from surgical intervention for acute type A aortic dissection (ATAAD) only due to age. It is important to consider biological age and the clinical features of the patients at the time of surgery. Age is a relative but not absolute contraindication for surgery in ATAAD. Long-term survival was not statistically different between males and females.	f	\N
22689018	Ampullary and extensive periampullary lesions can be difficult to treat and often require pancreaticoduodenectomy (PD) for complete removal, even if benign. However, PD may be overtreatment for noninvasive lesions, and pancreas-sparing total duodenectomy (PSTD) is an emerging valid surgical option for selected cases. We reviewed patients undergoing PSTD at our institution over 16 months and a comparison group who had undergone PD for benign duodenal disease over the past 15 years. We also reviewed cases in the English-language literature and performed a meta-analysis of those patients who had undergone PSTD. PSTD had been performed in four patients, who had an average hospital length of stay (LOS) of 13 days; two of them experienced complications. None required conversion to PD, experienced a postoperative fistula or endocrine or exocrine insufficiency, or required intensive care. Two of the PSTDs were performed laparoscopically. Open PD for benign duodenal disease was performed in 22 patients, with overall morbidity and pancreas fistula rates of 82 and 27 %, respectively. The meta-analysis found 128 unique cases of PSTD with morbidity and mortality rates of 46.4 and 2.3 %, respectively. Pancreaticobiliary leak was seen in 20 %, with an average LOS of 17 days. Although PSTD can be used to avoid PD and can be performed laparoscopically, it is technically challenging and still associated with morbidity.	f	\N
22691438	To describe the small retinal and systemic vessel involvement in Takayasu's arteritis. We described 3 patients with Takayasu's arteritis and small retinal vessel occlusion seen in our department between 2004 and 2011. We performed an extensive literature review and provided a global analysis of small retinal vessel involvement in Takayasu arteritis (i.e., total number of patients analyzed=9). Seven patients had small retinal artery occlusion, and two had venous involvement. Four cases were inaugural of the disease (44.4%). Takayasu's arteritis was extended (Type V) in the majority of patients presenting with small retinal vessel occlusion (5/9, 55.6%), and 8/9 reported cases (88.9%) presented with involvement of the supra-aortic branches. Immunosuppressive regimen allowed an improvement in 5/9 patients and stabilization in 1/9, but the situation worsened in 3/9 patients. The visual outcome was severe, and 3/9 patients (33.3%) experienced irreversible blindness. Occlusion of small retinal vessels is a rare and severe microcirculatory complication in Takayasu's arteritis, as well as necrotizing cutaneous vasculitis or myocarditis. Small retinal vessel involvement can be inaugural of the disease and seriously impact the visual prognosis in TA patients.	f	\N
22696253	Accumulating evidence demonstrated that bone marrow-derived mesenchymal stem cells (BMSCs) may transdifferentiate into cardiomyocytes and replace apoptotic myocardium so as to improve functions of damaged hearts. However, little information is known about molecular mechanisms underlying myogenic conversion of BMSCs. microRNAs as endogenous noncoding small molecules function to inhibit protein translation post-transcriptionally by binding to complementary sequences of targeted mRNAs. Here, we reported that miR-124 was remarkably downregulated during cardiomyocyte differentiation of BMSCs induced by coculture with cardiomyocytes. Forced expression of miR-124 led to a significant downregulation of cardiac-specific markers-ANP, TNT, and α-MHC proteins as well as reduction of cardiac potassium channel currents in cocultured BMSCs. On the contrary, the inhibition of endogenous miR-124 with its antisense oligonucleotide AMO-124 obviously reversed the changes of ANP, TNT, and α-MHC proteins and increased cardiac potassium channel currents. Further study revealed that miR-124 targeted the 3'UTR of STAT3 gene so as to suppress the expression of STAT3 protein but did not affect its mRNA level. STAT3 inhibitors AG490, WP1066, and S3I-201 were shown to attenuate the augmented expression of ANP, TNT, α-MHC, GATA-4 proteins, and mRNAs in cocultured BMSCs with AMO-124 transfection. Moreover, GATA-4 siRNA reduced the expression of ANP, TNT, α-MHC, and GATA-4 proteins but did not impact STAT3 protein in cocultured BMSCs, indicating GATA-4 serves as an effector of STAT3. In summary, we found that miR-124 regulated myogenic differentiation of BMSCs via targeting STAT3 mRNA, which provides new insights into molecular mechanisms of cardiomyogenesis of BMSCs.	f	\N
22697349	α-1 anti-trypsin (AAT) is the most abundant circulating serine protease inhibitor (serpin) and an acute phase reactant. Systemic deficiency in AAT (AATD) due to genetic mutations can result in liver failure and chronic lung disease such as emphysema. Considered the prototypic serpin, the emphysema observed in patients with AATD, consisting of progressive destruction of the alveoli and small airway structures, formed the basis of the protease/anti-protease imbalance theory of chronic obstructive pulmonary disease (COPD). Over the past decade, however, investigations of AATD have described multiple functions of AAT beyond those generally attributed to its antiprotease activity. Evidence now suggests that AAT plays an important role in modulating immunity, inflammation, proteostasis, apoptosis, and possibly cellular senescence programs. When integrated in vivo, these processes contribute to the lung maintenance program which preserves the lung despite a constant bombardment by damage associated molecular patterns (DAMPs) and/or pathogenassociated molecular patterns (PAMPs) initiated by cigarette smoke, pollutants, or infections. In this review, we discuss the clinical aspects of AATD as they pertain to emphysema; including similarities and differences to cigarette smoke-induced emphysema. Examining the lung maintenance program, we next consider the multiple mechanisms of airspace destruction and explore the role AATD contributes. Finally, we consider the data regarding treatment of AATD, including AAT supplementation and its current limitations, and suggest further avenues of research informed by the multiple functions of AAT.	f	\N
22697357	We describe two siblings with epiphora, telecanthus, expressionless face, thick facial skin, bulky nose and profound sensorineural hearing loss. Constellation of these features presented a phenotypic overlap with Blepharo-naso-facial syndrome (BNFS) and Nablus mask-like syndrome (NMLS). They in addition had posterior helical pits. The molecular basis of NMLS is known, while BNFS remains an elusive disorder. We report the first Indian family with features having significant overlap between the two but we attempt to summarize the frequency of reported features and bring out the most consistent features for these two syndromes for the treating clinician.	f	\N
22699458	Innate and adaptive immune responses in neurodegenerative diseases have become recently a focus of research and discussions. Parkinson's disease (PD) is a neurodegenerative disorder without known etiopathogenesis. The past decade has generated evidence for an involvement of the immune system in PD pathogenesis. Both inflammatory and autoimmune mechanisms have been recognized and studies have emphasized the role of activated microglia and T-cell infiltration. In this short review, we focus on dendritic cells, on their role in initiation of autoimmune responses, we discuss aspects of neuroinflammation and autoimmunity in PD, and we report new evidence for the involvement of neuromelanin in these processes.	f	\N
22699661	Hashimoto's thyroiditis as well as lichen planus has been associated to a number of disorders, generally of auto-immune origin. A novel possible association between oral lichen planus (OLP) and Hashimoto's thyroiditis (HT) is here proposed on the basis of a cross-sectional survey. One hundred and five unrelated OLP patients were considered. Diagnosis of HT was based on positive serum anti-TPO, anti-Tg, TSH levels and the typical ultrasound pattern of the thyroid gland. In the present survey, the prevalence of HT in the OLP group was 14.3 % whereas the prevalence of HT-related hypothyroidism in the general population was reported to be equal to 1 %. By Fisher's exact test, it was revealed that the difference between our data and historical prevalence of HT was found statistically significant. Actually, there is no definitive hypothesis that could explain the coexistence of OLP and HT. However, considering the onset timing of HT followed by OLP in 93.3 % of our series, we suspected a causal or predisposing role for HT. Specifically, we believe that in HT patients, circulating thyroid antibodies could contribute to trigger an organ-specific auto-immune response also in the oral mucosa or skin, leading to the development of LP lesions. Because of the large number of cases of asymptomatic chronic auto-immune thyroiditis, it would be useful that women over 40 years of age affected by OLP were screened for thyroid dysfunction, particularly HT.	f	\N
22711587	This study investigated associations between chronic inflammation and coagulation and incident locomotor disability using prospective data from the British Women's Heart and Health Study. Locomotor disability was assessed using self-reported questionnaires in 1999/2000, and 3 and 7 years later. Scores for inflammation and coagulation were obtained from summation of quartile categories of all available biomarkers from blood samples taken at baseline. 534 women developed locomotor disability after 3 years, 260 women after 7 years, while 871 women remained free of locomotor disability over the whole study period. After adjustment for demographic characteristics, lifestyle factors and health conditions, we found associations between inflammation and incident locomotor disability after three (OR per unit increase in score = 1.08, 95 % confidence interval (CI): 1.03, 1.13) and 7 years (OR = 1.10, 95 % CI: 1.03, 1.18) and between coagulation and incident locomotor disability after 3 (OR = 1.06, 95 % CI: 0.98, 1.14) and 7 years (OR = 1.09, 95 % CI: 1.00, 1.18). This corresponds to ORs between 1.8 and 2.4 comparing women with highest to lowest inflammation or coagulation scores. These results support the role of inflammation and coagulation in the development of locomotor disability in elderly women irrespective of their lifestyle factors and underlying age-related chronic diseases.	f	\N
22713729	As science matures, it becomes more mathematical, progressing from enumeration to the use of equations to the formulation of models. Clinical pharmacology has developed to the stage where models play an increasingly important role in predicting and analyzing drug pharmacokinetics and pharmacodynamics, and even in characterizing disease progression and therapeutic response. Useful models have two characteristics that are in ostensible conflict: (i) they must accurately represent the essential features of the underlying system and (ii) the representation must be sufficiently simplified to enable its salient features to be identified and investigated through further experimentation.	f	\N
22726388	Accurate diagnostic and monitoring tools for ulcerative colitis (UC) are missing. Our aim was to describe the proteomic profile of UC and search for markers associated with disease exacerbation. Therefore, we aimed to characterize specific proteins associated with inflamed colon mucosa from patients with acute UC using mass spectrometry-based proteomic analysis. Biopsies were sampled from rectum, sigmoid colon and left colonic flexure from twenty patients with active proctosigmoiditis and from four healthy controls for proteomics and histology. Proteomic profiles of whole colonic biopsies were characterized using 2D-gel electrophoresis, and peptide mass fingerprinting using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) was applied for identification of differently expressed protein spots. A total of 597 spots were annotated by image analysis and 222 of these had a statistically different protein level between inflamed and non-inflamed tissue in the patient group. Principal component analysis clearly grouped non-inflamed samples separately from the inflamed samples indicating that the proteomic signature of colon mucosa with acute UC is strong. Totally, 43 individual protein spots were identified, including proteins involved in energy metabolism (triosephosphate isomerase, glycerol-3-phosphate-dehydrogenase, alpha enolase and L-lactate dehydrogenase B-chain) and in oxidative stress (superoxide dismutase, thioredoxins and selenium binding protein). A distinct proteomic profile of inflamed tissue in UC patients was found. Specific proteins involved in energy metabolism and oxidative stress were identified as potential candidate markers for UC.	f	\N
22739032	Vascular disease and medical factors are associated with cognitive decline and cardiovascular events. We examined the association between vascular risk factors and events in the Alzheimer's Disease Neuroimaging Initiative cohort. The association between vascular risk factors and cardiovascular events in a cohort of 810 participants, including 400 with mild cognitive impairment, 184 with Alzheimer's, and 226 controls was investigated using a longitudinal hazard model. There were 31 events including 11 strokes, 7 myocardial infarctions, 5 revascularizations, and 8 deaths during an average follow-up of 31 months. Longitudinal cardiovascular event rates were low and similar between diagnostic groups. All baseline vascular risk factors that were expected to be associated with longitudinal cardiovascular events were, or were trending toward, associating with cardiovascular events except atrial fibrillation, depression, and apolipoprotein E genotype. Despite differences in baseline vascular risk factors, longitudinal cardiovascular event rates were similar between diagnostic groups.	f	\N
22740450	Cyclin dependent kinase (CDK) inhibitors, such as flavopiridol, demonstrate significant single-agent activity in chronic lymphocytic leukemia (CLL), but the mechanism of action in these nonproliferating cells is unclear. Here we demonstrate that CLL cells undergo autophagy after treatment with therapeutic agents, including fludarabine, CAL-101, and flavopiridol as well as the endoplasmic reticulum (ER) stress-inducing agent thapsigargin. The addition of chloroquine or siRNA against autophagy components enhanced the cytotoxic effects of flavopiridol and thapsigargin, but not the other agents. Similar to thapsigargin, flavopiridol robustly induces a distinct pattern of ER stress in CLL cells that contributes to cell death through IRE1-mediated activation of ASK1 and possibly downstream caspases. Both autophagy and ER stress were documented in tumor cells from CLL patients receiving flavopiridol. Thus, CLL cells undergo autophagy after multiple stimuli, including therapeutic agents, but only with ER stress mediators and CDK inhibitors is autophagy a mechanism of resistance to cell death. These findings collectively demonstrate, for the first time, a novel mechanism of action (ER stress) and drug resistance (autophagy) for CDK inhibitors, such as flavopiridol in CLL, and provide avenues for new therapeutic combination approaches in this disease.	f	\N
22744150	To provide information about occurrence and patterns of geriatric morbidity and need for long-term care in patients newly diagnosed with dementia compared to controls without dementia. An analysis of administrative data was conducted to compare the geriatric outpatient diagnoses and the patterns of care dependency of 1,848 incident dementia patients and 7,385 matched non-dementia controls older than 65 years in the incidence year. In most cases the geriatric characteristics show an increased (partly statistically significant) prevalence in the group with dementia as compared to controls. Moreover, dementia patients show a higher number of geriatric comorbidities in contrast to non-dementia controls. Furthermore, the percentage of persons with need for long-term care in the dementia-group is significantly higher than for controls (44.4 vs. 12.9 %). Prevention, early recognition or treatment of attendant symptoms are very important in daily clinical and nursing care in patients with dementia to ameliorate the progression of the disease and to improve the patients' quality of life.	f	\N
22744504	Screening for idiopathic scoliosis is not very popular in Poland. Some Polish towns and cities have prevention programmes aimed at discovering spine dysfunctions and disorders in children and adolescents. An assessment of the angle of trunk rotation (ATR) is a reliable, effective and non-invasive action that allows use to determine trunk asymmetry. Since then the scoliometer has spread throughout the United States and other countries, where it is a popular device in the clinical practice of diagnosing scoliosis. 9,500 children aged 7-10 were examined as part of a disease prevention programme entitled "Poznan Chooses Health - Bad Posture Prophylaxis in Class I-IV Primary School Children in Poznan". The analysis included results obtained in 2010 during initial posture assessment in 1000 children, Trunk asymmetry was measured by means of the Bunnell scoliometer. The measurement of the angle of trunk rotation was the spontaneous standing position with use the scoliometer during bending (Adams forward test) at three levels: proximal thoracic, main thoracic and lumbar. For the proximal thoracic section the 0° ATR value was found in 6 children, values of 1°-3° were recorded in 883 children, values of 4°-6° in 108 children, 7° or higher in 3 of the examined children. For the main thoracic section the 0° ATR value was found in 101 children, values of 1°-3° were recorded in 735 children, 4°-6° in 155 children, 7° or higher in 9 of the examined children. For the lumbar section ATR values of 0°, 1°-3°, 4°-6°, and 7° or higher were found, respectively, in 147, 883, 108 and 11 of the examined children.	f	\N
22744756	In newly diagnosed glioblastoma multiforme, surgery, combined radio and chemotherapy, and adjuvant chemotherapy with temozolomide is the standard of care. Therapy for recurrent glioblastoma is less well established and comprises re-operation, re-irradiation, chemotherapy, targeted therapy, inhibition of neoangiogenesis, and others. In this observational study we recorded the efficacy and toxicity of a combination of procarbazine, carmustine, and vincristine (PBV) for 69 patients with recurrent and/or progressive glioblastoma after surgery, concomitant radio and/or chemotherapy, and adjuvant first-line temozolomide therapy. Of 41 patients evaluable for response by MRI, partial response was observed for one, minor response for three, stable disease for at least 6 weeks for ten, and immediate progression for 27. Median PFS was 15 weeks, and PFS-6 was 21 % for 57 patients who could be followed; 12 other patients were lost to follow-up after application of the first PBV cycle. Grade III or IV leucopenia and/or grade III or IV thrombocytopenia were seen in 26 % and 26 % of cycles, respectively. Haematological complications led to interruption of treatment for four (7 %) patients. Non-haematological toxicity was moderate. Salvage PBV therapy in recurrent and/or progressive glioblastoma, pre-treated with temozolomide-based chemotherapy as first-line treatment, is of limited efficacy with a small number of long-term survivors, but is hampered by relevant myelotoxicity.	f	\N
22753355	Hepatic arterial infusional (HAI) chemotherapy combined with systemic chemotherapy is effective palliative therapy for unresectable colorectal cancer liver metastases (CRLM). Some patients considered for HAI have evidence of minimal extrahepatic disease (EHD), and the role of HAI in these situations is unknown. All patients with unresectable CRLM treated with HAI and systemic chemotherapy from 2000 to 2009 were included. Survival of patients who were ultimately proven to have low-volume EHD was compared to those without EHD. Three hundred seventy-three patients were included in this study. Seventy-nine percent of patients were previously treated with chemotherapy. One hundred forty-five patients (39%) ultimately proved to have EHD. Median overall survival from HAI pump placement in patients without EHD was 32 months compared to 16 months for patients with EHD, P < 0.001. Median overall survival from HAI pump placement in patients with a single site of EHD was 18 months compared to 9 months for those with multiple sites of EHD, P = 0.01. In this study of heavily pre-treated patients, overall survival was favorable in patients who proved to have EHD at one site.	f	\N
22761515	To explore areas of consensus and disagreement concerning the interhospital transfer of patients with a clinical diagnosis of ruptured abdominal aortic aneurysm. A three-round Delphi questionnaire approach was used among vascular and endovascular surgery and emergency medicine specialists to explore patient characteristics and clinical management issues for emergency interhospital transfer. Analysis is based on 38 responses to rounds 2 and 3 (19 vascular surgeons, 6 interventional radiologists, 13 emergency care specialists) with agreement reported when 70% of respondents were in agreement. Initially there was agreement that transfer patients should be <85 years of age, either alert or with fluctuating consciousness, with moderate or minimal systemic disease, needing no/some help with daily living. Round 3 clarified that patients requiring inotropes and those institutionalised for mental infirmity should be transferred. Those with cardiac arrest in current episode should not be transferred. There was no agreement as to whether those institutionalised with physical infirmities, unconscious/intubated patients or those with severe systemic disease should be transferred. Speed was accepted as important, with agreement for specialty trainees to arrange transfer if consultants were not on site. Consultant-consultant discussion was recommended for patients with severe systemic disease. CT confirmation of diagnosis was considered unnecessary before transfer but ultrasound assessment was desirable, and transfers should not be delayed by waiting for specific tests. There was no agreement about blood tests and ECG before transfer or whether blood should accompany the patient being transferred. There was no agreement as to whether specific staff/facilities needed to be in place at the specialist hospital. A systolic blood pressure ≥70 mm Hg was sufficient for transfer without the need for intravenous fluids unless deterioration occurred. There is broad agreement about the type of patient who should be eligible for transfer but disagreements about patient management before and during transfer remain.	f	\N
22766701	Cardiovascular disease (CVD) is one of the main causes of mortality in the world representing around 30% of all deaths. It constitutes also an important factor in morbidity and incapacity. There are several related CVD risk factors such as hypertension, metabolic syndrome (MetS) and hypercoagulability. The exact mechanisms that underlie the relation between those factors and CVD are not sufficiently known yet; pathogenic explanations are lacking also for the mechanisms relating metabolic factors to insulin resistance (IR) and the association with the development of atherosclerosis and thrombosis. The possible links between hypertension, hemostasis alterations and MetS are examined in this report.	f	\N
22766888	Metabolic syndrome (MS) is a cluster of risk factors that predispose to major cardiovascular diseases and its complications, determining liver and kidney impairment. In the last decade, the indications to transplantation are increasing, with a linear incidence of the complications of the procedure. MS represents one of the commonest, being in turn may the consequence of the underlying disease that required the transplantation, or the result of the medical treatment, as well as one of the most important factor influencing the morbidity and mortality of the transplanted patients. Due to the growing incidence of the MS in these patients, it is crucial to focus and clarify the leading causes determining the onset of the metabolic disarrangement, its outcome and the hypothetical mechanism through which the clinicians could reduce the impact of the disease. In fact, prevention, early recognition, and treatment of the factor that could predict the onset or progression of the MS after the transplantation may impact long term survival of patients, that is again the scope of the same transplant. This review will update the different mechanisMS of the pathogenesis of MS in this population, the clinical effects of the presence of the MS, observing the risk factors to be treated before and after the transplantation and suggesting the management of the follow-up.	f	\N
22767670	This phase I study evaluated the safety, pharmacokinetics, pharmacodynamics, and efficacy of the investigational oral drug MLN8237 (alisertib), a small-molecule Aurora A kinase (AAK) inhibitor, in 87 adult patients with advanced solid tumors. Sequential cohorts of patients received MLN8237 5 to 150 mg orally once daily or twice daily for 7, 14, or 21 days, followed by 14 days' rest per cycle. MLN8237 pharmacokinetics was characterized, and the relative bioavailability of an enteric-coated tablet (ECT) formulation was evaluated in reference to the original powder-in-capsule (PIC) formulation. Pharmacodynamic effects of MLN8237 on inhibition of AAK activity were evaluated in skin biopsies. Tolerability and response to treatment were assessed. Common toxicities included fatigue, nausea, and neutropenia. Plasma exposures increased dose proportionally (5-150 mg/d), and were similar for PIC and ECT. The terminal half-life was 23 hours. At the maximum tolerated dose of 50 mg twice daily on the 7-day schedule, the mitotic index of the skin basal epithelium was increased within 24 hours after MLN8237 administration on days 1 and 7, a finding consistent with AAK inhibition. One (1%) patient achieved a partial response lasting for more than 1 year and received MLN8237 for 51 cycles; 20 (23%) patients achieved stable disease for ≥3 months. This first-in-human trial of MLN8237 showed tolerability and favorable pharmacokinetics in this patient population. The recommended phase II dose of MLN8237 is 50 mg twice daily orally for 7 days in 21-day cycles, which is being evaluated further in the treatment of various solid tumors and hematologic malignancies.	f	\N
22804715	Peripheral arterial disease (PAD) is a chronic, progressive disease with a significant cardiovascular and cerebrovascular risk burden and a considerable impact on functional capacity and quality of life (QoL). Exercise programmes result in significant improvements in walking distances but long-term effects are uncertain. The aim of this study was to assess the one-year effects of participation in a 12-week supervised exercise programme on functional capacity and QoL for PAD patients. Patients were randomly allocated to a control (n = 16) or an exercise (n = 28) group. Data regarding functional capacity (Walking Impairment Questionnaire WIQ), disease-specific QoL (Intermittent Claudication Questionnaire ICQ) and generic QoL (SF-36) were collected at baseline, 12 weeks and 1 year. At 12 weeks, there was a trend towards improved QoL in both groups, with a tendency for greater improvement in the exercise group (p = 0.066) and a trend towards improved functional capacity (WIQ Stair-climbing p = 0.093) in the exercise group. At 1 year, ICQ scores in the exercise group were considerably better than those in the control group (p = 0.058), reflecting improved QoL and maintenance of benefits. Participation in a supervised exercise programme results in improvements in functional capacity and QoL at 1 year post-participation.	f	\N
22819313	Controversy exists regarding the extent of pelvic lymph node dissection (PLND) in radical prostatectomy (RP) for prostate cancer. Impact of the extent of PLND may be determined by the disease risk. The aim of our study was to find the association between the extent of PLND on biochemical progression and disease risk. The study included 360 consecutive patients treated with RP for clinically localized prostate cancer at our department between 2000 and 2003. Patients were randomized to receive extended PLND (n = 180) and standard PLND (n = 180) at RP. Clinical and pathological data were prospectively collected. The patients did not receive any neoadjuvant or adjuvant therapy. The relation of disease risk and the extent of PLND to biochemical progression-free survival (BPFS) were examined. There were no significant differences in age, prostate-specific antigen, and other preoperative features in patients who underwent standard and extended PLND. Mean patient age was 68 y old and median follow-up was 74 mo. BPFS for the standard PLND group and the extended PLND group was 90.1% and 91.3% in low risk disease (log rank P = 0.807), 73.1% and 85.7% in intermediate risk disease (log rank P = 0.042), and 51.1% and 71.4% in high risk disease (log rank P = 0.036), respectively. In multivariate Cox proportional hazard analysis, extended PLND was an independent prognostic factor of biochemical progression-free survival when adjusting for other clinical and pathologic features. In intermediate and high risk patients, extended PLND positively affects BPFS. In low risk patients, extended PLND may be omitted to reduce operation time and complications.	f	\N
22822599	Proctocolectomy and ileoanal anastomosis as a treatment of ulcerative colitis Sphincter-saving proctocolectomy, construction of ileal pouch (J pouch) and associated ileoanal anastomosis constitute an established surgical procedure in the treatment of patients having ulcerative colitis. The procedure has been found to improve the condition: the patient is usually relieved of medications and possible associated adverse effects, the cancer risk associated with the disease is minimized and the quality of life will improve. The most common complication is inflammation of the ileal pouch, developing in half of the patients.	f	\N
22824112	Metabolomics is the systematic study of the unique chemical fingerprints of small molecules or metabolite profiles that are related to a variety of cellular metabolic processes in a cell, organ, or organism. Although messenger RNA gene expression data and proteomic analyses do not tell the whole story of what might be happening in a cell, metabolic profiling provides direct and indirect physiologic insights that can potentially be detectable in a wide range of biospecimens. Although not specific to cardiac conditions, translating metabolomics to cardiovascular biomarkers has followed the traditional path of biomarker discovery from identification and confirmation to clinical validation and bedside testing. With technological advances in metabolomic tools (such as nuclear magnetic resonance spectroscopy and mass spectrometry) and more sophisticated bioinformatics and analytical techniques, the ability to measure low-molecular-weight metabolites in biospecimens provides a unique insight into established and novel metabolic pathways. Systemic metabolomics may provide physiologic understanding of cardiovascular disease states beyond traditional profiling and may involve descriptions of metabolic responses of an individual or population to therapeutic interventions or environmental exposures.	f	\N
22825384	Asthma is an inflammatory disease of the airways. It is suggested by characteristic history of recurrent episodes of wheezing, breathlessness, chest tightness, and/or cough especially at night or in early morning. In asthmatic patients spirometry or pulmonary function tests demonstrate airflow obstruction that improves significantly, defined as both a 12% and 200 ml improvement in either FEV1 in response to inhaled bronchodilator. Measurement of airways responsiveness to methacholine in specialized pulmonary function laboratories may help to diagnose asthma. The goals for successful management of asthma are to achieve and maintain control of symptoms and to prevent asthma exacerbations.	f	\N
22825649	This review summarizes and discusses the role and efficacy of moisturizers, particularly the more recently introduced ceramide-based formulations, in the skin care regimen of patients with both active and quiescent atopic dermatitis (AD). It is now well established that a complex interplay of environmental and genetic factors are responsible for disease onset and chronicity. Indeed, several novel genetic mechanisms have been recently discovered to be associated with AD pathogenesis. Moreover, it is increasingly recognized that the epidermal barrier plays a critical role in the initiation, perpetuation, and exacerbation of AD. The skin of patients with AD harbors several defects in epidermal barrier function, including filaggrin and ceramides. An improved understanding of these etiopathogenic factors has led to the development of topical ceramide-dominant moisturizers to replace the deficient molecules and re-establish the integrity of barrier defenses. Some of these products have demonstrated efficacy in the treatment of adult and childhood AD that are similar to mid-potency topical steroids. More importantly, they have been shown to be safe with very few associated side-effects. We recommend the addition of such new agents as both the first step of treatment and in the maintenance of clinically quiescent skin of patients with AD.	f	\N
22828371	Due to the limited incidence of posttransplant lymphoproliferative disorders (PTLD) in pediatric liver graft recipients, there is a scarcity of data on the characteristics of the disease in this population. We aimed to analyze the special features and behavior of PTLD arising after pediatric liver transplantation. A comprehensive search of the literature was conducted for the available data on PTLD in pediatric liver recipients pediatric PTLD through a search of Pubmed and Google Scholar using appropriate terms. We sought data on liver recipients younger than 18 years of age at the time of transplantation. From 51 reports, 43 fulfilled the inclusion criteria. Overall 250 cases of PTLD (212 pediatric PTLD) were found from 43 reports. Data on pediatric patients was compared to adults. Pediatric PTLD lesions were more likely of the polymorphic type (P=.004) and polyclonal (when age cut-off was defined at 12 years; P=.023). Remission rates, metastasis frequency and organ involvements were not different between the groups (P>.1 for all). Survival analysis showed no disparity between pediatric PTLD and adult patients (P>.1); but when data was reanalyzed for patients surviving at least 4 months post diagnosis, the log rank test showed that pediatric patients have a superior outcome compared to adults (P=.045). Pediatric liver recipients developing PTLD have relatively better disease presentation and behavior than that in adults. Stomach involvement was also more frequently seen in patients younger than 12 years, and should be more intensively evaluated. Future studies with a prospective approach and larger population size are needed for confirming our results.	f	\N
22828643	Several bacteria cause community-acquired invasive bacterial disease in children; many are vaccine preventable. Knowledge of pathogens causing community-acquired invasive bacterial disease is important when selecting antimicrobial therapy and implementing vaccine prevention strategies. We describe bacteriology of community-acquired invasive disease observed among 31,641 blood and sterile fluid cultures from children aged 28 days to 36 months in 3 Latin American countries over 2 years.	f	\N
22830284	Features of spread of cowpox in the contemporary conditions are examined. A decrease of population immunity to pox in the population of Russia caused by cancellation of pox immunization, hidden circulation of cowpox virus in various species of rodents, as well as lack of vigilance to pathogenic orthopoxviurses in healthcare workers were noted to create the real preconditions for the emergence of infection of humans caused by cowpox virus. Thereby presence of means of express laboratory diagnostics of cowpox and means of effective medical protection for the prevention of development of this disease in the population of Russia becomes an actual necessity.	f	\N
22833442	Multiple myeloma is a heterogeneous disease, which is characterized by the occurrence of specific genomic abnormalities that are both of diagnostic and prognostic relevance. Since the detection of these abnormalities through molecular-genetic techniques is hampered by the overall low percentage of plasma cells present in primary bone marrow aspirates, we assessed the efficacy of these techniques in enriched plasma cell fractions from 61 multiple myeloma patients. Using interphase FISH, genomic abnormalities could be detected in 96% of the enriched samples as compared to 61% in the cultured whole bone marrow samples. We also found that microarray-based genomic profiling of enriched plasma samples facilitates the detection of additional, possibly clinically relevant, genomic abnormalities. We conclude that the genomic delineation of enriched plasma cells from multiple myeloma patients results in a significantly increased detection rate of clinically relevant genomic abnormalities. In order to facilitate molecular-genetic data interpretation, we recommend morphological assessment of plasma cell purity after enrichment.	f	\N
22844693	The restorative integral support (RIS) model is a whole person response that assists people to overcome adversity. The adverse childhood experiences (ACE) Study conducted by Kaiser Permanente and the Centers for Disease Control and Prevention shows the association between stressors in childhood and multiple later-life health and social problems. Older adults experiencing co-occurring disorders are an under-served and vulnerable population where gaps in both practice models and research to inform effective service provision exist. The current empirical case study presents Senior Hope as one social service agency employing RIS to intervene on the linkage between ACEs and co-occurring disorders to assist older adults. RIS usefully articulates the way in which Senior Hope is developing ACE-informed programs that mobilize resilience and recovery to help older adults achieve positive mental health outcomes. Implementation and research on the RIS model is recommended to enhance services for groups with ACE characteristics.	f	\N
22847755	Putative animal reservoirs and environmental samples were studied to investigate potential routes of transmission for indigenous hepatitis E virus (HEV) infection in Hokkaido, Japan. A total of 468 liver samples and 954 environmental samples were collected from 2003 to 2011 for this study. Four swine livers (1 %) were positive for HEV RNA; two strains belonged to genotype 3 and the other two strains were genotype 4. Genotype 3 HEV was detected in a sewage sample and a seawater sample. HEV strains derived from swine liver, seawater and raw sewage samples shared 93-100 % sequence similarity with human HEV strains.	f	\N
22849219	This paper examines the State's assumption of medical care for patients with "permanent needs" in 19th century Spain. These patients were the incurably ill, the chronically ill and the elderly. This process is contextualized within the liberal reforms of the Spanish healthcare system in the reign of Isabel 11 (1833-1868). The goal of these reforms was the creation and consolidation of a national health system that would gradually replace the religious health charities. Healthcare reform became necessary due to the increase in migration that started in the 1830's and intensified in the 1850's. Traditional care networks formed by the family, local community and religious charities were no longer available to those who had left their village or town. In addition, many religious charities were bankrupted by the seizure of their properties in a programme of confiscation. Similar healthcare reform processes were taking place in the United Kingdom, France and Germany, among other European countries, and involved significant changes in the lives of patients, who became strictly controlled and medicalised. My aim was to identify changes in the patients' experience of illness through a case study of the living conditions of inmates at the Nuestra Señora del Carmen Hospital for Incurable Men, based in Madrid from 1852 to 1949. This was one of the institutions devoted to caring for patients with "permanent needs" and was under the direct control of the General State Administration.	f	\N
22851496	Nitrotyrosine is a post-translationally modified amino acid with distinctly different properties than tyrosine or any other of the genetically encoded amino acids. Detecting proteins containing nitrotyrosine is the first step towards a better understanding of the role of nitrotyrosine in health and disease. Moreover, quantifying the extent of nitrotyrosine and determining its location in a protein forms the basis for a better understanding of the effect of tyrosine nitration on biological function. Described in this unit is a method to detect tyrosine-nitrated proteins in tissue sections and on western blots after creating a fluorescent complex between aminotyrosine, salicylaldehyde, and Al(3+). In addition, an approach is detailed for labeling aminotyrosine with biotin to enrich peptides from complex samples. Both methods require reduction of nitrotyrosine to aminotyrosine, which can be achieved with sodium dithionite or hemin plus dithiothreitol.	f	\N
22869886	Anti-GD2 monoclonal antibody (MoAb) combined with granulocyte-macrophage colony-stimulating factor (GM-CSF) has shown efficacy against neuroblastoma (NB). Prognostic variables that could influence clinical outcome were explored. One hundred sixty-nine children diagnosed with stage 4 NB (1988 to 2008) were enrolled onto consecutive anti-GD2 murine MoAb 3F8 ± GM-CSF ± 13-cis-retinoic acid (CRA) protocols after achieving first remission (complete remission/very good partial remission). Patients enrolled in regimen A (n = 43 high-risk [HR] patients) received 3F8 alone; regimen B (n = 41 HR patients), 3F8 + intravenous GM-CSF + CRA, after stem-cell transplantation (SCT); and regimen C (n = 85), 3F8 + subcutaneous GM-CSF + CRA, 46 of 85 after SCT, whereas 28 of 85 required additional induction therapy and were deemed ultra high risk (UHR). Marrow minimal residual disease (MRD) was measured by quantitative reverse transcription polymerase chain reaction. Survival probability was calculated by the Kaplan-Meier method, and prognostic variables were analyzed by multivariate Cox regression model. At 5 years from the start of immunotherapy, progression-free survival (PFS) improved from 44% for HR patients receiving regimen A to 56% and 62% for those receiving regimens B and C, respectively. Overall survival (OS) was 49%, 61%, and 81%, respectively. PFS and OS of UHR patients were 36% and 75%, respectively. Relapse was mostly at isolated sites. Independent adverse prognostic factors included UHR (PFS) and post-cycle two MRD (PFS and OS), whereas the prognostic factors for improved outcome were missing killer immunoglobulin-like receptor ligand (PFS and OS), human antimouse antibody response (OS), and regimen C (OS). Retrospective analysis of consecutive trials from a single center demonstrated that MoAb 3F8 + GM-CSF + CRA is effective against chemotherapy-resistant marrow MRD. Its positive impact on long-term survival can only be confirmed definitively by randomized studies.	f	\N
22870861	Newborn screening for the inborn error of metabolism, classical galactosaemia prevents life-threatening complications in the neonatal period. It does not however influence the development of long-term complications and the complex pathophysiology of this rare disease remains poorly understood. The objective of this study was to report the development of a healthcare database (using Distiller Version 2.1) to review the epidemiology of classical galactosaemia in Ireland since initiation of newborn screening in 1972 and the long-term clinical outcomes of all patients attending the National Centre for Inherited Metabolic Disorders (NCIMD). Since 1982, the average live birth incidence rate of classical galactosaemia in the total Irish population was approximately 1:16,476 births. This reflects a high incidence in the Irish 'Traveller' population, with an estimated birth incidence of 1:33,917 in the non-Traveller Irish population. Despite early initiation of treatment (dietary galactose restriction), the long-term outcomes of classical galactosaemia in the Irish patient population are poor; 30.6 % of patients ≥ 6 yrs have IQs <70, 49.6 % of patients ≥ 2.5 yrs have speech or language impairments and 91.2 % of females ≥ 13 yrs suffer from hypergonadotrophic hypogonadism (HH) possibly leading to decreased fertility. These findings are consistent with the international experience. This emphasizes the requirement for continued clinical research in this complex disorder.	f	\N
22873223	Chronic fibrotic liver diseases such as viral hepatitis eventually develop liver cirrhosis, which causes occurrence of hepatocellular carcinoma (HCC). Given the limited therapeutic efficacy in advanced HCC, prevention of HCC development could be an effective strategy for improving patient prognosis. However, there is still no established therapy to meet the goal. Studies have elucidated a wide variety of molecular mechanisms and signaling pathways involved in HCC development. Genetically-engineered or chemically-treated experimental models of cirrhosis and HCC have been developed and shown their potential value in investigating molecular therapeutic targets and diagnostic biomarkers for HCC prevention. In this review, we overview potential targets of prevention and currently available experimental models, and discuss strategies to translate the findings into clinical practice.	f	\N
22882216	The use of monoclonal antibodies in the treatment of malignancy and autoimmune diseases has rapidly expanded in the last decade. Rituximab, a monoclonal antibody to the CD20 antigen on B cells, was first approved by the US FDA in 1997 to treat non-Hodgkin's B-cell lymphoma. It is now used, however, for a variety of diseases in both on- and off-label uses. It was approved by the FDA for use in refractory rheumatoid arthritis in 2007, and in April 2011 it was approved for the treatment of anti-neutrophil cytoplasmic antibody-associated vasculitides (including granulomatosis with polyangiitis [Wegener's granulomatosis] and microscopic polyangiitis), based on the promising results of the RAVE trial. Within the field of nephrology, in addition to its use in anti-neutrophil cytoplasmic antibody-associated vasculitides, it is has been used in the treatment of membranous nephropathy, membranoproliferative glomerulonephritis and lupus nephritis.	f	\N
22882559	To test a theoretically and empirically supported model of the relationships among percent truncal fat (truncal obesity); disease severity (carbon monoxide diffusing capacity [DLCO]); symptoms (dyspnea); functional capacity (6-min walk test distance); and functional performance (functional performance index) of elderly people with chronic obstructive pulmonary disease (COPD). A model of functional performance was proposed using a multidimensional framework as expounded by Leidy, and incorporating Wilson and Cleary's model for the relationship between symptoms and functional status. Path analysis was used to examine the relationships among variables. The researchers used a descriptive, cross-sectional design. Subjects were phone screened and completed electrocardiography, physical examination, spirometry testing, and a 4-min walk test as part of initial screening. Enrolled subjects completed a whole-body dual-energy x-ray absorptiometry scan to measure truncal obesity, 6-min walk test, upper body functional performance test, and questionnaires. Subjects were grouped into normal weight, overweight, or obese according to body mass index. The sample consisted of 76 people 55 years of age and older with mild to severe COPD. Percent truncal fat (truncal obesity) did not affect functional performance directly, but did affect it indirectly through dyspnea. The 6-min walk test distance, dyspnea, and DLCO accounted for 29% of the variability in functional performance. We believe that the effectiveness of pulmonary rehabilitation will be enhanced when nurses consider weight loss as a controllable factor for overweight and obese clients. The increasing prevalence of obesity in this population may dictate collaboration between dieticians and pulmonary rehabilitation nurses for effective rehabilitation programs. These findings suggest that percent truncal fat (truncal obesity) may be an indirect factor in the performance of daily activities of people with COPD. We anticipate that clinicians will use knowledge derived from this study to develop interventions to reduce or minimize truncal fat (truncal obesity) and its effects on people with COPD.	f	\N
22883409	To establish a rat model of ulcerative colitis with syndrome of spleen deficiency and dampness stagnancy. Sixty rats were divided into normal control group, ulcerative colitis group, ulcerative colitis with syndrome of spleen deficiency and dampness stagnancy group (model group) and strengthening spleen for resolving dampness group. Ulcerative colitis in rats was induced by enema containing trinitrobenzene sulfonic acid (TNBS) and ethanol. The rats in the model group were suffered from standing in water, limiting sleeping time and abnormal diet based on administration of TNBS and ethanol. The rats in the spleen strengthening and dampness resolving group were gastrically administered with Shenlin Baizhu Powder, a compound traditional Chinese herbal medicine. Symptoms, signs and pathological changes in colon tissue of rats were observed after modeling. The levels of interleukin (IL)-6, IL-8 and tumor necrosis factor-α (TNF-α) in serum of rats were measured by enzyme-linked immunosorbent assay. The rats in the model group showed lethargy, poor appetite, loss of energy, diarrhea and bloody stool. Their body weight decreased significantly compared with the normal control group, and similar changes were found in the comparison of food intake, drinking amount, urine amount, stool wet weight and assay of spontaneous activity (P<0.05). When observed under a light microscope, the colon tissues of rats in the model group showed mucosal edema, congestion, inflammatory cell infiltration and ulceration. The degree of colon injury and IL-6, IL-8 and TNF-α levels were significantly increased (P<0.05) as compared to those in the normal control group. The changes mentioned above were improved by Shenlin Baizhu Powder (P<0.05). The rat model of ulcerative colitis with syndrome of spleen deficiency and dampness stagnancy is successfully induced and has the characteristics of ulcerative colitis of humans both in pathological changes and in syndrome.	f	\N
22888223	Membranous nanostructures, such as nanovesicles and nanotubules, are an important pool of biological membranes. Recent results indicate that they constitute cell-cell communication systems and that cancer development is influenced by these systems. Nanovesicles that are pinched off from cancer cells can move within the circulation and interact with distant cells. It has been suggested and indicated by experimental evidence that nanovesicles can induce metastases from the primary tumor in this way. Therefore, it is of importance to understand better the mechanisms of membrane budding and vesiculation. Here, a theoretical description is presented concerning consistently related lateral membrane composition, orientational ordering of membrane constituents, and a stable shape of nanovesicles and nanotubules. It is shown that the character of stable nanostructures reflects the composition of the membrane and the intrinsic shape of its constituents. An extension of the fluid mosaic model of biological membranes is suggested by taking into account curvature-mediated orientational ordering of the membrane constituents on strongly anisotropically curved regions. Based on experimental data for artificial membranes, a possible antimetastatic effect of plasma constituents via mediation of attractive interaction between membranous structures is suggested. This mediated attractive interaction hypothetically suppresses nanovesiculation by causing adhesion of buds to the mother membrane and preventing them from being pinched off from the membrane.	f	\N
22892258	The emergency department (ED) is a common setting for evaluation of patients with urolithiasis based on acute symptoms and a propensity for recurrent disease. We sought to characterize practice patterns in the emergency treatment of stone disease, and to identify potential disparities in care based on non-medical factors. We performed a cross-sectional analysis of ED visits using the National Hospital Ambulatory Medical Care Survey from 2005-2009. Visits with a diagnosis of urolithiasis were identified. The associations between patient, provider and institutional characteristics were analyzed with regard to timing of clinical assessment, use of diagnostic imaging, and use of medical expulsive therapy (MET). The likelihood of a delay in clinical assessment ranged from 30.8%-37.9%. Neither patient nor provider characteristics were associated with a delay in assessment, although urban location (p = 0.004) was more likely, and proprietary ownership was less likely (p = 0.002) to be associated with delay. Factors associated with use of CT included ambulance arrival (p = 0.043), initial ED visit (p = 0.000), and Northeast region (p = 0.030). Patients seen by a resident/intern were more likely to receive MET (p = 0.028). Overall, 10.8% of patients were presenting for follow up treatment, and 7.1% had been seen in the same ED within the last 72 hours. Kidney stones are associated with a high rate of repeated presentations to the ED. Certain non-medical factors did impact details of management. Future efforts should focus on optimizing clinical pathways to improve the efficiency of acute care for kidney stone patients.	f	\N
22910631	Like many intracellular microbes, the protozoan parasite Toxoplasma gondii injects effector proteins into cells it invades. One group of these effector proteins is injected from specialized organelles called the rhoptries, which have previously been described to discharge their contents only during successful invasion of a host cell. In this report, using several reporter systems, we show that in vitro the parasite injects rhoptry proteins into cells it does not productively invade and that the rhoptry effector proteins can manipulate the uninfected cell in a similar manner to infected cells. In addition, as one of the reporter systems uses a rhoptry:Cre recombinase fusion protein, we show that in Cre-reporter mice infected with an encysting Toxoplasma-Cre strain, uninfected-injected cells, which could be derived from aborted invasion or cell-intrinsic killing after invasion, are actually more common than infected-injected cells, especially in the mouse brain, where Toxoplasma encysts and persists. This phenomenon has important implications for how Toxoplasma globally affects its host and opens a new avenue for how other intracellular microbes may similarly manipulate the host environment at large.	f	\N
22911240	In this study, the clinical outcome and prognostic factors of adult medulloblastoma patients receiving multimodal treatment were investigated. The clinical manifestations, treatment variables, and outcome of adult patients with medulloblastoma at our institution between 1983 and 2009 were retrospectively reviewed. A total of 20 adult patients were included (median age 22 years). Craniospinal irradiation (CSI) was given postoperatively. The craniospinal axis received a median of 30 Gy (range 23.4-39.6 Gy) in fractions of 1.6-2 Gy/day, and the tumor was boosted to a total median dose of 50 Gy (range 50-55.25 Gy). The 3-year disease-free survival (DFS) and overall survival (OS) rates for all patients were 45% and 50%, respectively. In univariate analysis, Karnofsky Performance Scale (KPS) > 70, neurologic symptoms duration > 30 days, lateral tumor location, standard risk patients, no hydrocephalus, radiotherapy (RT) treatment field (CSI + brain boost), and CSI dose ≥ 30 Gy were associated with better DFS. Standard-risk patients, RT treatment field (CSI + brain boost), and CSI dose ≥ 30 Gy were also significantly associated with better OS. The combined modality treatment results in a favorable outcome for adult medulloblastoma patients. Further investigation of the prognostic factors, radiation-related factors, and systemic chemotherapy is needed.	f	\N
22917170	Diarrhea is a common clinical feature of inflammatory bowel diseases and may be accompanied by abdominal pain, urgency, and fecal incontinence. The pathophysiology of diarrhea in these diseases is complex, but defective absorption of salt and water by the inflamed bowel is the most important mechanism involved. In addition to inflammation secondary to the disease, diarrhea may arise from a variety of other conditions. It is important to differentiate the pathophysiologic mechanisms involved in the diarrhea in the individual patient to provide the appropriate therapy. This article reviews microscopic colitis, ulcerative colitis, and Crohn's disease, focusing on diarrhea.	f	\N
22924030	Although many parameters were investigated about weaning and mortality in critical patients in intensive units, no studies have yet investigated predictors in prolonged mechanical ventilation (PMV) patients following successful weaning. A cohort of 142 consecutive PMV patients with successful weaning in our respiratory care center was enrolled in this study. Successful weaning is defined as a patient having smooth respiration for more than 5 days after weaning. The results showed as follows: twenty-seven patients (19%) had the reinstitution within 14 days, and 115 patients (81%) had the reinstitution beyond 14 days. Renal disease RIFLE-LE was associated with the reinstitution within 14 days (P = 0.006). One year mortality rates showed significant difference between the two groups (85.2% in the reinstitution within 14 days group versus 53.1% in the reinstitution beyond 14 days; P < 0.001). Kaplan-Meier analysis showed that age ≥70 years (P = 0.04), ESRD (P = 0.02), and the reinstitution within 14 days (P < 0.001) were associated with one-year mortality. Cox proportional hazards regression model showed that only the reinstitution within 14 days was the independent predictor for mortality (P < 0.001). In conclusion, the reinstitution within 14 days was a poor predictor for PMV patients after successful weaning.	f	\N
22931913	Prediction of outcome for melanoma patients with surgically resected macroscopic nodal metastases is very imprecise. We performed a comprehensive clinico-pathologic assessment of fresh-frozen macroscopic nodal metastases and the preceding primary melanoma, somatic mutation profiling, and gene expression profiling to identify determinants of outcome in 79 melanoma patients. In addition to disease stage <II at initial presentation, the following clinical and pathologic factors were independent predictors of improved outcome (odds ratios for survival >4 years, 90% confidence interval): the presence of a nodular component in the primary melanoma (6.8, 0.6-76.0), and small cell size (11.1, 0.8-100.0) or low pigmentation (3.0, 0.8-100.0) in the nodal metastases. Absence of BRAF mutation (20.0, 1.0-1000.0) or NRAS mutation (16.7, 0.6-1000.0) were both favorable prognostic factors. A 46-gene expression signature with strong overrepresentation of immune response genes was predictive of better survival (10.9, 0.4-325.6); in the full cohort, median survival was >100 months in those with the signature, but 10 months in those without. This relationship was validated in two previously published independent stage III melanoma data sets. We conclude that the presence of BRAF mutation, NRAS mutation, and the absence of an immune-related expressed gene profile predict poor outcome in melanoma patients with macroscopic stage III disease.	f	\N
22933250	Renal xenobiotic transporters are important determinants of urinary secretion and reabsorption of chemicals. In addition to glomerular filtration, these processes are key to the overall renal clearance of a diverse array of drugs and toxins. Alterations in kidney transporter levels and function can influence the efficacy and toxicity of chemicals. Studies in experimental animals have revealed distinct patterns of renal transporter expression in response to sex hormones, pregnancy, and growth hormone. Likewise, a number of disease states including diabetes, obesity, and cholestasis alter the expression of kidney transporters. The goal of this review is to provide an overview of the major xenobiotic transporters expressed in the kidneys and an understanding of metabolic conditions and hormonal factors that regulate their expression and function.	f	\N
22933945	The aim of the study was to evaluate the clinical efficacy of superselective intra-arterial targeted neo-adjuvant chemotherapy in the treatment of estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and human epidermal growth factor receptor 2 (HER2)-negative (triple-negative) breast cancer. PATIENTS AND METHODS.: A total of 47 triple-negative breast cancer patients (29 at stage II, 13 at stage III and 5 at stage IV) were randomly assigned to two groups: targeted chemotherapy group (n=24) and control group (n=23). Patients in the targeted chemotherapy group received preoperative superselective intra-arterial chemotherapy with CEF regimen (C: cyclophosphamide [600 mg/m(2)]; E: epirubicin [90 mg/m(2)]; F: 5-fluorouracil [600 mg/m(2)]), and those in the control group received routine neoadjuvant chemotherapy with CEF. The duration of the treatment, changes in lesions and the prognosis were determined. The average course of the treatment was 15 days in the targeted chemotherapy group which was significantly shorter than that in the control group (31 days) (P<0.01). The remission rate of lesions was 91.6% in the targeted chemotherapy group and 60.9% in the control group, respectively. Among these patients, 9 died within two years, including 2 (both at IV stage) in the targeted chemotherapy group and 7 (2 at stage II, 4 at stage III and 1 at stage IV) in the control group. As an neoadjuvant therapy, the superselective intra-arterial chemotherapy is effective for triple-negative breast cancer, with advantages of the short treatment course and favourable remission rates as well as prognoses.	f	\N
22934539	The existing literature suggests that theories and models can serve as valuable frameworks for the design and evaluation of health interventions. However, evidence on the use of theories and models in social marketing interventions is sparse. The purpose of this systematic review is to identify to what extent papers about social marketing health interventions report using theory, which theories are most commonly used, and how theory was used. A systematic search was conducted for articles that reported social marketing interventions for the prevention or management of cancer, diabetes, heart disease, HIV, STDs, and tobacco use, and behaviors related to reproductive health, physical activity, nutrition, and smoking cessation. Articles were published in English, after 1990, reported an evaluation, and met the 6 social marketing benchmarks criteria (behavior change, consumer research, segmentation and targeting, exchange, competition and marketing mix). Twenty-four articles, describing 17 interventions, met the inclusion criteria. Of these 17 interventions, 8 reported using theory and 7 stated how it was used. The transtheoretical model/stages of change was used more often than other theories. Findings highlight an ongoing lack of use or underreporting of the use of theory in social marketing campaigns and reinforce the call to action for applying and reporting theory to guide and evaluate interventions.	f	\N
22935019	Heart failure is seen as a complex disease caused by a combination of a mechanical disorder, cardiac remodeling and neurohormonal activation. To define heart failure the systems biology approach integrates genes and molecules, interprets the relationship of the molecular networks with modular functional units, and explains the interaction between mechanical dysfunction and cardiac remodeling. The biomechanical model of heart failure explains satisfactorily the progression of myocardial dysfunction and the development of clinical phenotypes. The earliest mechanical changes and stresses applied in myocardial cells and/or myocardial loss or dysfunction activate left ventricular cavity remodeling and other neurohormonal regulatory mechanisms such as early release of natriuretic peptides followed by SAS and RAAS mobilization. Eventually the neurohormonal activation and the left ventricular remodeling process are leading to clinical deterioration of heart failure towards a multi-organic damage. It is hypothesized that approaching heart failure with the methodology of systems biology we promote the elucidation of its complex pathophysiology and most probably we can invent new therapeutic strategies.	f	\N
22940074	A 33-year-old woman with Wernicke's encephalopathy (WE) due to poor oral intake after allogeneic stem cell transplantation for acute myeloid leukemia showed a sequential development of bilateral gaze-evoked nystagmus (GEN), rightward gaze palsy, and upbeat nystagmus. Initial MRIs obtained when she had GEN only showed a lesion involving the medullary tegmentum, and follow-up MRIs revealed additional lesions in the pontine and midbrain tegmentum along with development of rightward gaze palsy, and finally bilateral medial thalamus lesions in association with upbeat nystagmus. The evolution of abnormal ocular motor findings and serial MRI changes in our patient with WE provide imaging evidence on relative vulnerability of the neural structures, and on the progression of lesions and ocular motor findings in thiamine deficiency.	f	\N
22956992	Cerebral palsy (CP) is an upper motor neuron disease that results in a spectrum of movement disorders. Secondary to the neurological lesion, muscles from patients with CP are often spastic and form debilitating contractures that limit range of motion and joint function. With no genetic component, the pathology of skeletal muscle in CP is a response to aberrant complex neurological input in ways that are not fully understood. This study was designed to gain further understanding of the skeletal muscle response in CP using transcriptional profiling correlated with functional measures to broadly investigate muscle adaptations leading to mechanical deficits.Biopsies were obtained from both the gracilis and semitendinosus muscles from a cohort of patients with CP (n = 10) and typically developing patients (n = 10) undergoing surgery. Biopsies were obtained to define the unique expression profile of the contractures and passive mechanical testing was conducted to determine stiffness values in previously published work. Affymetrix HG-U133A 2.0 chips (n = 40) generated expression data, which was validated for selected transcripts using quantitative real-time PCR. Chips were clustered based on their expression and those from patients with CP clustered separately. Significant genes were determined conservatively based on the overlap of three summarization algorithms (n = 1,398). Significantly altered genes were analyzed for over-representation among gene ontologies and muscle specific networks.The majority of altered transcripts were related to increased extracellular matrix expression in CP and a decrease in metabolism and ubiquitin ligase activity. The increase in extracellular matrix products was correlated with mechanical measures demonstrating the importance in disability. These data lay a framework for further studies and development of novel therapies.	f	\N
22958194	Ancestral background, specifically African descent, confers higher risk for development of inhibitory antibodies to factor VIII (FVIII) in haemophilia A. It has been suggested that differences in the distribution of FVIII gene (F8) haplotypes, and mismatch between endogenous F8 haplotypes and those comprising products used for treatment could contribute to risk. Data from the Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort were used to determine the association between F8 haplotype 3 (H3) vs. haplotypes 1 and 2 (H1 + H2) and inhibitor risk among individuals of genetically determined African descent. Other variables known to affect inhibitor risk including type of F8 mutation and human leucocyte antigen (HLA) were included in the analysis. A second research question regarding risk related to mismatch in endogenous F8 haplotype and recombinant FVIII products used for treatment was addressed. Haplotype 3 was associated with higher inhibitor risk among those genetically identified (N = 49) as of African ancestry, but the association did not remain significant after adjustment for F8 mutation type and the HLA variables. Among subjects of all racial ancestries enrolled in HIGS who reported early use of recombinant products (N = 223), mismatch in endogenous haplotype and the FVIII proteins constituting the products used did not confer greater risk for inhibitor development. Haplotype 3 was not an independent predictor of inhibitor risk. Furthermore, our findings did not support a higher risk of inhibitors in the presence of a haplotype mismatch between the FVIII molecule infused and that of the individual.	f	\N
22964476	Tocopherol, a member of the vitamin E family, consists of four forms designated as α, β, γ, and δ. Several large cancer prevention studies with α-tocopherol have reported no beneficial results, but recent laboratory studies have suggested that δ- and γ-tocopherol may be more effective. In two different animal models of breast cancer, the chemopreventive activities of individual tocopherols were assessed using diets containing 0.3% of tocopherol (α-, δ-, or γ-) or 0.3% of a γ-tocopherol rich mixture (γ-TmT). Although administration of tocopherols did not prevent human epidermal growth factor receptor 2 (HER2/neu)-driven tumorigenesis, δ- and γ-tocopherols inhibited hormone-dependent mammary tumorigenesis in N-methyl-N-nitrosourea (NMU)-treated female Sprague-Dawley rats. NMU-treated rats showed an average tumor burden of 10.6 ± 0.8 g in the control group at 11 weeks, whereas dietary administration of δ- and γ-tocopherols significantly decreased tumor burden to 7.2 ± 0.8 g (P < 0.01) and 7.1 ± 0.7 g (P < 0.01), respectively. Tumor multiplicity was also reduced in δ- and γ-tocopherol treatment groups by 42% (P < 0.001) and 32% (P < 0.01), respectively. In contrast, α-tocopherol did not decrease tumor burden or multiplicity. In mammary tumors, the protein levels of proapoptotic markers (BAX, cleaved caspase-9, cleaved caspase-3, cleaved PARP) were increased, whereas antiapoptotic markers (Bcl-2, XIAP) were inhibited by δ-tocopherol, γ-tocopherol, and γ-TmT. Furthermore, markers of cell proliferation (PCNA, PKCα), survival (PPAR-γ, PTEN, phospho-Akt), and cell cycle (p53, p21) were affected by δ- and γ-tocopherols. Both δ- and γ-tocopherols, but not α-tocopherol, seem to be promising agents for the prevention of hormone-dependent breast cancer.	f	\N
22980951	The role of non-complement activating antibodies (ncAbs) to mismatched donor human leukocyte antigen (HLA) in the pathogenesis of chronic lung rejection is not known. We used a murine model of obliterative airway disease (OAD) induced by Abs to major histocompatibility major histocompatibility complex (MHC) class I and serum from donor-specific Abs developed in human lung transplant (LTx) recipients to test the role of ncAbs in the development of OAD and bronchiolitis obliterans syndrome (BOS). Anti-MHC ncAbs were administered intrabronchially in B.10 mice or in C3 knockout (C3KO) mice. Lungs were analyzed by histopathology. Lymphocytes secreting interleukin (IL)-17, interferon-γ, or IL-10 to collagen V and K-α1 tubulin (Kα1T) were enumerated by enzyme-linked immunospot assay. Serum antibodies to collagen V and Kα1T were determined by enzyme-linked immunosorbent assay. Cytokine and growth factor expression in lungs was determined by real-time polymerase chain reaction. Donor-specific Abs from patients with BOS and control BOS-negative LTx recipients were analyzed by C1q assay. Administration of ncAbs in B.10 mice or C3KO resulted in OAD lesions. There were significant increases in IL-17- and interferon-γ-secreting cells to collagen V and Kα1T, along with serum Abs to these antigens. There was also augmented expression of monocyte chemotactic protein-1, IL-6, IL-1β, vascular endothelial growth factor, transforming growth factor-β, and fibroblastic growth factor in mice administered ncAbs by Day 3. Among 5 LTx recipients with BOS, only 1 had C1q binding donor-specific Abs. Complement activation by Abs to MHC class I is not required for development of OAD and human BOS. Therefore, anti-MHC binding to epithelial and endothelial cells can directly activate pro-fibrotic and pro-inflammatory cascades leading to immune response to self-antigens and chronic rejection.	f	\N
22981307	The "Cohorte Enfant Scanner", a study designed to investigate the risk of radiation-induced cancer after childhood exposure to CT (computed tomography) examinations, used clinical information contained in the "programme de médicalisation des systèmes d'information" (PMSI) database, the French hospital activities national program based upon diagnosis related groups (DRG). However, the quality and adequacy of the data for the specific needs of the study should be verified. The aim of our work was to estimate the percentage of the cohort's children identified in the PMSI database and to develop an algorithm to individualize the children with a cancer or a disease at risk of cancer from medical diagnoses provided by the DRGs database. Of the 1519 children from the "Cohorte Enfant Scanner", who had had a CT scan in the radiology department of a university hospital in 2002, a cross linkage was performed with the DRGs database. All hospitalizations over the period 2002-2009 were taken into account. An algorithm was constructed for the items "cancer" and "disease at risk for cancer" on a sample of 150 children. The algorithm was then tested on the entire population. Overall, 74% of our population was identified in the DRGs database. The algorithm individualized cancer diagnoses with 91% sensitivity (95% confidence interval [95%CI]: 86%; 97%) and 98% specificity (95%CI: 97%; 99%) and 86% positive predictive value (95%CI: 80%; 93%). For the diagnosis of disease at risk for cancer, the sensitivity, specificity and positive predictive value were respectively 91% (95%CI: 84%; 98%), 94% (95%CI: 92%; 95%) and 52% (95%CI: 43%; 61%). The DRG database identified with excellent sensitivity and specificity children with diagnoses of cancer or disease at risk for cancer. Hence, potential confounding factors related to the disease of the child can be taken into account for analyses performed with the cohort.	f	\N
22990715	Few studies have explored the epidemiology of beta cell loss in youth with diabetes. This report describes the evolution and major determinants of beta cell function, assessed by fasting C-peptide (FCP), in the SEARCH for Diabetes in Youth study. Participants were 1,277 youth with diabetes (948 positive for diabetes autoantibodies [DAs] and 329 negative for DAs), diagnosed when aged <20 years, who were followed from a median of 8 months post diagnosis, for approximately 30 months. We modelled the relationship between rate of change in log FCP and determinants of interest using repeated measures general linear models. Among DA-positive youth, there was a progressive decline in beta cell function of 4% per month, independent of demographics (age, sex, race/ethnicity), genetic susceptibility to autoimmunity (HLA risk), HbA(1c) and BMI z score, or presence of insulin resistance. Among DA-negative youth, there was marked heterogeneity in beta cell loss, reflecting an aetiologically mixed group. This group likely includes youths with undetected autoimmunity (whose decline is similar to that of DA-positive youth) and youth with non-autoimmune, insulin-resistant diabetes, with limited decline (~0.7% per month). SEARCH provides unique estimates of beta cell function decline in a large sample of youth with diabetes, indicating that autoimmunity is the major contributor. These data contribute to a better understanding of clinical evolution of beta cell function in youth with diabetes, provide strong support for the aetiological classification of diabetes type and may inform tertiary prevention efforts targeted at high-risk groups.	f	\N
23005903	A tubo-ovarian abscess (TOA) is a common complication of pelvic inflammatory disease in premenopausal women; however, in virginal females, TOAs are an exceedingly rare occurrence. Within this rare subset of patients, there is almost always an underlying condition, such as vaginal voiding, or a concomitant disease process. A virginal adolescent female with no prior medical history presented with a large pelvic mass which proved to be a TOA. An exploratory laparotomy was eventually required to establish the diagnosis. Open drainage and antibiotic therapy successfully treated the patient. With only the organism, Streptococcus viridians, isolated in her cultures, an etiology of direct ascension from the lower genitourinary tract is implicated. We believe this to be the youngest case of a TOA occurring in a virginal adolescent female without a predisposing condition. A TOA should be considered in the differential diagnosis of pelvic masses in previously healthy pediatric patients regardless of their sexual activity.	f	\N
23008381	Japanese encephalitis (JE) is an epidemic encephalitis characterised by altered sensorium, convulsions, headache, brainstem signs with pyramidal and extrapyramidal features. Immune-mediated manifestation as acute transverse myelitis (ATM) has not been previously reported in JE. We describe a 40-year-old man who presented with an acute onset quadriparesis with urinary retention, which was preceded by fever and headache 3 weeks prior. He had elevated IgM titres against JE virus in serum and cerebrospinal fluid. MRI of cervico-thoracic spine demonstrated signal intensity alterations extending from C1 to D10 spinal segments. The patient was treated with intravenous methyl prednisolone for 5 days. He regained normal power at 6 months follow-up and repeat MRI study demonstrated complete resolution of the lesion. We conclude that in a case of JE, one should be vigilant for early diagnosis of possible complication as ATM, in which an early institution of immunomodulator therapy prevents adverse consequences.	f	\N
23018067	OBJECTIVES. To evaluate attainment of low-density lipoprotein cholesterol goals among hypercholesterolaemic patients undergoing lipid-lowering drug treatment in Hong Kong and to identify potential determinants of treatment outcomes. DESIGN. Cross-sectional observational study. SETTING. A single site in Hong Kong, as part of the CEPHEUS Pan-Asian survey. PATIENTS. Subjects with hypercholesterolaemia aged 18 years or above, who had been on lipid-lowering drug treatment for at least 3 months with no dose adjustment for at least 6 weeks. RESULTS. A total of 561 such patients (mean age, 65.3; standard deviation, 9.7 years) were evaluated. Most had major cardiovascular risk factors; 534 (95.2%) of 561 patients had coronary heart disease and 534 (95.4%) of 560 patients had low-density lipoprotein cholesterol goals set at lower than 70 mg/dL. In all, 465 (82.9%) patients attained their respective low-density lipoprotein cholesterol goals. Among 75 patients who had coronary heart disease or equivalent risk, and multiple risk factors with a 10-year coronary heart disease risk of over 20%, 62 (82.7%) attained their respective low-density lipoprotein cholesterol goals. Significant predictors of low-density lipoprotein cholesterol goal attainment included the patient's baseline lipid profile (total cholesterol and low-density lipoprotein cholesterol levels), blood pressure, and drugs (statin/non-statin) used for treatment. CONCLUSIONS. Hypercholesterolaemic patients undergoing lipid-lowering drug treatment in the present Hong Kong study were able to achieve a very high attainment rate for the low-density lipoprotein cholesterol goal, despite the fact that most of them had major cardiovascular risk factors.	f	\N
23020826	A patient with central nervous system involvement of Behçet's disease was refractory to conventional immunosuppressive therapy and showed secondary failure of the anti-TNF agent infliximab. This presented as a progressive weakness of the legs and reduction in walking distance. The cerebrospinal fluid showed signs of inflammation including a vastly elevated IL-6 concentration. Given this result, the anti-IL-6 receptor antibody tocilizumab was administered and a good improvement of inflammatory parameters and a satisfactory increase of the walking distance were achieved.	f	\N
23028288	The prioritization of candidate disease-causing genes is a fundamental challenge in the post-genomic era. Current state of the art methods exploit a protein-protein interaction (PPI) network for this task. They are based on the observation that genes causing phenotypically-similar diseases tend to lie close to one another in a PPI network. However, to date, these methods have used a static picture of human PPIs, while diseases impact specific tissues in which the PPI networks may be dramatically different. Here, for the first time, we perform a large-scale assessment of the contribution of tissue-specific information to gene prioritization. By integrating tissue-specific gene expression data with PPI information, we construct tissue-specific PPI networks for 60 tissues and investigate their prioritization power. We find that tissue-specific PPI networks considerably improve the prioritization results compared to those obtained using a generic PPI network. Furthermore, they allow predicting novel disease-tissue associations, pointing to sub-clinical tissue effects that may escape early detection.	f	\N
23028439	Several independent studies have supported the association of DYX1C1 with dyslexia, but its role in general reading development remains unclear. Here, we investigated the contribution of this gene to reading, with a focus on orthographic skills, in a sample of 284 unrelated Chinese children aged 5 to 11 years who were participating in the Chinese Longitudinal Study of Reading Development. We tested this association using a quantitative approach for Chinese character reading, Chinese character dictation, orthographic judgment, and visual skills. Significant or marginally significant associations were observed at the marker rs11629841 with children's orthographic judgments at ages 7 and 8 years (all P values<0.020). Significant associations with Chinese character dictation (all P values<0.013) were also observed for this single-nucleotide polymorphism (SNP) at ages 9, 10, and 11 years. Further analyses revealed that the association with orthographic skills was specific to the processing of specific components of characters (P values<0.046). No association was found at either SNP of rs3743205 or rs57809907. Our findings suggest that DYX1C1 influences reading development in the general Chinese population and supports a universal effect of this gene.	f	\N
23049998	Although "uremic fetor" has long been felt to be diagnostic of renal failure, the compounds exhaled in uremia remain largely unknown so far. The present work investigates whether breath analysis by ion mobility spectrometry can be used for the identification of volatile organic compounds retained in uremia. Breath analysis was performed in 28 adults with an eGFR ≥ 60 ml/min per 1.73 m(2), 26 adults with chronic renal failure corresponding to an eGFR of 10-59 ml/min per 1.73 m(2), and 28 adults with end-stage renal disease (ESRD) before and after a hemodialysis session. Breath analysis was performed by ion mobility spectrometryafter gas-chromatographic preseparation. Identification of the compounds of interest was performed by thermal desorption gas chromatography/mass spectrometry. Breath analyses revealed significant differences in the spectra of patients with and without renal failure. Thirteen compounds were chosen for further evaluation. Some compounds including hydroxyacetone, 3-hydroxy-2-butanone and ammonia accumulated with decreasing renal function and were eliminated by dialysis. The concentrations of these compounds allowed a significant differentiation between healthy, chronic renal failure with an eGFR of 10-59 ml/min, and ESRD (p<0.05 each). Other compounds including 4-heptanal, 4-heptanone, and 2-heptanone preferentially or exclusively occurred in patients undergoing hemodialysis. Impairment of renal function induces a characteristic fingerprint of volatile compounds in the breath. The technique of ion mobility spectrometry can be used for the identification of lipophilic uremic retention molecules.	f	\N
23050521	Data from the 2011 Survey of Pathways to Diagnosis and Services The median age when school-aged children with special health care needs (CSHCN) and autism spectrum disorder (ASD) were first identified as having ASD was 5 years. School-aged CSHCN identified as having ASD at a younger age (under age 5 years) were identified most often by generalists and psychologists, while those identified later (aged 5 years and over) were identified primarily by psychologists and psychiatrists. Nine out of 10 school-aged CSHCN with ASD use one or more services to meet their developmental needs. Social skills training and speech or language therapy are the most common, each used by almost three-fifths of these children. More than one-half of school-aged CSHCN with ASD use psychotropic medication.	f	\N
23058984	Mast cells (MCs) are well known for their detrimental effects in the context of allergic disorders. Strategies that limit MC function can therefore have a therapeutic value. Previous studies have shown that siramesine, a sigma-2 receptor agonist originally developed as an anti-depressant, can induce cell death in transformed cells through a mechanism involving lysosomal destabilization. Since MCs are remarkably rich in lysosome-like secretory granules we reasoned that MCs might be sensitive to siramesine. Here we show that murine and human MCs are highly sensitive to siramesine. Cell death was accompanied by secretory granule permeabilization, as shown by reduced acridine orange staining and leakage of granule proteases into the cytosol. Wild type siramesine-treated MCs underwent cell death with typical signs of apoptosis but MCs lacking serglycin, a proteoglycan crucial for promoting the storage of proteases within MC secretory granules, died predominantly by necrosis. A dissection of the underlying mechanism suggested that the necrotic phenotype of serglycin(-/-) cells was linked to defective Poly(ADP-ribose) polymerase-1 degradation. In vivo, siramesine treatment of mice caused a depletion of the MC populations of the peritoneum and skin. The present study shows for the first time that MCs are highly sensitive to apoptosis induced by siramesine and introduces the possibility of using siramesine as a therapeutic agent for treatment of MC-dependent disease.	f	\N
23061325	A paradox exists in health disparities research where African-American cigarette smokers consume fewer cigarettes per day, yet experience higher rates of tobacco-related disease compared to White American smokers. In this study we conducted focus group interviews among alternative high school youth (N = 78; age 18-19 years old) in an urban area in Southwest Texas to investigate if African-American youth smoke cigarettes differently than their White-American and Hispanic-American counterparts. The majority of African-American participants reported inhaling deeper and smoking their cigarettes "to the filter" because of their concern over wasting any part of an expensive cigarette. White and Hispanic respondents most often put out their cigarettes closer to the middle, and did not express concern about wasting cigarettes. The implication from this qualitative study is that because African Americans smoke differently they are exposed to a higher level of harmful particulate per cigarette. Further research on smoking topography is warranted.	f	\N
23063289	A meta-analysis of publicly available gene expression changes in A549 cells upon treatment with anti-cancer drugs is reported. To reduce false positives, both fold-change and significance level cutoffs were used. Simulated datasets and permutation analysis were used to guide choice of ratio cutoff. Of the genes identified, FDXR is the only gene differentially expressed in six of the seven drug treatments. Though FDXR has been reported to be differentially expressed upon treatment with 5-fluorouracil and its expression correlated to long term disease survival, to our knowledge this is a first study implicating a wide effect of anti-cancer drug treatment on FDXR expression. The other genes identified which are differentially expressed in four out of the seven drug treatments are CDKN1A and PARVB which are upregulated and MYC, HBP1, LDLR, SIM2, ALX1 and GPHN which are downregulated.	f	\N
23063663	Liver cancer is one of most deadly cancers worldwide. Hepatocellular carcinoma (HCC) represents a major histological subtype of liver cancers. As cancer is a genetic disease, genetic lesions play a major role in HCC tumorigenesis and progression. Although significant progress has been made to uncover genetic alterations in HCCs, our understanding of genetics involved in the initiation and progression of HCC is far from complete. Next generation sequencing (NGS) has provided a new paradigm in biomedical research to delineate the genetic basis of human diseases. While identification of cancer somatic mutations has been serendipitous, genome sequencing has provided an unbiased approach to systematically catalog somatic mutations and elucidate the mechanisms of tumourigenesis. A number of recently published NGS studies on HCCs have not only confirmed previously known mutations in CTNNB1 and TP53 in HCC, but also identified novel genetic alterations in HCC including mutations in genes involved in epigenetic regulation. WNT, cell cycle and chromatin remodeling pathways have emerged as key oncogenic drivers in HCCs. The frequently altered genes and pathways in HCC reflect classical cancer hallmarks. These findings have started to depict a genetic landscape in HCC and will facilitate development of novel therapeutics for the treatment of this deadly disease.	f	\N
23063979	Vascular calcification is a hallmark of cardiovascular disease. Interleukin-24 (IL-24) has been known to suppress tumor progression in a variety of human cancers. However, the role of IL-24 in the pathophysiology of diseases other than cancer is unclear. We investigated the role of IL-24 in vascular calcification. IL-24 was applied to a β-glycerophosphate (β-GP)-induced rat vascular smooth muscle cell (VSMC) calcification model. In this study, IL-24 significantly inhibited β-GP-induced VSMC calcification, as determined by von Kossa staining and calcium content. The inhibitory effect of IL-24 on VSMC calcification was due to the suppression of β-GP-induced apoptosis and expression of calcification and osteoblastic markers. In addition, IL-24 abrogated β-GP-induced activation of the Wnt/β-catenin pathway, which plays a key role in the pathogenesis of vascular calcification. The specificity of IL-24 for the inhibition of VSMC calcification was confirmed by using a neutralizing antibody to IL-24. Our results suggest that IL-24 inhibits β-GP-induced VSMC calcification by inhibiting apoptosis, the expression of calcification and osteoblastic markers, and the Wnt/ β-catenin pathway. Our study may provide a novel mechanism of action of IL-24 in cardiovascular disease and indicates that IL-24 is a potential therapeutic agent in VSMC calcification.	f	\N
23070622	Multivisceral transplantation includes the simultaneous transplantation of multiple abdominal viscera including the stomach, duodenum, pancreas, and small intestine, with (multivisceral transplant, MVT) or without the liver (modified MVT, MMVT). This study reviews the changing indications and outcomes for this procedure over a 7-year period at a university medical center. This study is a retrospective case review of MVTs performed between 2004 and 2010 at a single center. All cases were either MVT or MMVT and included a simultaneous kidney transplant, if indicated. Graft failure was defined as loss of the graft or complete loss of function. Graft function was monitored by clinical function, laboratory values, and serial endoscopy with biopsy. During the study period, 95 patients received 100 transplants including 84 MVT and 16 MMVT. There were 19 patients who received a simultaneous kidney graft. There were 24 pediatric and 76 adult recipients (range 7 months to 66 years). Indications included intestinal failure alone, intestinal failure with cirrhosis, complete portal mesenteric thrombosis, slow-growing central abdominal tumors, intestinal pseudoobstruction, and frozen abdomen. All patients received antibody-based induction immunosuppression with calcineurin inhibitor-based maintenance immunosuppression. At a median mortality adjusted follow-up of 25 months, 1- and 3-year patient survival is 72 % and 57 %. There was a learning curve with this complex procedure resulting in a 48 % patient survival during the period from 2004 to 2007, followed by a 70 % patient survival during the period from 2008 to 2010. Post-transplant complications included rejection (50 % MMVT and 17 % MVT), infection (>90 % first year), graft versus host disease (13 %), and post-transplant lymphoproliferative disorder (5 %). Indications for MVT and MMVT have broadened to include patients with terminal conditions not amenable to other medical therapies such as slow-growing tumors of the mesenteric root, complete portomesenteric thrombosis, and abdominal catastrophes/frozen abdomen. Outcomes have improved over time with many patients returning to full functional status and enjoying long-term survival.	f	\N
23079185	Elevated serum levels of the proinflammatory cytokine tumor necrosis factor alpha (TNFα) correlate with an increased risk for atherothrombotic events and TNFα is known to induce prothrombotic molecules in endothelial cells. Based on the preexisting evidence for the impact of TNFα in the pathogenesis of autoimmune disorders and their known association with an acquired hypercoagulability, we investigated the effects of TNFα and the role of the TNF receptor subtypes TNFR1 and TNFR2 for arteriolar thrombosis in vivo. Arteriolar thrombosis and platelet-rolling in vivo were investigated in wildtype, TNFR1-/-, TNFR2-/- and TNFR1-/R2-/- C57BL/6 mice using intravital microscopy in the dorsal skinfold chamber microcirculation model. In vitro, expression of prothrombotic molecules was assessed in human endothelial cells by real-time PCR and flow cytometry. In wildtype mice, stimulation with TNFα significantly accelerated thrombotic vessel occlusion in vivo upon ferric chloride injury. Arteriolar thrombosis was much more pronounced in TNFR1-/- animals, where TNFα additionally led to increased platelet-endothelium-interaction. TNFα dependent prothrombotic effects were not observed in TNFR2-/- and TNFR1-/R2- mice. In vitro, stimulation of human platelet rich plasma with TNFα did not influence aggregation properties. In human endothelial cells, TNFα induced superoxide production, p-selectin, tissue factor and PAI-1, and suppressed thrombomodulin, resulting in an accelerated endothelial dependent blood clotting in vitro. Additionally, TNFα caused the release of soluble mediators by endothelial cells which induced prothrombotic and suppressed anticoagulant genes comparable to direct TNFα effects. TNFα accelerates thrombus formation in an in vivo model of arteriolar thrombosis. Its prothrombotic effects in vivo require TNFR2 and are partly compensated by TNFR1. In vitro studies indicate endothelial mechanisms to be responsible for prothrombotic TNFα effects. Our results support a more selective therapeutic approach in anticytokine therapy favouring TNFR2 specific antagonists.	f	\N
23083013	Atopic dermatitis (AD) is a chronic and relapsing inflammatory skin disease affecting > 10% of children and 1-3% of adults, and can cause significant morbidity. The incidence of AD seems to be increasing. Omalizumab, a monoclonal antibody, has recently been suggested as a potential new systemic treatment for patients with recalcitrant AD with elevated IgE levels, based on its efficacy in treating asthma and allergic rhinitis. We report a study of 10 patients with AD (aged 19-35 years) who received anti-IgE treatment for persistent asthma. All patients, regardless of IgE value, were treated with a fixed schedule of eight cycles of omalizumab 300 mg administered subcutaneously at intervals of 2 weeks. Eczema symptoms were scored at baseline and after 2, 4 and 6 months of treatment. There was a steady improvement in the objective SCORAD (SCORing Atopic Dermatitis), with significantly lower scores observed at the 6-month evaluation. At 2 months after the end of treatment, two patients had a very good result (SCORAD reduction of > 50%), five patients had a satisfactory result (reduction of 25-50%), and three patients had no clinically relevant result (reduction of 25-50%). No patient had worsening of the AD (increase of > 25% in SCORAD), and once a clinical improvement occurred, none of the patients experienced worsening of their eczema symptoms while on omalizumab. With the caveats of the financial expense and unknown long-term risks of malignancy associated with omalizumab, this drug should be considered for treatment-resistant patients with AD, particularly patients with high IgE level whose symptoms are not controlled by routine therapies. Omalizumab has proven useful in treating asthma, but it may also prove valuable for other conditions, such as allergic rhinitis, food allergies, chronic urticaria, and AD, as shown by the present study.	f	\N
23087412	We recently proposed two novel criteria to assess the usefulness of risk prediction models for public health applications. The proportion of cases followed, PCF(p), is the proportion of individuals who will develop disease who are included in the proportion p of individuals in the population at highest risk. The proportion needed to follow-up, PNF(q), is the proportion of the general population at highest risk that one needs to follow in order that a proportion q of those destined to become cases will be followed (Pfeiffer, R.M. and Gail, M.H., 2011. Two criteria for evaluating risk prediction models. Biometrics 67, 1057-1065). Here, we extend these criteria in two ways. First, we introduce two new criteria by integrating PCF and PNF over a range of values of q or p to obtain iPCF, the integrated PCF, and iPNF, the integrated PNF. A key assumption in the previous work was that the risk model is well calibrated. This assumption also underlies novel estimates of iPCF and iPNF based on observed risks in a population alone. The second extension is to propose and study estimates of PCF, PNF, iPCF, and iPNF that are consistent even if the risk models are not well calibrated. These new estimates are obtained from case-control data when the outcome prevalence in the population is known, and from cohort data, with baseline covariates and observed health outcomes. We study the efficiency of the various estimates and propose and compare tests for comparing two risk models, both of which were evaluated in the same validation data.	f	\N
23089926	Lipoprotein lipase (LPL) is a key enzyme in lipid metabolism and is associated with obesity, dyslipidemias, hypertension (HTN) and type 2 diabetes mellitus (T2DM). LPL gene polymorphisms can be related with the development of cardiovascular risk factors. The present study was conducted to analyze the relationship of the HindIII and S447X polymorphisms in LPL gene with cardiovascular risk factors in Mexican families. The study population comprised ninety members of 30 Mexican families, in which an index case had obesity, were included in the study. We evaluated the body composition by bioelectrical impedance. Peripheral blood samples were collected to determine biochemical parameters. Screening for both polymorphisms was made by PCR-RFLPs. In the parents, both polymorphisms were in Hardy-Weinberg's equilibrium. We found that the genotype T/T of HindIII was associated with diastolic blood pressure ≥ 85 mmHg (OR=1.1; p=0.011), whereas the genotype C/C of S447X was associated with systolic blood pressure ≥ 130 mmHg (OR=1.2; p<0.001), diastolic blood pressure ≥ 85 mmHg (OR = 1.3; p< 0.001), T2DM (OR=1.3; p< 0.001) and with increase of total cholesterol (β =23.6 mg/mL; p=0.03). These data suggest that the HindIII and S447X LPL gene polymorphisms can confer susceptibility for the development of hypertension and T2DM in Mexican families.	f	\N
23092312	Many coronary heart disease (CHD) events occur in individuals classified as intermediate risk by commonly used assessment tools. Over half the individuals presenting with a severe cardiac event, such as myocardial infarction (MI), have at most one risk factor as included in the widely used Framingham risk assessment. Individuals classified as intermediate risk, who are actually at high risk, may not receive guideline recommended treatments. A clinically useful method for accurately predicting 5-year CHD risk among intermediate risk patients remains an unmet medical need. This study sought to develop a CHD Risk Assessment (CHDRA) model that improves 5-year risk stratification among intermediate risk individuals. Assay panels for biomarkers associated with atherosclerosis biology (inflammation, angiogenesis, apoptosis, chemotaxis, etc.) were optimized for measuring baseline serum samples from 1084 initially CHD-free Marshfield Clinic Personalized Medicine Research Project (PMRP) individuals. A multivariable Cox regression model was fit using the most powerful risk predictors within the clinical and protein variables identified by repeated cross-validation. The resulting CHDRA algorithm was validated in a Multiple-Ethnic Study of Atherosclerosis (MESA) case-cohort sample. A CHDRA algorithm of age, sex, diabetes, and family history of MI, combined with serum levels of seven biomarkers (CTACK, Eotaxin, Fas Ligand, HGF, IL-16, MCP-3, and sFas) yielded a clinical net reclassification index of 42.7% (p < 0.001) for MESA patients with a recalibrated Framingham 5-year intermediate risk level. Across all patients, the model predicted acute coronary events (hazard ratio = 2.17, p < 0.001), and remained an independent predictor after Framingham risk factor adjustments. These include the slightly different event definition with the MESA samples and inability to include PMRP fatal CHD events. A novel risk score of serum protein levels plus clinical risk factors, developed and validated in independent cohorts, demonstrated clinical utility for assessing the true risk of CHD events in intermediate risk patients. Improved accuracy in cardiovascular risk classification could lead to improved preventive care and fewer deaths.	f	\N
23097963	This work, partial pressure of the respiratory gases in the capillary blood (pH, PaO2, PaCO2) was studied, following the protective action of the beta2-drenergic stimulator-Hexoprenaline and alpha2-adrenergic blocker-Tolazoline in the bronchoconstriction caused by a beta-blocker-Propranolol. in patients with increased bronchial reactibility. pH, oxygen partial pressure (PaO2), dioxide carbon partial pressure (PaCO2) in the arterial blood, with the assistance of the analyzer IL, following some minutes of sample taking were defined in all patients. As a standard to verify the accuracy of the measurement, ampoule solutions of pH, PaO2 and PaCO2 were utilized (Acidobasel, Berlin). Following the inhalation of the beta-blocker-Propranolol (20 mg/ml-aerosol), there was an evident decrease (p < 0.05) of pO2 and a non-significant increase (p > 0.1) of pCO2. Beta2-adrenergcic stimulator-Hexoprenaline (2 inh x 0.2 mg), shows an protective effect in the decrease of pO2 (p < 0.05) following the bronchoconstriction being provoked by Propranolol. Alpha2-adrenergic blocker-Tolazoline (20 mg/ml-aerosol), has not shown a protective action in the bronchoconstriction caused with propranolol, therefore significant decrease (p < 0.05) of pO2 and a non-significant increase (p > 0.1) of pCO2 appeared. This shows that stimulation of beta2-adrenergic receptor has protective action in changes of the respiratory gases. Meantime, blocker of the alpha2-adrenergic receptor (Tolazoline) has not shown a protective action in changes of the respiratory gases.	f	\N
23101267	CD200 and its receptor were recognized as having the multiple immunoregulatory functions. Their immunoregulatory, suppressive, and tolerogenic potentials could be very effectively exploited in the treatment of many diseases, e.g. Alzheimer disease, rheumatoid arthritis, and allergy to name only some. Many research projects are aimed to develop clinically valuable methods being based on the structure and function of these paired molecules. In this review, we would like to introduce CD200/CD200R functions in a clinical context.	f	\N
23114434	Surveillance of nosocomial infections is meanwhile a cornerstone of infection prevention activities in hospitals. The objective of this article is to compare healthcare-associated infection rates in intensive care patients, neonatal intensive care patients and operated patients (ICU-KISS, OP-KISS, NEO-KISS) of the German nosocomial infection surveillance system (KISS) with the corresponding data of the US American National Healthcare Safety Network (NHSN) and the European Centre for Disease Prevention and Control (ECDC). In general, the methodological differences among the three surveillance systems are minor but there are some exceptions. Therefore, differences between countries have to be interpreted very carefully as they may be due to differences in diagnostics, patient mix, types of interventions, length of stay, selection of participating hospitals, post-discharge surveillance activities and interpretation of case definitions. Organizational aspects, such as mandatory participation with public disclosure on infection rates may also have an impact.	f	\N
23117745	Arterial calcification is the result of the same highly organized processes as seen in bone, which rely on a delicate balance between osteoblasts and osteoclasts. Although previously understood as passive precipitation, evidence has accumulated to suggest that arterial calcification is the result of organized, regulated processes bearing many similarities to osteogenesis in bone, including the presence of subpopulations of arterial wall cells that retain osteoblastic lineage potential. These cells have the potential to form mineralized nodules and express osteoblast markers, including bone morphogenetic protein-2, osteocalcin, osteopontin, and alkaline phosphatase. By contrast, osteoclast-like cells mediate the catabolic process of mineral resorption. Recent data shows that cells positive for tartrate-resistant acid phosphatase, a major marker for osteoclasts, have been histologically identified in atherosclerotic lesions and are referred to as osteoclast-like cells. Evidence has accumulated to suggest that initial arterial calcification through passive precipitation of calcium phosphate initiates balanced mineralization regulated by osteoclast-like and osteoblast-like cells. Subsequently, various pathogenic conditions may trigger an imbalance between osteoblastogenesis and osteoclastogenesis, leading to either calcification in stenotic/occlusive disease or destruction of the extracellular matrix in aneurysmal disease. Further elucidation of these newly emerging concepts could lead to a novel therapeutic approach to arterial stenotic/occlusive disease and/or abdominal aortic aneurysm.	f	\N
23126056	Amyloidosis is a clinical entity that results from deposition of an extracellular protein material that causes disruption in normal architecture and impairs function of multiple organs and tissues. Secondary amyloidosis (AA) is a rare but serious complication that appears in the context of cancer, chronic inflammation, and chronic infectious disease, including rheumatoid arthritis. Renal failure is the most common clinical presentation of AA, ranging from nephrotic syndrome and impaired renal function to renal failure, with a potential for high morbidity. We present a case of a 52-year-old female patient diagnosed with rheumatoid arthritis at age 27. She was hospitalized due to worsening clinical condition. Physical examination revealed marked peripheral edema in both lower extremities. Laboratory tests showed an increase of inflammatory reactants, anemia, electrolyte disbalance, and severe hypoalbuminemia and hypoproteinemia. She had proteinuria 15.4 g/24 h and renal function estimated by creatinine clearance was 78 mL/min, within the second degree of chronic kidney disease. Renal biopsy was performed for evaluation of renal insufficiency with nephrotic range proteinuria. Congo red staining showed the presence of characteristic amyloid deposits that immunoreacted with the antibody against amyloid A protein, thus confirming the diagnosis of secondary amyloidosis.	f	\N
23132831	Development of effective therapeutic strategies to eliminate cancer stem cells, which play a major role in drug resistance and disease recurrence, is critical to improve cancer treatment outcomes. Our study showed that glioblastoma stem cells (GSCs) exhibited low mitochondrial respiration and high glycolytic activity. These GSCs were highly resistant to standard drugs such as carmustine and temozolomide (TMZ), but showed high sensitivity to a glycolytic inhibitor 3-bromo-2-oxopropionate-1-propyl ester (3-BrOP), especially under hypoxic conditions. We further showed that combination of 3-BrOP with carmustine but not with TMZ achieved a striking synergistic effect and effectively killed GSCs through a rapid depletion of cellular ATP and inhibition of carmustine-induced DNA repair. This drug combination significantly impaired the sphere-forming ability of GSCs in vitro and tumor formation in vivo, leading to increase in the overall survival of mice bearing orthotopic inoculation of GSCs. Further mechanistic study showed that 3-BrOP and carmustine inhibited glyceraldehyde-3-phosphate dehydrogenase and caused a severe energy crisis in GSCs. Our study suggests that GSCs are highly glycolytic and that certain drug combination strategies can be used to effectively overcome their drug resistance based on their metabolic properties.	f	\N
23133607	Functional genetic variations play important roles in shaping phenotypic differences among individuals through affecting gene expression, and thus, very likely to influence disease susceptibility, such as cancer susceptibility. One critical question in this era of post-genome wide association studies (GWAS) is how to assess the functional significance of the genetic variations identified from GWAS. In the current study, with lymphoblastoid cell lines (LCLs) from 74 non-related women with familial ovarian cancer and 47 unrelated controls matched on gender and race, we explored the associations between seven ovarian cancer risk variants identified from GWAS (rs3814113 on 9p22.2, rs2072590 on 2q31, rs2665390 on 3q25, rs10088218, rs1516982, rs10098821 on 8q24.21, and rs2363956 on 19p13) and whole genome mRNA expression profiles. We observed 95 significant trans-associations at a permutation level of 0.001. Compared to the other risk variants, rs10088218, rs1516982, and rs10098821 on 8q24.21 had the greatest number of significant associations (25, 16, and 38, respectively). Two possible cis-associations were observed between rs10098821 and c-Myc, and rs2072590 and HS.565379 (Permutated P = 0.0198 and 0.0399, respectively). Pathway enrichment analysis showed that several key biological pathways, such as cell cycle (P = 2.59×10(-06)), etc, were significantly overrepresented. Further characterization of significant associations between mRNAs and risk alleles might facilitate understanding the functions of GWAS discovered risk alleles in the genetic etiology of ovarian cancer.	f	\N
23136226	A combination of bortezomib (1.3 mg/m(2)), melphalan (5 mg/m(2)), and dexamethasone (40 mg) (BMD), with all three drugs given as a contemporary intravenous administration, was retrospectively evaluated. Fifty previously treated (median 2 previous lines) patients with myeloma (33 relapsed and 17 refractory) were assessed. The first 19 patients were treated with a twice-a-week (days 1, 4, 8, 11, 'base' schedule) administration while, in the remaining 31 patients, the three drugs were administered once a week (days 1, 8, 15, 22, 'weekly' schedule). Side-effects were predictable and manageable, with prominent haematological toxicity, and a better toxic profile in 'weekly' schedule (36% versus 66% in 'base' schedule). The overall response rate was 62%. After median follow-up of 24.5 months (range 2.7-50 months), the median progression-free survival (PFS) was 21.6 with no difference between the two schedules and the median overall survival (OS) was 33.8 months. Independently from the adopted schedule, we found that also in a cohort of relapsed/refractory patients achieving at least partial remission improved PFS (35.2 versus 9 months) and OS (unreached median versus 18 months). Taken together, our observations suggest that BMD is an effective regimen in advanced myeloma patients with acceptable toxicity.	f	\N
23137772	Molecular cytogenetic evaluation of human osteosarcoma (OS) has revealed the characteristically high degree of genomic reorganization that is the hallmark of this cancer. The extent of genomic disorder in OS has hindered identification of the genomic aberrations driving disease progression. With pathophysiological similarities to its human counterpart, canine OS represents an ideal model for comparison of conserved regions of genomic instability that may be disease-associated rather than genomic passengers. This study used high-resolution oligonucleotide array comparative genomic hybridization and a variety of informatics tools to aid in the identification of disease-associated genome-wide DNA copy number aberrations in canine and human OS. Our findings support and build upon the high level of cytogenetic complexity, through the identification of shared regions of microaberration (<500 kb) and functional analysis of possible orthologous OS-associated genes to pinpoint the cellular processes most commonly affected by aberration in human and canine OS. Aberrant regions contained previously reported genes such as CDC5L, MYC, RUNX2, and CDKN2A/CDKN2B, while expanding the gene of interest list to include ADAM15, CTC1, MEN1, CDK7, and others. Such regions of instability may thus have functional significance in the etiology of OS, the most common primary bone tumor in both species.	f	\N
23143555	The objective of the study is to investigate the mechanisms of cyclophosphamide sequential therapy for patient with primary Sjögren's syndrome-associated interstitial lung disease (PSS-ILD). This was a retrospective review of 15 patients (2005-2008) with PSS-ILD who underwent cyclophosphamide sequential therapy. Peripheral blood and bronchoalveolar lavage (BALF) were obtained before and 3, 6, 12 and 24 months after the treatment. The TNF-α and TGF-β1 mRNA levels in peripheral blood were measured using reverse transcription polymerase chain reaction. Serum and BALF TNF-α, TGF-β1 and MMP-9 levels were measured using sandwich enzyme-linked immunosorbent assay. The average levels of serum TNF-α (0.39 ± 0.22) and TGF-β1 (0.31 ± 0.18) mRNA in patients with PSS-ILD were higher compared with that in patients with PSS without ILD. TNF-α level (0.23 ± 0.19) was significantly decreased 3 months after cyclophosphamide treatment (t = 2.533, p < 0.05), and TGF-β1 (0.31 ± 0.18) level markedly decreased after 6 months of treatment (t = 2.617, p < 0.05). The levels of serum TNF-α (11.2 ± 2.6) μg/L, TGF-β1 (72 ± 19) μg/L and MMP-9 (38 ± 9) μg/L in patients with PSS-ILD were higher than that in patients with PSS without ILD. TGF-β1 (36 ± 12) μg/L level decreased significantly after 3 months of treatment (t = 2.526, p < 0.05), and TNF-α level (7.1 ± 1.3) μg/L markedly decreased after 6 months of therapy (t = 2.578, p < 0.05). MMP-9 level (18 ± 4) μg/L decreased significantly after 12-month treatment (t = 2.329, p < 0.05). The levels of BALF TNF-α (17.1 ± 3.5) μg/L, TGF-β1 (36 ± 17) μg/L and MMP-9 (27 ± 10) μg/L in patients with PSS-ILD were higher than that in patients with PSS without ILD. TGF-β1 (21 ± 14) μg/L level decreased significantly after 3-month treatment, and TNF-α level (9.4 ± 1.7) μg/L was decreased after 6 months of cyclophosphamide treatment that may be associated with its inhabitation on production of TNF-α, TGF-β1 and MMP-9.	f	\N
23144854	The Glutathione S-transferase P1 (GSTP1) polymorphism have been considered a risk modifier for developing head and neck cancer (HNC) in many studies; however, the results of such studies are inconsistent. The aim of this study was to evaluate the possible association between the GSTP1 Ile105Val polymorphism and risk of HNC. We performed a search in the relevant electronic database and a meta-analysis based on 28 published case-control studies that included 6,404 cases and 6,523 controls. To take into account the possibility of heterogeneity across the studies, a Chi-square based I(2)-statistic test was performed. Crude pooled odds ratios (ORs) with 95% confidence intervals (CIs) were assessed using both fixed-effects and random-effects models. The results of this meta-analysis showed that the GSTP1 Ile105Val polymorphism was not significantly associated with risk of HNC in the overall study population (pooled OR 1.00, 95% CI 0.92-1.09) or in subgroup analyses stratified by ethnicity, sample size, tumor site or publication year. Moreover, substantial evidence of heterogeneity among the studies was observed. Publication year was identified as the main cause of heterogeneity. This meta-analysis does not support a significant association between the GSTP1 Ile105Val polymorphism and risk of HNC.	f	\N
23145068	Electrode implantation into the subthalamic nucleus for deep brain stimulation in Parkinson's disease (PD) is associated with a temporary motor improvement occurring prior to neurostimulation. We studied this phenomenon by functional magnetic resonance imaging (fMRI) when considering the Unified Parkinson's Disease Rating Scale (UPDRS-III) and collateral oedema. Twelve patients with PD (age 55.9± (SD)6.8 years, PD duration 9-15 years) underwent bilateral electrode implantation into the subthalamic nucleus. The fMRI was carried out after an overnight withdrawal of levodopa (OFF condition): (i) before and (ii) within three days after surgery in absence of neurostimulation. The motor task involved visually triggered finger tapping. The OFF/UPDRS-III score dropped from 33.8±8.7 before to 23.3±4.8 after the surgery (p<0.001), correlating with the postoperative oedema score (p<0.05). During the motor task, bilateral activation of the thalamus and basal ganglia, motor cortex and insula were preoperatively higher than after surgery (p<0.001). The results became more enhanced after compensation for the oedema and UPDRS-III scores. In addition, the rigidity and axial symptoms score correlated inversely with activation of the putamen and globus pallidus (p<0.0001). One month later, the OFF/UPDRS-III score had returned to the preoperative level (35.8±7.0, p = 0.4).In conclusion, motor improvement induced by insertion of an inactive electrode into the subthalamic nucleus caused an acute microlesion which was at least partially related to the collateral oedema and associated with extensive impact on the motor network. This was postoperatively manifested as lowered movement-related activation at the cortical and subcortical levels and differed from the known effects of neurostimulation or levodopa. The motor system finally adapted to the microlesion within one month as suggested by loss of motor improvement and good efficacy of deep brain stimulation.	f	\N
23146629	We report a 14-year-old-boy with markedly elevated serum creatine kinase (CK) levels, in whom massive triglyceride storage was found in peripheral blood leukocytes and in muscle biopsy. Sequencing PNPLA2, the gene encoding the adipose triglyceride lipase (ATGL) and responsible for the neutral lipid storage disease with myopathy (NLSDM), we identified two heterozygous mutations, including a previously reported nonsense and a novel missense mutation in the patatin domain of the gene. Lipid storage myopathy can be clinically silent in childhood and presenting only with hyperCKemia.	f	\N
23154328	Trismus is a common problem among oral cancer patients. This report aimed to study the inciting factors of trismus and to find out the rationale of trismus release. Between 1996 and 2008, 61 oral cancer patients with retrievable records of interincisor distance (IID) were analyzed by retrospective chart review. The IID decreased from 31.4 (12.4) to 24.9 (12.0) mm in 36 patients undergoing cancer ablation only (P = 0.001). Other variables prompting trismus include buccal cancer (P = 0.017), radiotherapy (P = 0.008), and recurrence (P = 0.001). In contrast, the IID improved from 11.7 (7.1) to 22.7 (11.9) mm in 25 patients receiving cancer ablative and trismus releasing surgeries (P = 0.000). The improvement fared better in individuals with IID less than 15 mm than the others (P = 0.037). In conclusion, involvement of buccal region, ablative surgery, radiotherapy, and recurrence are provocative factors of trismus. Patients with IID less than 15 mm will benefit from releasing surgery significantly. Others may better be handled with conservative managements firstly, and enrolled as candidates of surgical release only until the patients entertained a 28-month period of disease-free interval, by which time the risk of recurrence would be markedly reduced.	f	\N
23159635	Activin, a member of the transforming growth factor-β family, has been known to be a growth and differentiating factor. Despite its pluripotent effects, the roles of activin signaling in prostate cancer pathogenesis are still unclear. In this study, we established several cell lines that express a constitutive active form of activin type IB receptor (ActRIBCA) in human prostate cancer cells, ALVA41 (ALVA-ActRIBCA). There was no apparent change in the proliferation of ALVA-ActRIBCA cells in vitro; however, their migratory ability was significantly enhanced. In a xenograft model, histological analysis revealed that the expression of Snail, a cell-adhesion-suppressing transcription factor, was dramatically increased in ALVA-ActRIBCA tumors, indicating epithelial mesenchymal transition (EMT). Finally, mice bearing ALVA-ActRIBCA cells developed multiple lymph node metastases. In this study, we demonstrated that ActRIBCA signaling can promote cell migration in prostate cancer cells via a network of signaling molecules that work together to trigger the process of EMT, and thereby aid in the aggressiveness and progression of prostate cancers.	f	\N
23167225	In this study, we hypothesized that subclinical impairment of left ventricular (LV) mechanical function in bicuspid aortic valve (BAV) patients is independent of valvular hemodynamics represented by valvuloarterial impedance and aortic elastic characteristics. Therefore, we aimed to test left ventricular mechanics in cases of isolated non-stenotic BAV with non-dilated aorta. Thirty-three patients with isolated BAV exhibiting non-dilated aorta, and 25 age-and gender-matched healthy subjects were included in the study. Patients with aortic valve velocity > 1.5 m/s and mild-to-moderate aortic regurgitation or ascending aorta diameter > 3.5 cm were excluded from the study. Aortic elasticity parameters and valvulo-arterial impedance were calculated. Strain measurements were reported as the peak longitudinal strain (LS) for four chamber (4C), long axis (LAX) and two chamber (2C) views. Strain rate (Sr) measurements were reported as the peak systolic strain rate (Sr-sm), early diastolic strain rate (Sr-em) and late diastolic strain rate (Sr-am) for 4C, LAX and 2C views. Systolic and diastolic diameters of the ascending aorta, aortic elastic properties (aortic strain, aortic distensibility, aortic stiffness and aortic elastic modulus), and valvulo-arterial impedances were found to be comparable between the BAV and control groups. BAV group was observed to have statistically significantly lower 4C (18.9 +/- 1.7 vs. 17.8 +/- 1.5, p = 0.02), LAX (19.7 +/- 1.7 vs. 17.7 +/- 1.3, p = 0.001) and 2C (20.1 +/- 1.8 vs. 17.7 +/- 1.2, p < 0.001) peak longitudinal strain values compared with the control group. Moreover, LV-GS values were found to be significantly lower in the BAV group than in the control group (19.6 +/- 1.1 vs. 17.7 +/- 0.9, p < 0.001). However, there was no statistically significant difference between the groups in terms of Sr-sm, Sr-em ve Sr-am values in the 4C, LAX, and 2C views. BAV might affect LV systolic functions, assessed by 2D strain imaging, in a fashion independent from the valvular dynamics and aortic elasticity. This might show that BAV is not only a valvular disease, but possibly a ventricular disease as well.	f	\N
23168153	Allergic rhinitis (AR) is a highly prevalent allergic disease and also counts among the 10 most frequent reasons for medical consultation. Its impact on quality of life (QoL) and work productivity has been established but comparisons with other diseases are rare in the literature. The aim of this study was to evaluate the impact of AR in health-related QoL (HRQoL) and work productivity in primary care patients, compared with other prevalent diseases such as hypertension, diabetes mellitus (DM) type II, and symptomatic depression. Six hundred sixteen patients were included in a multicenter cross-sectional observational study. A generic HRQoL questionnaire, 36-item Short Form, and a specific questionnaire, "Work Productivity and Activity Impairment" were handed out to measure QoL and work productivity impact of the diseases. To assess clinical severity with a comparable scale between diseases Clinical Global Impression (CGI) had been used. Symptomatic depression was found to produce the greatest impairment on work productivity with a decrease of 59.5%, with significant differences compared with AR, hypertension, and DM type II (p < 0.05). Symptomatic depression was found to produce the highest negative impact on daily activities with a statistically significant reduction of 59.4% (p < 0.05) compared with AR (26.6% decrease), hypertension (8.8% decrease), and DM (16.7% decrease) patients. Differences between AR and DM or hypertension were also significant (p < 0.05). Restriction on daily activities for AR was 27.8%, which is significantly higher (p < 0.05) than hypertension (19.8% decrease) but not DM (25.7% decrease). Depression had the highest impairment on daily activities (59.4%), compared with the remaining three groups (p < 0.05). AR impairs work productivity in a greater magnitude than hypertension and DM type II.	f	\N
23174870	Head and neck cancer is the fifth most common type of cancer worldwide. The objective of this study was to evaluate the clinical and epidemiological parameters in a head and neck surgery service. Cross-sectional study using patients' records, developed in otolaryngology and head and neck department of a university hospital in the northwest of the state of São Paulo. A total of 995 patients in the head and neck surgery service between January 2000 and May 2010 were evaluated. The variables analyzed included: age, gender, skin color, tobacco and alcohol consumption, primary site, staging and histological tumor type, treatment and number of deaths. The disease was more frequent among men (79.70%), smokers (75.15%) and alcohol abusers (58.25%). The most representative sites were oral cavity (29.65%) and larynx (24.12%) for the primary site; squamous cell carcinoma (84.92%) was the most frequent histological type, and surgery (29.04%) and radiotherapy (14.19%) were the most common treatments. The cancer that affects patients assisted by the head and neck surgery service occurs mainly men, smokers and alcohol abusers, and the oral cavity and larynx are the sites with the highest incidence. The high rate of patients with stages III and IV indicates late diagnosis by the treatment centers, which reflects the need for prevention education campaigns for early diagnosis of the disease.	f	\N
23178050	Antidepressants might increase compliance with cardiovascular disease risk reduction interventions. However, antidepressants have been linked to deleterious metabolic effects. In the present multicenter study, we sought to determine whether patients who take antidepressants derive the expected benefits from cardiac rehabilitation in terms of improvements in multiple atherosclerotic risk factors. A cohort of 26,957 patients who had completed a baseline assessment before participating in an exercise-based cardiac rehabilitation program constituted the study population. The patients were stratified into 3 cohorts (i.e., nondepressed, depressed unmedicated, and depressed medicated) at baseline according to a self-reported history of depression and the current use of antidepressants. Risk factors were assessed at baseline and after ∼12 weeks of program participation. A self-reported history of depression was present at baseline in 5,172 patients (19.2%). Of these patients, 2,147 (41.5%) were taking antidepressants. Patients in the nondepressed cohort (49.4% completion) were more likely (p <0.001) to complete the exit assessment than patients in the depressed unmedicated (44.5% completion) or depressed medicated (43.5% completion) cohorts. Patients in all 3 cohorts who completed the exit assessment showed significant improvement in multiple risk factors. Moreover, the magnitude of improvement in blood pressure, serum lipids and lipoproteins, fasting glucose, weight, and body mass index was similar (p >0.05) in patients taking antidepressants and those who were not. In conclusion, our study is the first to show that antidepressants do not offset the average magnitude of improvement in multiple atherosclerotic risk factors that occurs with completion of a cardiac rehabilitation program.	f	\N
23179223	Exposomic studies of the rapidly changing environment of the Three Gorges Reservoir (TGR) after its impounding is elaborated as a novel field of human and environmental research. Molecular exposomics is focused on the measure of all exposures to molecules and especially persistent organic pollutants-like compounds are of emerging interest due to their lifetime existence in the environment and humans. Theoretical considerations in general and particular for the TGR are deduced and presented using quantitative approaches for this research field. Since exposomics is strongly time-dependent, a theory is presented to link extension of exposure, time, and related effects. Similarity to the first law of thermodynamics is outlined. On top of this, the integrated use of biomarkers is presented employing chemical analysis for biomarkers of exposure and effects, biomarkers in vivo, in vitro approaches and the link between chemical mixtures, and the onset of disease and lethality. Besides real organisms, also virtual organisms are favored to act as well-defined sub-compartments such as fat of biota and with respect to time of exposure. Exposomics is the perspective of risk evaluation and chronic exposures in the running century. It needs novel theories, approaches, and integrated action between medical and environmental disciplines. The existing knowledge about molecular stressors has to be assembled and put into a context especially with respect not only to time resp. lifetime exposure of humans but also eco-toxicological findings by using highly conserved phylogenetic mechanisms to enable links between human and risks of environmental biota. The TGR is a good example not only to employ biomonitoring of real but also virtual organisms due to the lack of established ecotopes in this changing environment so far. Progress in understanding long-term risks requires a proper theory as well as novel tools such as virtual organisms. On top, multidisciplinary approaches and the utilization of existing knowledge about the exposure of the environment and humans have to be merged and directed into mutual concepts. Effect-oriented and chemical analysis must be designed time-oriented to determine lifetime exposures of mankind and nature. Perspectively, a first attempt about exposomic theory and concepts is proposed and has to be developed experimentally further enclosing virtual besides of real organisms and compartments. Environmental and human exposomics have to be considered as a unified global issue in order to effectively utilize their mutual existing knowledge most effectively. The TGR is a challenging model system aiming this objective.	f	\N
23179576	In this study of 100,949 new users of oral bisphosphonates age ≥ 35 years, "early quitters" were found to differ from others with poor refill compliance in terms of socioeconomic, demographic, and treatment-related characteristics. New risk factors for poor compliance and persistence were identified. Poor compliance with anti-osteoporotic therapy is an on-going worldwide challenge. In this study, we hypothesized that "early quitters" differ in socioeconomics, demographics, co-medications, and comorbid conditions from other patients with low compliance. The study was a register-based nationwide cohort study of anti-osteoporotic therapy comprising 100,949 men and women. Statistical analysis including backward stepwise logistic regression analysis was used to explain causes of treatment failure and Kaplan-Meier survival analysis to estimate persistence of treatment. It was noted that 56.6 % of the patients were persistent and compliant, 4.7 % of the patients were persistent but "low compliant" while 38.7 % of the patients were "early quitters". "Early quitters" were found to differ in socioeconomics from "low compliant" patients. Differences concerning increased risk of "early quitters" were associated with high household income, subjects' age 71.9-79 years, living in the countryside or village, prior treatment with analgesics and anti-parkinson drugs, and dementia. Differences concerning decreased risk of "early quitters" were associated with male, living in an apartment, children living at home, living close to a university hospital, anti-osteoporotic therapy other than alendronate, number of drugs especially above three, pulmonary disease, collagen disease. The results suggest a need for improved support for patients to facilitate the interpretation of the disease and the perception of the benefits and risks of treatment-to reduce the risk of "early quitters". We were able to identify new risk groups that may be candidates for targeted actions.	f	\N
23198711	To examine the long-term relationships between costs, utilization, and patient-centered medical home (PCMH) clinical practice systems. Clinical practice systems were evaluated at baseline by the Physician Practice Connections-Research Survey (PPC-RS). Annual costs and utilization of a retrospectively constructed cohort of 58,391 persons receiving primary care at 1 of 22 medical groups over a 5-year period (2005-2009) were compared. Multivariate regressions adjusting for patient demographics, health status, and autoregressive errors compared PPC-RS scores and study outcomes for the entire cohort and 3 subcohorts defined by medical complexity (medication count 0-2 [n = 29,657], 2-6 [n = 19,505], >7 [n = 9229]). Outcomes (adjusted to 2005 dollars) were total costs, outpatient costs, inpatient costs, inpatient days, and emergency department (ED) use. For the entire cohort, a 10% increase in PPC-RS scores was associated with 3.9 (medication count: 0-2), 6 (3-6), and 11.6 (>7) fewer ED visits per 1000 in 2005; and 5.1, 7.6, and 13.6 fewer ED visits in 2009. That 10% increase was not associated with the 0-2 medication subcohort's total (-$22/person in 2005; $184/person in 2009), outpatient (-$11/person in 2005; $42/person in 2009), or inpatient ($26/person in 2005; $29/person in 2009) costs. However, it was associated with significantly decreased total (-$446/person in 2005; -$184/person in 2009) and outpatient (-$241/person in 2005; -$54/person in 2009) costs for the most medically complex subcohort (>7 medications). Association of PCMH clinical practice systems with reduced costs appears limited to the most medically complex patients.	f	\N
23199744	Due to their unique electric, magnetic, and optical properties, engineered nanostructures have been applied to provide diagnostic, therapeutic, as well as prognostic information about the status of disease. In this study, we report a multifunctional nanoprobe based on PEGylated Gd(2)O(3):Yb(3+), Er(3+) nanorods (denoted as PEG-UCNPs) for in vivo up-conversion luminescence (UCL), T(1)-enhanced magnetic resonance (MR), and X-ray computed tomography (CT) multi-modality imaging. A facile and large-scale hydrothermal system combining the merits of an in situ thermal decomposition method and a surface-modified approach is introduced to construct high-quality PEG-UCNPs. By grafting PEG molecules on the surface of PEG-UCNPs, the nanostructures possess excellent stability against in vivo environment and hold long blood circulation time. Cell-cytotoxicity assay, hemolyticity, as well as post-injection histology, hematology, and inflammation analysis further demonstrate their non-cytotoxic character and indicate further in vivo application. In detail, the capability of PEG-UCNPs as high-performance contrast agents for UCL/MR/CT imaging is evaluated successfully through small-animal experiments. Additionally, pharmacokinetics, biodistribution, and clearance route are studied after intravenous injection in a mouse model, reflecting their overall safety.	f	\N
23208668	The surgical lesion of different brain structures has been used as a treatment for Parkinson's disease (PD) for several decades. More recently, the favored therapeutic approach has involved the administration of levodopa and the use of DBS. These two major therapeutic advances have greatly modified both the clinical condition of patients and the history of the disease. With the introduction of L-dopa in 1967, patients could regain mobility, because their akinesia, tremor, and rigidity were greatly improved, with consequent significant improvement in quality of life and increased life expectancy. However, after the so-called "honeymoon" period in which the disease seemed to be controlled, motor fluctuations and L-dopa-induced dyskinesias mitigated the initial enthusiasm. In the 1990s, unilateral pallidotomy and DBS of the globus palllidus internus and STN reduced these motor fluctuations and dyskinesias remarkably, thereby inaugurating a new era in the surgical treatment of PD. Short- and medium-term follow-up studies of patients who underwent surgery have documented sustained, significant motor benefits. However, given the progressive nature of PD and the purely symptomatic effects of pallidotomy and DBS, the long-term clinical evolution of these surgical patients currently seems to be associated with a new PD phenotype, mainly characterized by axial motor problems and cognitive impairment. Here, we analyze the long-term clinical outcomes of surgical PD patients with at least 5-year follow-up, focusing on the long-term motor symptoms that were initially responsive to surgery.	f	\N
23216270	Although associations between autoimmune disorders (AIs) and the development of myeloid neoplasms have been described, the pathologic features and natural history of these malignancies have not been well characterized. We evaluated whether patients with AIs with acute myeloid leukemia (AML) were similar in nature to patients traditionally considered to have therapy-related AML (t-AML). Twenty-three patients with AML with a documented prior AI were included in our analysis. Median age at AML diagnosis was 59 years (range 32-78 years), and four patients were men (17%). Median latency between AI diagnosis and AML was 7.0 years. Ten patients (43%) had normal cytogenetics and six patients (26%) had favorable risk disease. In patients older than 65, all four patients had a normal karyotype. Median follow-up for all patients was 19.8 months (range 1.8-100.4 months), with 12 patients alive at last follow-up and median overall survival for all patients of 68.1 months. The encouraging survival data lend support to the notion that AML in patients with AIs appears to have characteristics and outcome more analogous to de novo than t-AML.	f	\N
23217354	MicroRNAs are endogenously expressed small noncoding RNAs that regulate gene expression at the post-transcriptional level. MicroRNAs have emerged as key regulators of several physiological and pathophysiological processes in the cardiovascular system. Aberrant expression of microRNAs has been implicated in the pathophysiological processes underlying the development of atherosclerosis and cardiovascular disease, including change in endothelial function, vascular smooth muscle cell proliferation and migration, macrophage function, and foam cell formation. In this review, we summarize the recent data showing the roles of microRNAs in cell studies, studies on atherosclerotic mice, and human studies.	f	\N
23219418	The appearance of liver metastases during the follow-up of a patient with a skin melanoma has classically been considered a sign of a very poor prognosis. There are limited therapeutic options, since these lesions are non-resectable and form part of a disseminated disease in several organs. In certain cases, in those where the disease is restricted to the liver or accompanied by a resectable extra-hepatic disease, hepatectomy can be useful, obtaining acceptable survivals of about 25% at 5 years, although hepatic or skin recurrence is usually early. The limited number of patient cases published, the absence of randomised studies, and the heterogeneity of the series, makes it difficult to reach conclusions to be able to recommend which patients may benefit from liver resection, with an acceptable level of scientific evidence, and thus define its real usefulness. There are also no action plans defined as to when and what type of adjuvant therapy we should use.	f	\N
23222568	The rarity of conjunctival melanoma has impeded progress in the management of patients with this cancer; however, much progress has occurred in recent years. Primary acquired melanosis is now differentiated histologically into hypermelanosis and conjunctival melanocytic intra-epithelial neoplasia, for which an objective reproducible scoring system has been developed. Mapping and clinical staging of conjunctival disease has improved. Adjunctive radiotherapy and topical chemotherapy have made tumour control more successful, with reduced morbidity. Genetic analyses have identified BRAF and other mutations, which may predict responsiveness to new chemotherapeutic agents, for example Vemurafenib, should metastatic disease develop. Multicentre studies are under way to enhance survival prediction by integrating clinical stage of disease with histological grade of malignancy and genetic abnormalities. Such improved prognostication would not only be more relevant to individual patients, but would also provide greater opportunities for basic science research.	f	\N
23222982	The study aimed to assess the efficacy of the adopted principles of the treatment of lung abscess without sequestration on the example of 2397 patients. Treatment led to the complete recovery in 1731 (72,2%) patients. The 614 (25,6%) patients showed the chronization of the process and 52 (2,2%) died. The surgical treatment of lung abscess without sequestration (performed in cases of uneffective conservative treatment) led to the complete recovery on 45.7% more often and the chronization of the process was registered on 26.8% more seldom, whereas the lethality rate was higher than by conservative treatment on 8%.	f	\N
23226290	MiRNAs are key regulators of tumorigenesis that are aberrantly expressed in the circulation and tissue of patients with cancer. The aim of this study was to determine whether miRNA dysregulation in the circulation reflected similar changes in tumour tissue. Athymic nude mice (n = 20) received either a mammary fat pad (n = 8, MFP), or subcutaneous (n = 7, SC) injection of MDA-MB-231 cells. Controls received no tumour cells (n = 5). Tumour volume was monitored weekly and blood sampling performed at weeks 1, 3 and 6 following tumour induction (total n = 60). Animals were sacrificed at week 6 and tumour tissue (n = 15), lungs (n = 20) and enlarged lymph nodes (n = 3) harvested. MicroRNAs were extracted from all samples (n = 98) and relative expression quantified using RQ-PCR. MiR-221 expression was significantly increased in tumour compared to healthy tissue (p<0.001). MiR-10b expression was significantly higher in MFP compared to SC tumours (p<0.05), with the highest levels detected in diseased lymph nodes (p<0.05). MiR-10b was undetectable in the circulation, with no significant change in circulating miR-221 expression detected during disease progression. MiR-195 and miR-497 were significantly decreased in tumour tissue (p<0.05), and also in the circulation of animals 3 weeks following tumour induction (p<0.05). At both tissue and circulating level, a positive correlation was observed between miR-497 and miR-195 (r = 0.61, p<0.001; r = 0.41, p<0.01 respectively). This study highlights the distinct roles of miRNAs in circulation and tissue. It also implicates miRNAs in disease dissemination and progression, which may be important in systemic therapy and biomarker development.	f	\N
23227561	We reviewed the tuberculosis (TB) surveillance database to determine the mode of detection, delays in achieving a TB diagnosis, and patients' occupational status upon registration. Of the 23,261 TB patients who were newly notified in 2010, 81.7% were diagnosed at medical institutions. Of these, 12.0% were diagnosed during hospitalisation with a disease other than TB, and 9.9% were diagnosed during outpatient visits with diseases other than TB. The overall proportion of TB cases detected by contact examination was only 2.8%, but this mode of detection was higher (56.1%) among younger TB patients aged 0-14 years. Of the 18,328 pulmonary TB patients, 27.3% had only respiratory symptoms, 31.0% had both respiratory and other symptoms, and 16.4% had only non-respiratory symptoms. Approximately one-quarter of elderly patients aged > or = 80 years with symptomatic pulmonary TB had only non-respiratory symptoms. pulmonary TB tended to have long total delays (the amount of time between the onset of symptoms and diagnosis). Among elderly patients, patient delays tended to be short, whereas doctor delays tended to be long. Of the 2,785 female pulmonary TB patients aged 20-59 years, 14.5% were medical workers and 10.4% of these were nurses.	f	\N
23251076	NK cells exhibit the highest cytotoxic capacity within the immune system. Alteration of their number or functionality may have a deep impact on overall immunity. This is of particular relevance in aging where the elderly population becomes more susceptible to infection, cancer, autoimmune diseases, and neurodegenerative diseases amongst others. As the fraction of elderly increases worldwide, it becomes urgent to better understand the aging of the immune system to prevent and cure the elderly population. For this, a better understanding of the function and phenotype of the different immune cells and their subsets is necessary. We review here NK cell functions and phenotype in healthy aging as well as in various age-associated diseases.	f	\N
23254356	Similar to T-helper (Th) cells, CD8(+) T cells also differentiate into distinct subpopulations. However, the existence of IL-9-producing CD8(+) T (Tc9) cells has not been elucidated so far. We show that murine CD8(+) T cells activated in the presence of IL-4 plus TGF-β develop into transient IL-9 producers characterized by specific IFN-γ and IL-10 expression patterns as well as by low cytotoxic function along with diminished expression of the CTL-associated transcription factors T-bet and Eomesodermin. Similarly to the CD4(+) counterpart, Tc9 cells required for their differentiation STAT6 and IRF4. Tc9 cells deficient for these master regulators displayed increased levels of Foxp3 that in turn suppressed IL-9 production. In an allergic airway disease model, Tc9 cells promoted the onset of airway inflammation, mediated by subpathogenic numbers of Th2 cells. This support was specific for Tc9 cells because CTLs failed to exert this function. We detected increased Tc9 frequency in the periphery in mice and humans with atopic dermatitis, a Th2-associated skin disease that often precedes asthma. Thus, our data point to the existence of Tc9 cells and to their supportive function in Th2-dependent airway inflammation, suggesting that these cells might be a therapeutic target in allergic disorders.	f	\N
23254704	Organ transplantation and other major surgeries are impacted by ischemia-reperfusion injury (IRI). Mesenchymal stromal cells (MSCs) recently became an attractive alternative therapeutic tool to combat IRI. The present review highlights the effects of MSCs in the preclinical animal models of IRI and clinical trials, and explains their potential modes of action based on the pathophysiological IRI cascade. The application of MSCs in animal models of IRI show anti-inflammatory and anti-apoptotic effects, particularly for damage to the kidneys, heart and lungs. The mechanism of MSC action remains unclear, but may involve paracrine factors which could include the transfer of microvesicles, RNA or mitochondria. Although few clinical trials have reached completion, adverse effects appear minimal. MSCs show promise in protecting against IRI-induced damage. They appear to help recovery mainly by affecting the levels of inflammation and apoptosis during the organ repair process. In addition, they may mediate immunomodulatory effects on the innate and adaptive immune processes triggered during reperfusion and reduce fibrosis. Success in preclinical animal models has led to the initiation of ongoing clinical trials.	f	\N
23265076	Diabetes is an important contributor to the burden of disease in South Africa and prevalence rates as high as 33% have been recorded in Cape Town. Previous studies show that quality of care and health outcomes are poor. The development of an effective education programme should impact on self-care, lifestyle change and adherence to medication; and lead to better control of diabetes, fewer complications and better quality of life. Pragmatic cluster randomized controlled trialParticipants: Type 2 diabetic patients attending 45 public sector community health centres in Cape TownInterventions: The intervention group will receive 4 sessions of group diabetes education delivered by a health promotion officer in a guiding style. The control group will receive usual care which consists of ad hoc advice during consultations and occasional educational talks in the waiting room. To evaluate the effectiveness of the group diabetes education programmeOutcomes: diabetes self-care activities, 5% weight loss, 1% reduction in HbA1c. self-efficacy, locus of control, mean blood pressure, mean weight loss, mean waist circumference, mean HbA1c, mean total cholesterol, quality of lifeRandomisation: Computer generated random numbersBlinding: Patients, health promoters and research assistants could not be blinded to the health centre's allocationNumbers randomized: Seventeen health centres (34 in total) will be randomly assigned to either control or intervention groups. A sample size of 1360 patients in 34 clusters of 40 patients will give a power of 80% to detect the primary outcomes with 5% precision. Altogether 720 patients were recruited in the intervention arm and 850 in the control arm giving a total of 1570. The study will inform policy makers and managers of the district health system, particularly in low to middle income countries, if this programme can be implemented more widely. Pan African Clinical Trial Registry PACTR201205000380384.	f	\N
23268170	Kawasaki disease is a common paediatric vasculitide. It is usually diagnosed by its classical constellation of mucocutaneous signs. Recurrent Kawasaki disease is a rare phenomenon that occurs in approximately 3% of all patients diagnosed with Kawasaki disease. Its presentation is usually similar to the first episode of Kawasaki disease, and early diagnosis with prompt treatment is key in preventing associated cardiovascular morbidities. Recurrent Kawasaki disease is not well reported, and atypical presentations have not been previously reported in medical literature. Here, we report the case of a young girl with recurrent Kawasaki disease who presented atypically with acute airway obstruction secondary to retropharyngeal phlegmon.	f	\N
23275389	To determine the longitudinal effects of TNF inhibitors on BMD and radiographic progression in patients with AS and to assess independent factors associated with increased BMD in the lumbar spine. Sixty-three patients with AS were included. Twenty-six patients were treated with TNF inhibitors and 37 were not. BMD in the lumbar spine and right femur was measured by DXA at baseline and 1 and 2 years later. Lumbar spine radiography was performed at baseline and after 2 years. Radiographic progression was scored using the Stoke AS Spinal Score (SASSS) and the modified SASSS. Univariate and multivariate linear regression analyses were performed to identify factors independently associated with spinal BMD increase. BMD in the lumbar spine and total proximal femur of patients receiving TNF inhibitors increased consistently over 2 years compared with that in patients not receiving TNF inhibitors (P < 0.01 and P = 0.02), and treated patients showed increased SASSS scores (P = 0.05); however, syndesmophyte development was no different between the two groups. There was a significant difference in the change of SASSS in patients treated with both TNF inhibitors and bisphosphonates compared with those treated with TNF inhibitors alone (P < 0.01). TNF inhibitor therapy and the increase in SASSS were independently associated with increased lumbar spine BMD (P = 0.009 and P < 0.001). TNF inhibitors appear to be associated with increased SASSS scores and improvements in BMD. Further prospective studies with larger subject numbers are needed to validate this paradoxical role of TNF inhibitors.	f	\N
23278140	In contrast to adolescent acne, infantile acne (IA) is a rare condition with only a limited body of available literature. In this descriptive, retrospective study, we reviewed six cases from 2002 to 2010 treated with oral isotretinoin. The average age of onset was 6.16 months (range 0-21 mos). Consistent with the previous, limited literature, we found predominantly boys are affected, a predilection for the cheeks, and a polymorphic inflammatory morphology. Two patients had a family history of acne. All cases were successfully and safely treated with oral isotretinoin. The suggested treatment of childhood acne is similar to that of adolescents (graded according to the severity of the skin disease and risk of scarring). Oral isotretinoin appears to be an effective and safe treatment for severe IA.	f	\N
23280098	Influenza A viruses circulating in pigs in Brazil are still not characterized, and only limited data are available about swine influenza epidemiology in the country. Therefore, we characterized the hemagglutinin (HA) and neuraminidase (NA) genes of influenza viruses isolated from Brazilian pigs. We also evaluated one case of probable swine-to-human transmission. Twenty influenza viruses isolated from pigs during 2009-2010 in five Brazilian states (Minas Gerais, Sao Paulo, Parana, Rio Grande do Sul, and Mato Grosso) were used. One human isolate, from a technician who became ill after visiting a swineherd going through a respiratory disease outbreak, was also used in the study. Phylogenetic analysis for the HA and NA genes and hemagglutinin amino acid sequence alignment were performed. All isolates clustered with pandemic H1N1 2009 (pH1N1) viruses and appeared to have a common ancestor. Genetic diversity was higher in the HA than in the NA gene, and the amino acid substitution S203T in one of HA's antigenic sites was found in most of the samples. The human isolate was more related to swine isolates from the same herd visited by the technician than to other human isolates, suggesting swine-to-human transmission. Our results show that pH1N1 was disseminated and the predominant subtype in Brazilian pigs in 2009-2010.	f	\N
23284040	Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is one of the two established Hodgkin lymphoma (HL) subtypes. The risk factors of NLPHL are largely unknown. In general, genetic factors are known to have a modest effect on the risk of HL; however, familial risk in NLPHL has not been previously examined. We conducted a population-based study by using the Finnish registries and evaluated the familial risk in NLPHL. We launched a population-based search to identify patients with NLPHL and their relatives by examining the records of the Finnish Cancer Registry, established in 1953, and the official Finnish population registries. We collected a data set of 692 patients with NLPHL, identified their 4,280 first-degree relatives, and calculated the registry-based standardized incidence ratios (SIRs) for different cancers in the first-degree relatives. In addition, the primary tumor biopsies of HL-affected relatives were collected when possible, the HL diagnoses were re-reviewed by a hematopathologist, and the SIR for NLPHL was calculated on the basis of confirmed NLPHL diagnoses. On the basis of confirmed NLPHL diagnoses, the SIR for NLPHL was 19 (95% CI, 8.8 to 36) in the first-degree relatives. The risk was most prominent in female relatives of young patients. The registry-based SIR for classical HL was 5.3 (95% CI, 3.0 to 8.8), and for non-Hodgkin lymphoma, it was 1.9 (95% CI, 1.3 to 2.6). Our results implicate an unexpectedly high familial component in the development of NLPHL. Research is warranted to identify the putative genetic and environmental factors underlying this finding and to develop strategies for better management of patients with NLPHL and their relatives.	f	\N
23293016	Kawasaki disease (KD) is a systemic inflammatory illness of childhood that particularly affects the coronary arteries. It can lead to coronary artery aneurysms, myocardial infarction, and sudden death. Clinical and epidemiologic data support an infectious cause, and the etiology remains unknown, but recent data support infection with a 'new' virus. Genetic factors influence KD susceptibility; the incidence is 10-fold higher in children of Asian when compared with Caucasian ethnicity. Recent research has identified genes affecting immune response that are associated with KD susceptibility and outcome. A re-examination of the pathologic features of KD has yielded a three process model of KD vasculopathy, providing a framework for understanding the KD arterial immune response and the damage it inflicts and for identifying new therapeutic targets for KD patients with coronary artery abnormalities. The researcher is faced with many challenges in determining the pathogenesis of KD. A systems biology approach incorporating genomics, proteomics, transcriptomics, and microbial bioinformatics analysis of high-throughput sequence data from KD tissues could provide the keys to unlocking the mysteries of this potentially fatal illness of childhood.	f	\N
23295556	To describe the course and management of a protracted outbreak after intercontinental transfer of 2 patients colonized with multidrug-resistant Acinetobacter baumannii (MDRAB). An 18-month outbreak investigation. An 860-bed university hospital in France. Case patients (ie, carriers) were those colonized or infected with an MDRAB isolate. During the epidemic period, all intensive care unit (ICU) patients and contacts of carriers who were transferred to wards were screened for MDRAB carriage. Contact precautions, environmental screening, and auditing of healthcare worker (HCW) practices were implemented; rooms were cleaned with hydrogen peroxide mist disinfection. One ICU, in which most of the cases occurred, was closed on 4 occasions for thorough cleaning and disinfection. The 2 index case patients were identified as 2 patients who carried the same MDRAB strain and who were admitted to the hospital after repatriation from Tahiti 5 months apart. During an 18-month period, a total of 84 secondary cases occurred. Reintroduction of MDRAB into the ICUs occurred from patients previously colonized or from healthcare personnel. Termination of the outbreak was only achieved when all carriers from wards or the ICU were cohorted to an isolation unit with dedicated healthcare personnel. Intercontinental transfer of carriers of MDRAB can result in extensive outbreaks and serious disruption of the hospital's organization. Transmission from carriers most likely occurred via the hands of HCWs, poor cleaning protocols, airborne spread, and contaminated water from sink traps. This protracted outbreak was controlled only after implementation of an extensive control program and eventual cohorting of all carriers in an isolation unit with dedicated healthcare personnel.	f	\N
23296696	Previously, most dengue cases in Singapore were hospitalized despite low incidence of dengue hemorrhagic fever (DHF) or death. To minimize hospitalization, the Communicable Disease Centre at Tan Tock Seng Hospital (TTSH) in Singapore implemented new admission criteria which included clinical, laboratory, and DHF predictive parameters in 2007. All laboratory-confirmed dengue patients seen at TTSH during 2006-2008 were retrospectively reviewed for clinical data. Disease outcome and clinical parameters were compared over the 3 years. There was a 33.0% mean decrease in inpatients after the new criteria were implemented compared with the period before (p < 0.001). The proportion of inpatients with DHF increased significantly from 31.7% in 2006 to 34.4% in 2008 (p = 0.008); 68 DHF cases were managed safely on an outpatient basis after compared with none before implementation. DHF inpatients had more serious signs such as clinical fluid accumulation (15.5% vs 2.9% of outpatients), while most DHF outpatients had hypoproteinemia (92.7% vs 81.3% of inpatients). The eight intensive care unit admissions and five deaths during this time period all occurred among inpatients. The new criteria resulted in a median cost saving of US$1.4 million to patients in 2008. The new dengue admission criteria were effective in sustainably reducing length of hospitalization, yielding considerable cost savings. A minority of DHF patients with mild symptoms recovered uneventfully through outpatient management.	f	\N
23301916	Wiskott-Aldrich syndrome (WAS) is a rare X-linked recessive disease characterized by eczema, thrombocytopenia and immune deficiency. WAS gene mutations impair WAS protein function which cause WAS. The WAS-related disorders of X-linked thrombocytopenia (XLT) and X-linked congenital neutropenia (XLN) may have similar but less severe symptoms those are also caused by mutations of the same gene. We present two cases of WAS in neonates with WAS gene mutations. Early genetic diagnosis can help to the treatment and prevention this disease.	f	\N
23313927	Mexican Americans are the fastest aging segment of the U.S. population, yet little scientific literature exists regarding the Alzheimer's disease (AD) among this segment of the population. The extant literature suggests that biomarkers of AD will vary according to race/ethnicity though no prior work has explicitly studied this possibility. The aim of this study was to create a serum-based biomarker profile of AD among Mexican American. Data were analyzed from 363 Mexican American participants (49 AD and 314 normal controls) enrolled in the Texas Alzheimer's Research & Care Consortium (TARCC). Non-fasting serum samples were analyzed using a luminex-based multi-plex platform. A biomarker profile was generated using random forest analyses. The biomarker profile of AD among Mexican Americans was different from prior work from non-Hispanic populations with regards to the variable importance plots. In fact, many of the top markers were related to metabolic factors (e.g., FABP, GLP-1, CD40, pancreatic polypeptide, insulin-like-growth factor, and insulin). The biomarker profile was a significant classifier of AD status yielding an area under the receiver operating characteristic curve, sensitivity, and specificity of 0.77, 0.92, and 0.64, respectively. Combining biomarkers with clinical variables yielded a better balance of sensitivity and specificity. The biomarker profile for AD among Mexican American cases is significantly different from that previously identified among non-Hispanic cases from many large-scale studies. This is the first study to explicitly examine and provide support for blood-based biomarkers of AD among Mexican Americans. Areas for future research are highlighted.	f	\N
23316660	Polyarteritis nodosa (PAN) is a multi-system disease, characterized by necrotizing vasculitis of medium-sized arteries that may affect any organ system. Cutaneous PAN is the cutaneous limited form of PAN. It affects 10% of all cases of PAN and usually demonstrates a benign and chronic course. We hereby describe a 47-year-old female with diabetes mellitus who presented with painful ulcers on both legs. The clinical and histological findings were consistent with PAN. A thorough investigation ruled out systemic PAN and cutaneous PAN was determined. Despite intensive therapies including corticosteroids and azathioprine, marked progression of the ulcers was noted and large areas of necrosis appeared. The patient underwent above-knee amputation of both legs and eventually died in less than three years. Although cutaneous PAN is known to have a benign and chronic course, we have presented an unusual progressive and severe course that resulted in the death of the patient.	f	\N
23324593	An under-appreciated clue about pathogenesis in Parkinson disease (PD) is the distribution of pathology in the early and middle stages of the disease. This pathological 'roadmap' shows that in addition to dopaminergic neurons in the substantia nigra pars compacta (SNc), a significant number of other central and peripheral neuronal populations exhibit Lewy pathology, phenotypic dysregulation or frank degeneration in PD patients. This spatially distributed, at-risk population of neurons shares a number of features, including autonomously generated activity, broad action potentials, low intrinsic calcium buffering capacity and long, poorly myelinated, highly branched axons. Many, and perhaps all, of these traits add to the metabolic burden in these neurons, suggesting that mitochondrial deficits could drive pathogenesis in PD-in agreement with a large segment of the literature. What is less clear is how this neuronal phenotype might shape the susceptibility to proteostatic dysfunction or to the spread of α-synuclein fibrils deposited in the extracellular space. The review explores the literature on these issues and their translational implications.	f	\N
23327371	Over the past few decades a large number of new and emerging infectious diseases have been recognised in humans, partly because of improved diagnostic technologies and increased awareness and also, partly because of dynamic ecological changes between human hosts and their exposure to animals and the environment (Coker et al. 2011). Some 177 new pathogenic organisms have been recognised to be 'emerging', that is, have newly arisen or been newly introduced into human populations; almost three quarters of these, 130 (73%), have come from zoonotic origins (Cascio et al. 2011; Cutler, Fooks &amp; Van Der Poel 2010; Taylor, Latham &amp; Woolhouse 2001; Woolhouse &amp; Gowtage-Sequeria 2005). One of the most prevalent and important human infectious disease is influenza, a disease responsible globally for a quarter million deaths annually. In the USA alone the toll from influenza is estimated at 36 000 deaths and 226 000 hospitalisations, and it ranks as the most important cause of vaccine preventable mortality in that country (CDC 2010). The epidemiological behaviour of human influenza clearly defines it as an emerging infectious disease and the recent understanding of its zoonotic origins has contributed much to the understanding of its behaviour in humans (Fauci 2006).	f	\N
23330027	Acute rheumatic fever (ARF) and rheumatic heart disease (RHD) constitute important public health problems in developing countries. Children with ARF and RHD seen at Children's Hospital-Sudan from May 2008-2009 were examined clinically and by echocardiography. Blood cytokines (interleukin 10 (IL10), Tumor necrosis factor alpha (TNF- alpha) and interferon gamma (IFN-gamma) were done. Thirty six children were enrolled; 63% had established RHD, and 37% ARF. Mitral regurgitation (MR) was the most common lesion (94%).Ninety five percent of the valve lesions were severe. The serum interleukin IL10 level ranged between 3-6 pg/ml. TNF alpha levels were 9- 100 pg/ml in 12 patients (40%), 101-1000 pg/ml in 10 patients (33%), more than 1000 in 8 patients (26%). The level of IFN gamma ranged between 2-7 pg/m in all patients except 2 (84 and 135 pg/ml). RHD is manifested with severe valvular lesions and a high TNF alpha indicating and ongoing inflammation.	f	\N
23330952	The authors present 1-year results in 60 patients with cervical radiculopathy due to spondylosis and stenosis that was treated with a bilateral percutaneous facet implant. The implant consists of a screw and washer that distracts and immobilizes the cervical facet for root decompression and fusion. Clinical and radiological results are analyzed. Between 2009 and 2011, 60 patients were treated with the DTRAX Facet System in a multicenter prospective single-arm study. All patients had symptomatic clinical radiculopathy, and conservative management had failed. The majority of patients had multilevel radiographically confirmed disease. Only patients with single-level radiculopathy confirmed by history, physical examination, and in some cases confirmatory nerve blocks were included. Patients were assessed preoperatively with Neck Disability Index, visual analog scale, quality of life questionnaire (Short Form-12 version 2), CT scans, MRI, and dynamic radiographs. Surgery was percutaneous posterior bilateral facet implants consisting of a screw and expandable washer and iliac crest bone aspirate. Patients underwent postoperative assessments at 2 weeks, 6 weeks, 3 months, 6 months, and 1 year with validated outcome questionnaires. Alterations of segmental and overall cervical lordosis, foraminal dimensions, device retention and fusion criteria were assessed for up to 1 year with CT reconstructions and radiographs. Fusion criteria were defined as bridging trabecular bone between the facets, translational motion < 2 mm, and angular motion < 5°. All patients were followed to 1 year postoperatively. Ages in this cohort ranged from 40 to 75 years, with a mean of 53 years. Forty-two patients were treated at C5-6, 8 at C6-7, 7 at C4-5, and 3 at C3-4. Fifty-six had bilateral implants; 4 had unilateral implants due to intraoperative facet fracture (2 patients) and inability to access the facet (2 patients). The Neck Disability Index, Short Form-12 version 2, and visual analog scale scores were significantly improved at 2 weeks and remained significantly improved up to 1 year. At the treated level, 93% had intrafacet bridging trabecular bone on CT scans, translational motion was < 2 mm in 100% and angular movement was < 5° in 83% at the 1-year follow-up. There was no significant change in overall cervical lordosis. There was a 1.6° loss of segmental lordosis at the treated level at 1 year that was significant. Foraminal width, volume, and posterior disc height was significantly increased at 6 months and returned to baseline levels at 1 year. There was no significant decrease in foraminal width and height at adjacent levels. There were no reoperations or surgery- or device-related complications, including implant failure or retained hardware. Results indicate that the DTRAX Facet System is safe and effective for treatment of cervical radiculopathy.	f	\N
23336917	The use of ventricular assist devices in patients with complex congenital heart disease has not been well described. We present a case of successful ventricular assist device support in a 38-year-old man with congenitally corrected transposition of the great arteries and severe secondary pulmonary hypertension.	f	\N
23338998	The aim of this study was to verify if genetic factors influence the short- and long-term therapeutic responses to oestroprogestagen (OP) therapy, implemented in girls with functional hypothalamic amenorrhoea (FHA) in order to improve their bone mineral density (BMD). The study included 78 FHA girls who underwent a four-year sequential OP therapy with 17-beta oestradiol and didrogesterone. Changes in the lumbar spine BMD were determined at the end of the therapy and six years after its discontinuation, and analysed in regards to PvuII and XbaI polymorphisms of oestrogen receptor-alpha gene, BsmI polymorphism of vitamin D3 receptor gene, and Sp1 polymorphism of the type-1 collagen gene. After four years of OP therapy, a significant increase in BMD was documented in the studied group. Follow-up densitometry performed six years after completing the therapy revealed a significant decrease in BMD level; nonetheless, the values of this parameter were still significantly higher compared to pretreatment level. Neither the particular polymorphisms nor their combinations influenced the relative change in BMD at the end of the therapy and after a six-year follow-up. Variability of genes involved in oestrogen, vitamin D3 and collagen metabolism does not influence the short- and long-term results of OP therapy in girls with FHA.	f	\N
23344286	Preeclampsia complicates approximately 3-5% of pregnancies and remains one of the major causes of maternal and neonatal morbidity. It shares pathogenic similarities with adult cardiovascular disease as well as many risk factors. Attempts at prevention of preeclampsia using various supplements and classes of medications have failed or had limited success, and they were not convincing enough to lead to widespread adoption of any particular strategy. Contrary to the experience with preeclampsia, prevention of cardiovascular mortality and other cardiovascular events in nonpregnant patients using 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors, or statins, is widely accepted. Pravastatin and other statins have been shown to reverse various pathophysiologic pathways associated with preeclampsia, such as angiogenic imbalance, endothelial injury, inflammation, and oxidative stress. These beneficial effects are likely to contribute substantially to preventing preeclampsia and provide biological plausibility for the use of pravastatin in this setting. Pravastatin has favorable safety and pharmacokinetic profiles. In addition, animal studies and human pregnancy exposure data do not support teratogenicity claims for pravastatin. Therefore, the Eunice Kennedy Shriver National Institute of Child Health and Human Development Obstetric--Fetal Pharmacology Research Units Network started a pilot trial to collect maternal--fetal safety data and to evaluate pravastatin pharmacokinetics when used as a prophylactic daily treatment in high-risk pregnant women (identifier NCT01717586, clinicaltrials.gov).	f	\N
23346802	The purpose of this article was to describe the phenomena related to the mechanisms regulating alterations of vascular blood flow in ophthalmic and retrobulbar circulation. In this review, various indirect and direct methods of evaluating retinal blood flow have been discussed. Laser, contrast and ultrasonographic techniques, including color Doppler ultrasonography, electroretinography, electroencephalography, calorimetric investigations, with the radiographic entities and registering changes in tunica vasculosa circulation were described. Additionally, radiographic investigations, isometric measurements and studies with the use of pharmacological agents, evaluation of partial pressure of oxygen or carbon dioxide in both inhaled and exhaled air, and in daylight as well as in darkness were presented. Although there are many control methods of regulating mechanisms of bulbar circulation, none of those techniques used presently and in the past is ideal, hence the only investigations widely applied for this purpose have been both Doppler ultrasonography and laser methods. In the review influence of myogenic and neurogenic mechanisms on blood flow in eyeball was described. Moreover, the part of vessels coarcting and dilating substances in these hemodynamic phenomena has been included. In the course of various ophthalmic disease entities of vascular origin, different substances take part in general and local regulation of ocular and retrobulbar circulation, whose action mechanism might be the cause of hemodynamic disorders. Color Doppler ultrasonography remains one of the more frequently used methods which could indirectly register alterations of vascular blood flow in retrobulbar arteries.	f	\N
23347399	Methcathinone abuse is a new cause of manganism. The psychostimulant is prepared from pseudoephedrine using potassium permanganate as an oxidant. We describe the clinical, biological, neuroimaging characteristics and follow-up results in a large Estonian cohort of intravenous methcathinone users. During 2006-2012 we studied 38 methcathinone abusers with a mean age of 33 years. Subjects were rated by the Unified Parkinson's Disease Rating Scale (UPDRS), Hoehn and Yahr (HY), and Schwab and England (SE) rating scales. Twenty-four cases were reassessed 9-70 (20 ± 15) months after the initial evaluation. Manganese (Mn) in plasma and hair was analysed by inductively coupled plasma-atom emission spectrometry. Magnetic resonance imaging (MRI) was performed in 11, and single-photon emission computed tomography (SPECT) with iodobenzamide (IBZM) in eight subjects. The average total UPDRS score was 43 ± 21. The most severely affected domains in UPDRS Part III were speech and postural stability, the least affected domain was resting tremor. At follow-up there was worsening of HY and SE rating scales. Subjects had a higher mean level of Mn in hair (2.9 ± 3.8 ppm) than controls (0.82 ± 1.02 ppm), P = 0.02. Plasma Mn concentrations were higher (11.5 ± 6.2 ppb) in active than in former users (5.6 ± 1.8 ppb), P = 0.006. Active methcathinone users had increased MRI T1-signal intensity in the globus pallidus, substantia nigra and periaquaductal gray matter. IBZM-SPECT showed normal symmetric tracer uptake in striatum. Methcathinone abusers develop a distinctive hypokinetic syndrome. Though the biomarkers of Mn exposure are characteristic only of recent abuse, the syndrome is not reversible.	f	\N
23347458	We compared values of baseline serum cystatin C (SCysC), serum creatinine (SCr), and measured glomerular filtration rate (mGFR) for predicting end-stage renal disease (ESRD) in patients with type 2 diabetes and elevated albuminuria. Observational longitudinal study. Pima Indians with type 2 diabetes and elevated albumin-creatinine ratio (ACR ≥30 mg/g). Baseline SCysC, SCr, and mGFR. Individuals were followed up from their first examination with diabetes and ACR ≥30 mg/g until December 2010, onset of ESRD, or death, whichever came first. Incidence rates adjusted for age and sex were computed by Mantel-Haenszel stratification. The abilities of SCysC, SCr, and mGFR values to predict ESRD were compared with receiver operating characteristic curves. Of 234 Pima Indians with a mean age of 42.8 years who were followed up for a median of 10.7 (range, 0.6-21.3) years, 68 (29%) developed ESRD. The incidence of ESRD was significantly higher in patients in the lowest versus highest tertile of 1/SCysC (incidence rate ratio, 2.43; 95% CI, 1.31-4.50). By contrast, mGFR and 1/SCr had J-shaped associations with ESRD. In unadjusted analyses, 1/SCysC had the highest area under the receiver operating characteristic curve (AUROC; 0.719 ± 0.035) and mGFR had the lowest (0.585 ± 0.042; P < 0.001); the AUROC for 1/SCr was intermediate (0.672 ± 0.040; P = 0.1 and P = 0.03 vs 1/SCysC and mGFR, respectively). In analyses adjusted for age, sex, diabetes duration, height, weight, hemoglobin A1c level, and ACR, 1/SCysC had the highest AUROC (0.845 ± 0.026). Models with mGFR or 1/SCr alone had similar AUROCs (P = 0.9) and both were lower than the model with 1/SCysC alone (P = 0.02 and P = 0.03, respectively). The predictive values of the filtration markers are limited to the extent that their precision is based on a single measurement. SCysC level was a better predictor of ESRD than mGFR or SCr level in Pima Indians with type 2 diabetes and elevated albuminuria.	f	\N
23354259	The surgical treatment of acute colonic diverticulitis is associated with significant morbidity and mortality. However, patient and operative characteristics associated with mortality in this patient population are unclear. We hypothesize that demographic and perioperative variables can be used to predict postoperative mortality.The purpose of this study was to identify perioperative variables predictive of postoperative mortality after emergent surgery for acute diverticulitis. Patients with diverticulitis undergoing colostomy and/or partial colectomy with or without primary anastomosis were retrieved from the American College of Surgeons National Surgical Quality Improvement Program database for years 2005 to 2008 inclusive. Only patients undergoing emergent surgery for acute diverticulitis were included. Univariate analyses were performed to compare demographic characteristics, preoperative laboratory values, comorbidities, and intraoperative variables. Variables with a significant (p < 0.10) difference between survivors and nonsurvivors were included in a stepwise logistic regression model to determine predictors of 30-day mortality. Concordance indices (c indices) for postoperative mortality were calculated using 2005 to 2008 data to determine predictive accuracy and validated on 2009 data. A total of 2,214 patients met inclusion criteria. Mean age was 61 years, and 50% of patients were male. Thirty-day mortality was 5.1%. Nine preoperative variables were significantly associated with postoperative mortality on multivariable analysis. The c index of this nine-variable model was 0.901. Renal dysfunction, hypoalbuminemia, American Society of Anesthesiologists class, and age were chosen to create a simpler model, with a c index of 0.886 for 2005 to 2008 data and 0.893 for 2009 data. Four readily available perioperative variables can be used to predict 30-day mortality after emergent surgery for acute diverticulitis. Prognostic study, level II.	f	\N
23379818	MicroRNAs (miRNAs) are small noncoding RNAs that not only regulate gene expression during normal development but can also be active players in several diseases. To date, several studies have demonstrated a possible role for specific miRNAs in the regulation of pulmonary vascular homeostasis suggesting that novel therapeutic agents which target these modulators of gene expression could serve to treat pulmonary arterial hypertension (PAH). The characterization of miRNA-mediated gene modulation in the pulmonary circulation is expanding very rapidly. This review summarizes current relevant findings on the role of miRNAs in the pathogenesis of PAH and expands on the potential use of agents that target these molecules as future disease-modifying therapies. Further understanding of miRNA biology and function in the pulmonary circulation will serve to further enhance our understanding of their contribution to the pathogenesis of PAH. The implementation of a systems biology approach will help accelerate the discovery of miRNAs that influence angiogenesis and cellular responses to vascular injury. Experimental characterization of these miRNAs using in vitro and in vivo methods will be required to validate the biological roles of these miRNAs prior to the consideration of their use as therapeutic targets in future clinical trials.	f	\N
23382786	CXCR4 is a G-protein-coupled receptor involved in a number of physiological processes in the hematopoietic and immune systems. The SDF-1/CXCR4 axis is significantly associated with several diseases, such as HIV, cancer, WHIM syndrome, rheumatoid arthritis, pulmonary fibrosis and lupus. For example, CXCR4 is one of the major co-receptors for HIV entry into target cells, while in cancer it plays an important role in tumor cell metastasis. Several promising CXCR4 antagonists have been developed to block SDF-1/CXCR4 interactions that are currently under different stages of development. The first in class CXCR4 antagonist, plerixafor, was approved by the FDA in 2008 for the mobilization of hematopoietic stem cells and several other drugs are currently in clinical trials for cancer, HIV, and WHIM syndrome. While the long-term safety data for the first generation CXCR4 antagonists are not yet available, several new compounds are under preclinical development in an attempt to provide safer and more efficient treatment options for HIV and cancer patients.	f	\N
23389330	Childhood tuberculosis (TB) accounts for a significant proportion of the global tuberculosis disease burden. However, current and previous efforts to develop better diagnostic, therapeutic, and preventive interventions have focused on TB in adults, and childhood TB has been relatively neglected. The purpose of this review is to provide an update on the diagnostic and therapeutic recommendations for childhood TB with an emphasis on intrathoracic disease. The literature from a range of sources was reviewed and synthesized to provide an overview of the contemporary approaches for the diagnosis and treatment of childhood TB. This review summarizes the clinical, radiological, bacteriological, and immunological approaches to diagnose TB infection and disease in children. In addition, we summarize the updated guidelines for the treatment of TB in children. The development of better diagnostic and therapeutic methods for childhood TB remains a significant challenge. As the strategies for diagnosis and treatment of childhood TB continue to improve and the knowledge base increases, the implementation of these strategies will be crucial.	f	\N
23393912	The most common autosomal form of Chronic Granulomatous Disease, p47-phox deficient CGD, generally features a GT (deltaGT) deletion in the GTGT sequence at the start of exon 2 on the NCF-1 gene. This consistency is due to the coexistence of and the recombination between 2 homologous pseudogenes (psi s) and NCF-1. The GTGT: deltaGT ratio mirrors the NCF-I: NCF-1 psi ratio and is 2:4 in normal individuals. To determine the molecular basis of the Autosomal-CGD in a family with 2 children, a male and female, affected by the disease. The female patient suffered recurrent infection, retinitis pigmentosa and discoid lupus. Chemiluminescence (CL) was used to study the respiratory burst, while genetic analysis was done by RT-PCR, PCR, deltaGT and the 20bp gene scans. The CL response of the patient was profoundly low. The patient's p47-phox band was absent in the RT-PCR for NADPH-oxidase component mRNAs. The deltaGT scan showed that the patient's GTGT: deltaGT ratio was 0:6, the parents' and the younger brother's was 1:5 and the younger sister's was 2:4. Examination of other NCF-1/ NCF-1 psi s differences showed that the father had a compound deltaGT allele ie. deltaGT-20bp, inherited by the patient, and that both parents had compound GTGT alleles with a single 30bp segment in intron 1. The patient was a classic, homozygous deltaGT p47-phox deficient CGD with one allele harbouring a compound deltaGT-20bp gene. The deltaGT and 20bp gene scans offer a relatively simple and efficient means of defining a p47-phox deficient CGD patient.	f	\N
23394360	Acute kidney injury (AKI) is common in hospitalized human immunodeficiency virus (HIV)-infected patients and is associated with hospital mortality. We aimed to evaluate the impact of AKI on long-term mortality of hospitalized HIV-infected patients. Retrospective analysis of a cohort of 433 hospitalized HIV-infected patients who were discharged alive from the hospital. AKI was defined according to 'Risk Injury Failure Loss of kidney function End-stage kidney disease' creatinine criteria, as an increase of baseline serum creatinine (SCr) X 1.5 or in patients with baseline SCr > 4 mg/dL if there was an acute rise in SCr of at least 0.5 mg/dL. Cumulative mortality curves were determined by the Kaplan-Meier method, and log-rank test was employed to analyze statistically significant differences between curves. Cox regression method was used to determine independent predictors of mortality. Risk factors were assessed with univariate analysis, and variables that were statistically significant (P < 0.05) in the univariate analysis were included in the multivariate analysis. Sixty-four patients (14.8%) had AKI. Median follow-up was 37 months. At follow-up 81 patients (18.7%) died. At 1, 2 and 5 years of follow-up, the cumulative probability of death of patients with AKI was 21.2, 25 and 31.3%, respectively, as compared with 10, 13.3 and 16.5% in patients without AKI (log-rank, P = 0.011). In multivariate analysis AKI was associated with increased mortality (adjusted HR 1.7, 95% CI 1.1-3; P = 0.049). AKI was independently associated with long-term mortality of hospitalized HIV-infected patients.	f	\N
23394995	Maintenance of an adequate and properly regulated immune system is essential for health and well-being. Components in food may modulate immune responses in a positive way (immunonutrition), and some of these components are present in kiwifruit. Kiwifruit contains vitamin C, carotenoids, polyphenols, and dietary fiber, and these are all potentially beneficial to the immune system. Research that has contributed to our understanding of the beneficial effects that kiwifruit may have on immune responses spans from in vitro studies using cell lines and human blood cells, to using animal models targeting both mucosal and systemic immunity. Some limited human intervention trials have been undertaken and are described, in which kiwifruit has been shown to influence a number of biomarkers of oxidative stress and beneficial immune responses, to reduce the incidence and severity of symptoms of upper respiratory tract infections and potentially be more beneficial than supplementation with vitamin C alone.	f	\N
23395237	To investigate the expression and possible roles of Twist1 and Y-box-binding protein-1 (YB-1) in bladder cancer tissue. Twist1 belongs to the family of basic helix-loop-helix transcription factors. A functional link between Twist1 and YB-1 has recently been determined to play an important role in bladder cancer cell lines. Frozen samples from 75 patients with bladder cancer were analyzed by quantitative real-time polymerase chain reaction (PCR). Formalin-fixed and paraffin-embedded tissues from 53 patients with bladder cancer were examined by immunohistochemistry. Twist1 transcript levels were positively correlated with YB-1 transcript levels (coefficient of correlation = 0.42, P<0.001), tumor grade (low grade vs. high grade; P<0.001), invasiveness (non-muscle-invasive bladder cancer vs. muscle invasive bladder cancer; P = 0.0018), and metastasis (meta- vs. meta+; P<0.001). YB-1 transcript level was also correlated with grade (P = 0.029) and invasiveness (P = 0.006). By immunohistochemistry, Twist1 expression was also correlated with YB-1 expression (P<0.001). Further, both Twist1 and YB-1 expression were positively correlated with invasiveness (P = 0.007 and P = 0.002, respectively). Patients with high Twist1 expression and high YB-1 expression had lower overall survival rates, compared with patients with low expression (log-rank test, P = 0.040 and P<0.001, respectively). These results suggest a functional link between Twist1 and YB-1, and they indicate that Twist1 and YB-1 promote bladder cancer progression.	f	\N
23396208	Regulatory T (Treg) cells suppress autoimmune disease, and impaired Treg cell function is associated with rheumatoid arthritis. Here we demonstrate that forkhead box P3 (FOXP3) transcriptional activity and, consequently, Treg cell suppressive function are regulated by phosphorylation at Ser418 in the C-terminal DNA-binding domain. In rheumatoid arthritis-derived Treg cells, the Ser418 site was specifically dephosphorylated by protein phosphatase 1 (PP1), whose expression and enzymatic activity were induced in the inflamed synovium by tumor necrosis factor α (TNF-α), leading to impaired Treg cell function. Moreover, TNF-α-induced Treg cell dysfunction correlated with increased numbers of interleukin-17 (IL-17)(+) and interferon-γ (IFN-γ)(+)CD4(+) T cells within the inflamed synovium in rheumatoid arthritis. Treatment with a TNF-α-specific antibody restored Treg cell function in subjects with rheumatoid arthritis, which was associated with decreased PP1 expression and increased FOXP3 phosphorylation in Treg cells. Thus, TNF-α controls the balance between Treg cells and pathogenic TH17 and TH1 cells in the synovium of individuals with rheumatoid arthritis through FOXP3 dephosphorylation.	f	\N
23399616	Tyrosine kinase inhibitors (TKIs) are increasingly common treatments for cancer; however, their effective use is hampered by unwanted side effects. One of the most common of these is TKI-induced diarrhea, although so far very little is known about its mechanisms and the best management approaches. As such, this review will briefly cover the extent of the problem, models for researching the problem and touch on future directions for management approaches to the problem. As there is a paucity of knowledge regarding the mechanisms of TKI-induced diarrhea in humans, this review will discuss the rodent models that have been used in the investigation of TKI-induced gut injury. This will be put into context with the pharmacological targets of TKIs and how this new information might help to better tailor treatment and management of patients on these drugs. The recognition of TKI-induced diarrhea as a significant treatment side effect has prompted efforts into uncovering the pathogenesis of this complication. This will enable future patients to be better managed throughout their treatment with these highly effective cancer drugs.	f	\N
23399972	Blood pressure (BP) is characterized by marked short-term fluctuations occurring within a 24 h period (beat-to-beat, minute-to-minute, hour-to-hour, and day-to-night changes) and also by long-term fluctuations occurring over more-prolonged periods of time (days, weeks, months, seasons, and even years). Rather than representing 'background noise' or a randomly occurring phenomenon, these variations have been shown to be the result of complex interactions between extrinsic environmental and behavioural factors and intrinsic cardiovascular regulatory mechanisms. Although the adverse cardiovascular consequences of hypertension largely depend on absolute BP values, evidence from observational studies and post-hoc analyses of data from clinical trials have indicated that these outcomes might also depend on increased BP variability (BPV). Increased short-term and long-term BPV are associated with the development, progression, and severity of cardiac, vascular, and renal damage and with an increased risk of cardiovascular events and mortality. Of particular interest are the findings from post-hoc analyses of large intervention trials in hypertension, showing that within-patient visit-to-visit BPV is strongly prognostic for cardiovascular morbidity and mortality. This result has prompted discussion on whether antihypertensive treatment should be targeted not only towards reducing mean BP levels but also to stabilizing BPV with the aim of achieving consistent BP control over time, which might favour cardiovascular protection.	f	\N
23404743	In 2010, guidelines published by the National Institute for Clinical Excellence (NICE) suggested a change in the way patients with stable chest pain of suspected cardiac origin were investigated. These guidelines removed exercise treadmill testing from routine use and introduced cardiac CT to regular use. To investigate whether these guidelines had improved our service provision by reducing the number of further investigations required to make a diagnosis, and to see if our costs had increased now that the less expensive exercise treadmill tests were not recommended. Clinic letters were used to assess patients pretest likelihood of coronary artery disease for two six-month cohorts of consecutive patients seen in the rapid access chest pain clinic (January-June 2010 and July-December 2011) using NICE published methodology, and to ascertain which investigations patients had. Using NICE modelled costs, we generated comparative hypothetical costs for each cohort and an average cost per patient. In the January-June 2010 cohort, 435 patients with chest pain were seen, and in July-December 2011, 334 patients were seen. In the pre-NICE guidelines cohort, 23% of patients required two investigations as compared with 11.4% in the post-NICE guidelines cohort, with no patient requiring three investigations as compared with 3% in the original cohort. There was no significant increase in costs per patient in the post-NICE guidance group. Implementing NICE guidance reduced the number of investigations needed per patient, and did not prove more expensive for our department in the short term.	f	\N
23406712	The Centers for Medicare and Medicaid Services (CMS) require high-risk (HR) criteria for carotid artery stenting (CAS) reimbursement. The impact of these criteria on outcomes after carotid endarterectomy (CEA) and CAS remains uncertain. Additionally, if these HR criteria are associated with more adverse events after CAS, then existing comparative effectiveness analysis of CEA vs CAS may be biased. We sought to elucidate this using data from the SVS Vascular Registry. We analyzed 10,107 patients undergoing CEA (6370) and CAS (3737), stratified by CMS HR criteria. The primary endpoint was composite death, stroke, and myocardial infarction (MI) (major adverse cardiovascular event [MACE]) at 30 days. We compared baseline characteristics and outcomes using univariate and multivariable analyses. CAS patients were more likely to have preoperative stroke (26% vs 21%) or transient ischemic attack (23% vs 19%) than CEA. Although age ≥ 80 years was similar, CAS patients were more likely to have all other HR criteria. For CEA, HR patients had higher MACEs than normal risk in both symptomatic (7.3% vs 4.6%; P < .01) and asymptomatic patients (5% vs 2.2%; P < .0001). For CAS, HR status was not associated with a significant increase in MACE for symptomatic (9.1% vs 6.2%; P = .24) or asymptomatic patients (5.4% vs 4.2%; P = .61). All CAS patients had MACE rates similar to HR CEA. After multivariable risk adjustment, CAS had higher rates than CEA for MACE (odds ratio [OR], 1.2; 95% confidence interval [CI], 1.0-1.5), death (OR, 1.5; 95% CI, 1.0-2.2), and stroke (OR, 1.3; 95% CI,1.0-1.7), whereas there was no difference in MI (OR, 0.8; 95% CI, 0.6-1.3). Among CEA patients, age ≥ 80 (OR, 1.4; 95% CI, 1.02-1.8), congestive heart failure (OR, 1.7; 95% CI, 1.03-2.8), EF <30% (OR, 3.5; 95% CI, 1.6-7.7), angina (OR, 3.9; 95% CI, 1.6-9.9), contralateral occlusion (OR, 3.2; 95% CI, 2.1-4.7), and high anatomic lesion (OR, 2.7; 95% CI, 1.33-5.6) predicted MACE. Among CAS patients, recent MI (OR, 3.2; 95% CI, 1.5-7.0) was predictive, and radiation (OR, 0.6; 95% CI, 0.4-0.8) and restenosis (OR, 0.5; 95% CI, 0.3-0.96) were protective for MACE. Although CMS HR criteria can successfully discriminate a group of patients at HR for adverse events after CEA, certain CMS HR criteria are more important than others. However, CEA appears safer for the majority of patients with carotid disease. Among patients undergoing CAS, non-HR status may be limited to restenosis and radiation.	f	\N
23408511	Intellectual disability is a condition characterized by significant limitations in cognitive abilities and social/behavioral adaptive skills and is an important reason for pediatric, neurologic, and genetic referrals. Approximately 10% of protein-encoding genes on the X chromosome are implicated in intellectual disability, and the corresponding intellectual disability is termed X-linked ID (XLID). Although few mutations and a small number of families have been identified and XLID is rare, collectively the impact of XLID is significant because patients usually are unable to fully participate in society. To reveal the molecular mechanisms of various intellectual disabilities and to suggest small molecules which by binding to the malfunctioning protein can reduce unwanted effects. Using various in silico methods we reveal the molecular mechanism of XLID in cases involving proteins with known 3D structure. The 3D structures were used to predict the effect of disease-causing missense mutations on the folding free energy, conformational dynamics, hydrogen bond network and, if appropriate, protein-protein binding free energy. It is shown that the vast majority of XLID mutation sites are outside the active pocket and are accessible from the water phase, thus providing the opportunity to alter their effect by binding appropriate small molecules in the vicinity of the mutation site. This observation is used to demonstrate, computationally and experimentally, that a particular condition, Snyder-Robinson syndrome caused by the G56S spermine synthase mutation, might be ameliorated by small molecule binding.	f	\N
23409482	Although cutaneous amebiasis (CA) is a rare disease, it is a public health concern worldwide, particularly in developing nations. It gains importance because of its severe clinical course, which can be confused with other disorders. Therefore, knowledge of its clinical features, histopathology, and pathogenesis is essential. We present a retrospective analysis over 50 years of 26 patients with CA who were diagnosed and treated at 2 Mexican institutions. Our main focus was to draw clinical information to identify mechanisms by which amebae reach the skin, occurring in a relatively small percentage of infected individuals. The recorded data included age and sex of the patients, form of presentation, any associated illnesses and/or factors, and methods for diagnosis. Histologic slides were reviewed in all cases; cytologic preparations also were available for 6 cases. Most patients were male (overall male to female ratio, 1.9 to 1). The disease always presented as painful ulcers containing varying amounts of amebae microscopically; the amebae were fairly easy to identify with routine stains, particularly when examination of tissue or smears was prepared from the edges of the ulcer instead of the necrotic centers. Erythrophagocytosis by the trophozoites was found and represented an unequivocal sign of its pathogenicity. We review the 2 mechanisms by which the organisms reach the skin. Most cases resolve with the use of specific antiamebic drugs; however, if left untreated, progression is rapid and unrelenting, sometimes with massive destruction of skin and subcutaneous tissues. Therefore, CA is a particularly virulent form of amebiasis.	f	\N
23412808	The use of natural remedies and pharmacological mineral supplements for liver disease treatment has a long history. In present study, the levels of selenium (Se) and zinc (Zn) were determined in biological samples (serum and whole blood) of female hepatitis C patients (n = 132), age ranged 30-45 years, before and after 30 days treatment with herbal/pharmaceutical supplements. For comparative study, 128 age-matched female subjects, residing in the same residential areas and have socioeconomic status, were selected as referents. The Se and Zn in supplements, blood, and sera were determined by atomic absorption spectrometry. It was observed that Zn and Se in blood and serum samples of viral hepatitis C (HCV) patients were reduced in the range of 28.6-39 % and 24-36 %, respectively, as compared to those of referents. After herbal/pharmaceutical supplementations, 20.6-25.0 and 9.15-13.2 % of Zn and 10.6-12.1 and 19.6-21.4 % of Se were enhanced in sera and blood samples of HCV patients, respectively. The resulted data indicated that the levels of Se and Zn in addition to some biochemical parameters were improved in HCV patients after herbal/pharmaceutical supplementation. The effects of both supplements were not significantly different (p > 0.05).	f	\N
23412860	We report 20 infants aged between 1 month and 6 months found to have subdural bleeding and also multiple unexplained fractures in a pattern similar to that described earlier as temporary brittle bone disease. Child abuse seemed unlikely as a cause of the fractures as in no case was there clinical evidence of injury commensurate with the fracturing, as some patients had fractures while in hospital and as metaphyseal lesions, when present, were often symmetrical in distribution. Abuse seemed unlikely to have been the cause of the subdural bleeding in several patients; three had clear histories of accidental injury and five had evidence that the initial bleeding was likely to have taken place at birth. Abuse also seemed unlikely as the cause of the syndrome; the nine patients who were returned to their parents had no subsequent allegations of abuse with a mean follow-up period of 15.8 years. The finding of hypermobile joints in the parents of eight of the children is an additional pointer to a natural cause for this condition. The cause of this combination of fractures and subdural bleeding is not yet clear but it is important to be aware that it can result from natural disease.	f	\N
23423257	Antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) is a group of vasculitides characterized by small-to-medium-sized blood vessel vasculitis and the presence of ANCA. Although our understanding of the causes of AAV remains limited, new information supporting an autoimmune basis is emerging. This review highlights recent progresses in etiology, pathogenesis, classification, and treatment. A genome-wide association study has confirmed a role for genetic susceptibility in AAV, and links between environmental factors and AAV induction through abnormal neutrophil extracellular traps has been demonstrated. Ongoing international consensus initiatives have revised approaches to the classification of vasculitis that has been enhanced by the analysis of large-scale prospective clinical data sets. New autoantibodies to human lysosome-associated membrane protein-2 antibody, moesin, and plasminogen have been detected in AAV sera and a prognostic classification of renal biopsies developed. Clinical trial networks have extended the evidence base for the treatment of AAV, and rituximab has emerged as an alternative to cyclophosphamide for remission induction. Long-term outcomes following current treatment strategies have been determined and increased risks for cardiovascular and malignant disease reported.	f	\N
23425809	Liver diseases are responsible for metabolic disturbances and the loss of muscle mass and function. This study aims to correlate maximal oxygen uptake (VO2max) with the Model for End Stage Liver Disease (MELD) severity score and associate VO2max with mortality in patients with alcoholic cirrhosis. This prospective study included 27 patients who had a diagnosis of alcoholic liver cirrhosis. All subjects were followed for 3 years and performed an exercise test to determine VO2max. The study included 18 men and 9 women. We observed a strong inverse correlation between VO2max and MELD (r=-0.91, p<0.001). In a survival analysis, individuals who had a VO2max less than 14mL/kg showed 60% mortality when compared with those who had a VO2max greater than 14mL/kg (p<0.0001; OR: 3.29; 95% CI: 1.44-5.25). The VO2max is directly associated with the survival of patients with alcoholic cirrhosis and demonstrates a strong inverse correlation with the MELD severity score.	f	\N
23440103	We hereby report two patients with parathyroid carcinoma presenting extremely high calcium and PTH levels, severe bone disease, and palpable neck mass at diagnosis. They both underwent parathyroidectomy, and one of them evolved to lung metastasis. Important hypocalcemia was observed after surgery in both: after parathyroidectomy in one patient, and only after surgical removal of the metastasis in the other. Both required intravenous calcium replacement, thus revealing hungry bone syndrome (HBS). HBS usually reflects rapid mineralization after correction of hyperparathyroidism. The more severe the bone disease before surgery, the more prone the patient is to HBS after surgery. Despite being an unfavorable outcome, HBS state suggests that surgical removal of hypersecretory parathyroid tissue was accomplished. In this study, HBS was observed in both patients, who presented severe bone disease prior to surgery. HBS would be expected post-operatively in successful parathyroid carcinoma removal.	f	\N
23442763	The relationship between cytomegalovirus (CMV) infection and mortality among immunocompetent individuals is uncertain. We aimed to examine whether seropositivity for CMV and the level of CMV immunoglobulin G (IgG) antibody are associated with all-cause and cause-specific mortality. We used data from a random sample of 13 090 participants aged 40-79 years at recruitment in 1993-1997 to the European Prospective Investigation of Cancer-Norfolk population-based cohort study. We measured baseline IgG antibody levels against CMV. Death certificates were obtained for all participants who died before 31 March 2011. Codes for the underlying cause of death were used to investigate cause-specific mortality. A total of 2514 deaths occurred during a mean follow-up of 14.3 years (SD, 3.3 years). Compared to seronegative participants (age- and sex-adjusted mortality rate, 12.4 [95% confidence interval {CI}, 11.3-13.2] per 1000 person-years at risk), rates increased across thirds of IgG antibody levels (score test of trend P < .0001). CMV seropositivity (prevalence 59%) was associated with increased all-cause mortality (age- and sex-adjusted hazard ratio [HR], 1.16 [95% CI, 1.07-1.26]), similarly in men and women (P for interaction = .52). The association persisted after additionally adjusting for measures of socioeconomic status and possible confounders. Cause-specific analyses suggested that increased mortality from cardiovascular disease (HR, 1.06 [95% CI, .91-1.24]), cancer (HR, 1.13 [95% CI, .98-1.31]), and other causes (HR, 1.23 [95% CI, 1.04-1.47) all appeared to contribute to the overall associations. Seropositivity and higher IgG antibody levels against CMV are associated with increased mortality and after adjustment for a range of potential confounders in the general population.	f	\N
23443955	Radioiodine (RAI) is used in the treatment of hyperthyroidism and differentiated thyroid cancer. Radioiodine therapy is associated with dry eyes and some side effects are seen especially due to beta rays. In this study, the functional and cytological status of lacrimal glands after RAI therapy was evaluated. Twenty-five patients with a mean age of 55.16 years with planned low-dose RAI therapy were evaluated. Just before and 6 months after the treatment, the lacrimal glands were evaluated with tear break-up time (BUT), Schirmer's test, impression cytology and "Ocular Surface Disease Index (OSDI)" questionnaire. The mean value of Schirmer's test was 16.20 ± 3.61 pre-treatment and 11.28 ± 4.39 post-treatment for the right eye, and 15.76 ± 3.27 and 10.60 ± 4.42 for the left eye, respectively. The mean value of Schirmer's test decreased significantly post-treatment in both eyes (p = 0.0001). The BUT score also decreased significantly post-treatment (p = 0.001). The mean value of OSDI score was 27.5 ± 8.02 pre-treatment and 46.36 ± 10.27 post-treatment. The mean value of OSDI score increased post-treatment (p = 0.0001). The impression scores also increased post-treatment in both eyes (p = 0.0001). Even low-dose (≤30 mci) RAI treatment affects lacrimal gland functions. Low-dose RAI causes a decrease in the value of Schirmer's test and the BUT test, and an increase in the value of OSDI score and impression scores.	f	\N
23444587	In this paper, we explore the benefits of storytelling in health communication and, in particular, immunization education. During the mid-20th century polio epidemic, both personal stories and scientific information abounded in the media. However, as rates of vaccine-preventable diseases declined, narratives about the dangers of such diseases faded as did the public fear of them. Meanwhile, anti-vaccine advocates flooded the media and Internet with stories of injured children and tied those injuries, such as autism, to vaccines. Medical experts often counter anti-vaccine concerns with scientific information which can fail to persuade parents. Furthermore, evidence suggests that many people misunderstand quantitative information resulting in a misinterpretation of risk. Compared to scientific information, stories relate life lessons and values. They are effective because they are memorable and relatable. Evidence also suggests that storytelling can effectively improve health knowledge and behaviors. Inspired by In Harm's Way--True Stories of Uninsured Texas Children by the Children's Defense Fund and Faces of Influenza by the American Lung Association, we published Vaccine-Preventable Disease: The Forgotten Story, a collection of photographs and personal stories of families affected by vaccine-preventable diseases. We have found that the stories included in our booklet capture all the benefits of storytelling. Given the many benefits of storytelling, providers should strive to include stories along with medical facts in their daily practice.	f	\N
23446227	Neuroendocrine tumors (NET) are malignant solid tumors that arise in hormone-secreting tissue of the diffuse neuroendocrine system or endocrine glands. Although traditionally understood to be a rare disease, the incidence and prevalence of NET have increased greatly in the past 3 decades. However, during this time, progress in diagnosis and outcome of NET has generally been modest. In order to achieve improved outcome in NET, a better understanding of NET biology combined with more reliable serum markers and better techniques to identify tumor localization and small lesions are needed. Although some NET biomarkers exist, sensitive and specific markers that predict tumor growth and behavior are generally lacking. In addition, the integration of new molecular imaging technologies in patient diagnosis and follow-up has the potential to enhance care. To discuss developments and issues required to improve diagnostics and management of NET patients, with specific focus on the latest advances in molecular imaging and biomarker science, 17 global leaders in the fields of NET, molecular imaging and biomarker technology gathered to participate in a 2-day meeting hosted by Prof. Kjell Öberg at the University of Uppsala in Sweden. During this time, findings were presented regarding methods with potential prognostic and treatment applications in NET or other types of cancers. This paper describes the symposium presentations and resulting discussions.	f	\N
23447119	Erdheim-Chester disease (ECD) is a rare, non-Langerhans form of histiocytosis of unknown origin with distinct clinicopathologic and radiographic features. Reports detailing the cytology of ECD are rare. We describe a case of ECD with pericardial effusion. Cytologic examination revealed a hypercellular specimen composed of clusters and singly dispersed foamy macrophages with round nuclei and inconspicuous nucleoli, admixed with lymphocytes, eosinophils, and Touton-type multinucleated giant cells. Immunostains for CD68 were strongly positive in the foamy macrophages while S100 and CD1a were negative. The presence of foamy histiocytes, multinucleated giant cells, lymphocytes and eosinophils are also features of other systemic histiocytic disorders, including Langerhans cell histiocytosis (LCH), Rosai-Dorfman disease (RDD) and sarcoidosis. To the best of out knowledge, this is the first report describing the cytological features of ECD in a pericardial effusion.	f	\N
23449087	Single cell genomics has made increasingly significant contributions to our understanding of the role that somatic genome variations play in human neuronal diversity and brain diseases. Studying intercellular genome and epigenome variations has provided new clues to the delineation of molecular mechanisms that regulate development, function and plasticity of the human central nervous system (CNS). It has been shown that changes of genomic content and epigenetic profiling at single cell level are involved in the pathogenesis of neuropsychiatric diseases (schizophrenia, mental retardation (intellectual/leaning disability), autism, Alzheimer's disease etc.). Additionally, several brain diseases were found to be associated with genome and chromosome instability (copy number variations, aneuploidy) variably affecting cell populations of the human CNS. The present review focuses on the latest advances of single cell genomics, which have led to a better understanding of molecular mechanisms of neuronal diversity and neuropsychiatric diseases, in the light of dynamically developing fields of systems biology and "omics".	f	\N
23451796	Lowering blood glucose with insulin therapy towards beneficial target levels while also avoiding hypoglycaemia is a challenging task. An important confounding factor, which might be under-appreciated in this scenario, is that of variable glucose readings causing difficulties with dose adjustment. Furthermore, this glucose variability is, to some extent, a reflection of variability in the glucose-lowering action of the insulin therapy itself. Not only is glucose variability a major confounding factor in disease management but it is possibly also of direct prognostic consequence and is increasingly recognized as an informative measurement in diabetes management. The scope for insulin-induced glucose variability is particularly great with basal insulins because of their prolonged absorption from high-dose depots. Pharmacodynamic (PD) variability manifests as both fluctuations in the level of glucose-lowering effect over time, and as inconsistencies in the response from one injection to another. Well-controlled pharmacokinetic (PK)/PD studies using repeated isoglycaemic clamp methodology clearly how that many injected basal insulin products have high variable absorption with correspondingly variable action. Incomplete resuspension and precipitation appear to be important issues with regard to unpredictability in this action, while an inadequate duration of action relative to the dosing interval results in a fluctuating action profile. There are some ultra-long-acting basal insulins with novel protraction mechanisms currently in clinical development for which clamp studies show markedly improved PK/PD profiles.	f	\N
23456185	The temporal lobe is of importance for visuospatial orientation. Intracranial arachnoid cysts have a predilection for the temporal fossa, and might therefore affect visuospatial orientation. The aim was to find out whether temporal cysts affect maze learning and if surgical cyst decompression improves maze performance. Forty-five patients with a temporal arachnoid cyst and 17 control patients with cervical disc disease were tested in a labyrinth route in the hospital corridors the day before surgery and at least 3 months postoperatively. Thirty-five cyst patients (78 %) experienced postoperative improvement of their preoperative complaints. The cyst patients spent significantly longer time than the controls navigating through the maze in the preoperative test, 161 s and 127 s, respectively, but there was no difference in number of errors between the two groups. However, the cyst patients improved significantly in the postoperative test, both with regards to number of errors they made and time spent, contrary to the control patients, whose postoperative performance equalled that of the preoperative test. For the cyst patients, postoperative improvement in the labyrinth test correlated with the clinical outcome-but not the neuroradiological outcome-after the operation. Thus, temporal arachnoid cysts may affect visuospatial orientation and learning in a reversible manner.	f	\N
23459906	this paper reports the results of a nursing-administered theory-based intervention, the "Moving Heart Program", based on the implementation intention theory and pointed at improving physical activity adherence among coronary heart disease outpatients in Brazil. this experimental study applied assessments at baseline, 1 and 2 months after baseline. The Consolidated Standards of Reporting Trials statement was followed. Participants were randomly assigned to intervention, comprising action and coping plans on how to deal with anticipated barriers (n=69), or a standard-care control group (n=67). participants submitted to the intervention showed significant higher levels of physical activity 2 months after baseline and were significantly more active than the control group. the results indicate that the intervention is feasible for patients with coronary heart disease and can be a useful tool to facilitate intended lifestyle changes. This study brings relevant contributions to the Nursing field and other health-related areas, once the intervention presents low cost to health services and can be applied in cardiac rehabilitation programs, showing significant benefits to participants.	f	\N
23462063	To assess the effectiveness of flow reversal as an alternative means of cerebral protection by using transcranial Doppler recordings and diffusion-weighted imaging (DWI) as surrogate markers of brain injury. Eighteen patients with symptomatic carotid artery disease were recruited. Magnetic resonance imaging was performed before the intervention and at 3 and 24 hours and 30 days after the intervention to detect new ischemic lesions with DWI. Transcranial Doppler recordings were made during the procedure to assess for microembolic signals (MESs). Data were compared against data from a historical control cohort of patients who underwent CAS placement with or without filter protection (n = 15 each) under the same protocol in a different study. There were fewer periprocedural new lesions on DWI in the reverse-flow cohort compared with the historical control cohort with filter protection (P = .084). Reverse flow revealed significantly fewer MESs during the whole procedure compared with the filter-protected group (P = .01) but not the unprotected group (P = .55). There was a marked decrease in MES counts for reverse flow protection during the embologenic stages of the procedure (P = .004). Use of the reverse flow device was associated with fewer overall lesions on DWI and proportionately fewer positive scans compared with the use of filter-type devices (P = .08, not significant). Transcranial Doppler recordings demonstrated a significant reduction in embolization to the brain during carotid artery stent placement with the use of reverse-flow cerebral protection.	f	\N
23462484	Patients suffering from Parkinson's disease (PD) frequently experience painful sensations that may be due to central modification of nociception in PD. We compared pain thresholds and cerebral activity in nociceptive areas using Positron Emission Tomography (PET) during nociceptive stimulation before (OFF condition) and after (ON condition) levodopa challenge between nine PD patients with and nine PD patients without neuropathic pain. Pain thresholds were determined using a cold pressor test in the two conditions. We used H2(15)O PET to study the regional cerebral blood flow changes in subjects while they received alternate randomized noxious and innocuous cold stimuli during OFF and ON periods. Pain thresholds were not significantly different between PD patients with and without pain in either condition (OFF and ON). In both groups of PD patients, levodopa significantly raised pain threshold (F1,16 = 26.71; p < 0.0001) with a mean variation of -2.7 (±2.3 °C). In the OFF condition, PD patients with pain had a lower pain activation in the right prefrontal cortex and posterior insula and a higher pain activation in the right anterior cingulate cortex (BA32/8) than pain-free patients. Levodopa significantly reduced pain-induced-activation in the right insula and in the anterior cingulate cortex in both groups. Levodopa decreased nociceptive perception in both PD patients with and without pain. In PD patients with neuropathic pain the medial affective pathway was preferentially recruited whereas pain-free PD patients exhibited a greater activation in lateral discriminative nociceptive areas.	f	\N
23462618	The objective of this study was to compare the toxicological effects of different source-related ambient PM10 samples in regard to their chemical composition. In this context we investigated airborne PM from different sites in Aachen, Germany. For the toxicological investigation human alveolar epithelial cells (A549) and murine macrophages (RAW264.7) were exposed from 0 to 96 h to increasing PM concentrations (0-100 μg/ml) followed by analyses of cell viability, pro-inflammatory and oxidative stress responses. The chemical analysis of these particles indicated the presence of 21 elements, water-soluble ions and PAHs. The toxicological investigations of the PM10 samples demonstrated a concentration- and time-dependent decrease in cell viability and an increase in pro-inflammatory and oxidative stress markers.	f	\N
23470563	The IGF-I receptor (IGF-IR) has an important role in malignant disease and is the target of several drugs presently in clinical trials. Gene therapy has been explored as cancer treatment, mainly for delivery of genes that induce cell death or enhance the immunological response to cancer. Previously, we have shown that the implantation of autologous bone-marrow stromal cells producing a soluble form of IGF-IR (sIGFIR) inhibited experimental liver metastasis of several tumor types in mice. Here, we evaluated the utility of adenovirus-based gene delivery for generating therapeutically effective plasma levels of this decoy. We constructed a third generation gutless adenovirus expressing sIGFIR and found that HEK-293 cells transduced by this, but not control adenoviruses, secreted soluble receptor protein that blocked IGF-I-induced tumor cell migration, proliferation and survival in vitro. Following virus injection in vivo, viral DNA was detectable by PCR in several host organs, particularly the liver, and this resulted in the production of measurable sIGFIR plasma levels for up to 21 days post injection. In mice producing virus-encoded sIGFIR, experimental liver metastasis was inhibited, indicating that sIGFIR levels were therapeutically effective. The results show that adenovirus-based delivery of inhibitory soluble proteins can provide an effective anticancer strategy.	f	\N
23475581	Tissue oxidative stress is a common hallmark of atherosclerosis and non-alcoholic steatohepatitis (NASH), 2 conditions linked epidemiologically and pathophysiologically. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the master regulator of inducible antioxidant responses, that can attenuate cellular injury from oxidative stress induced by obesity and other redox insults. Nrf2 expression and activation is reduced in mouse and human vessels that harbor accelerated atherosclerosis and in livers with histologic criteria of NASH. Systemic antioxidants have thus been attractive therapeutic targets, but clinical trials have been largely unsuccessful in improving cardiovascular health. Macrophage-selective Nrf2 activation may, however, provide an approach to reduce vascular and hepatocyte injury without the complications of systemic antioxidants, since macrophages play key roles in the development and progression of both atherosclerosis and NASH. In this article, we review the common mechanisms of oxidative stress and inflammation in atherosclerosis and NASH, and discuss the role of Nrf2 in vascular and hepatocyte protection.	f	\N
23478151	Primary carcinoid tumors of the kidney are very rare, malignant tumors consisting of neuroendocrine cells. The pathogenesis of renal carcinoid is unclear because neuroendocrine cells are not normally found in adult renal parenchyma. Electron microscopy, immunohistochemistry, octreotide scan, positron emission tomography along with conventional radiographic imaging techniques are used in diagnosis and follow-up. Presenting symptoms usually include flank pain and haematuria. Early stage disease is treated with surgery only. However, randomized trials are lacking because of the very low number of reported cases. Thus, the role of debulking surgery, chemotherapy, radiotherapy, octreotide and targeted therapy in the management of advanced disease remains an open question. In this article the clinicopathologic features and prognosis of this very rare disease along with treatment outcomes of the reported cases are reviewed. In addition, we report a new case of a metastatic primary renal atypical carcinoid tumor treated with octreotide therapy.	f	\N
23479135	Platinum-based chemotherapy is the most common treatment for patients with advanced non-small cell lung cancer (NSCLC). Genetic polymorphisms in the base excision repair (BER) pathway are suspected to influence the response of patients to this type of therapy. In this study, we investigated whether nonsynonymous single nucleotide polymorphisms (SNPs) in the BER pathway were associated with the response, progression-free survival (PFS) and overall survival (OS) of NSCLC patients following platinum-based chemotherapy. We used TaqMan to genotype four SNPs (APE1 Asp148Glu, PARP1 Va1762Ala, XRCC1 Arg194Trp and XRCC1 Arg399Gln) in 147 patients with advanced NSCLC who had undergone routine platinum-based chemotherapy. Logistic regression analysis showed that subjects with the XRCC1-399 A allele had a significantly better response to platinum-based chemotherapy than those with the XRCC1-399 GG genotype (AA/AG vs. GG: adjusted OR = 2.35, 95 % CI = 1.11-5.00). Furthermore, multivariate Cox proportional hazard regression analysis showed that the PARP1-762 CC genotype was a significantly unfavorable prognostic factor for PFS (CC vs. CT/TT: adjusted HR = 1.90, 95 % CI = 1.02-3.52). In contrast, the APE1-148 GG genotype was a significantly protective prognostic factor for OS (GG vs. TT: adjusted HR = 0.33, 95 % CI = 0.12-0.92). We found that XRCC1 Arg399Gln, PARP1 Va1762Ala and APE1 Asp148Glu SNPs in the BER pathway may influence the prognosis of advanced NSCLC patients following platinum-based chemotherapy.	f	\N
23484318	To increase the death rate of fatal anaphylaxis in guinea pigs and the detectahie level of the tryptase of mast cell in hlood serum. Seventy-four guinea pigs were randomly divided into five groups: original model group, original model control group, improved model group, improved model control group, improved model with non-anaphylaxis group. Using mixed human serum as the allergen, the way of injection, sensitization and induction were improved. ELISA was used to detect the serum mast cell tryptase and total IgE in guinea pigs of each group. The death rate of fatal anaphylaxis in original model group was 54.2% with the different degree of hemopericardium. The severe pericardial tamponade appeared in 9 guinea pigs in original model group and original model control group. The death rate of fatal anaphylaxis in improved model group was 75% without pericardial tamponade. The concentration of the serum total IgE showed no statistically difference hetween original model group and original model control group (P > 0.05), hut the serum mast cell tryptase level was higher in the original model group than that in the original model control group (P > 0.05). The concentration of the serum total IgE and the serum mast cell tryptase level were significantly higher in improved model group than that in the improved model control group (P < 0.05). The death rate of the improved model significantly increases, which can provide effective animal model for the study of serum total IgE and mast cell tryptase.	f	\N
23484512	An increasing number of people with mild cognitive impairment (MCI) visits a memory clinic to find out whether their symptoms indicate Alzheimer's disease (AD). Markers in cerebrospinal fluid are increasingly used for the diagnosis of Alzheimer's disease. In the short term, CSF biomarkers are more accurate in ruling out progression to AD-type dementia than demonstrating progression. The predictive value of the CSF biomarkers increases with longer-duration follow-up and declines with age. The added value of CSF biomarkers is not yet clear in MCI patients in whom extensive clinical, neuropsychological examination or imaging have already been performed.	f	\N
23485507	An optimal prostate biopsy in clinical practice is based on a balance among adequate detection of clinically significant prostate cancers (sensitivity), assuredness regarding the accuracy of negative sampling (negative predictive value), limited detection of clinically insignificant cancers and good concordance with whole gland surgical pathology results to allow accurate risk stratification and disease localization for treatment selection. Inherent within this optimization is variation of the core number, location, labeling and processing for pathological evaluation. To date, there is no consensus in this regard. The purpose of this review is to 1) define the optimal number and location of biopsy cores during primary prostate biopsy among men with suspected prostate cancer, 2) define the optimal method of labeling prostate biopsy cores for pathological processing which will provide relevant and necessary clinical information for all potential clinical scenarios, and 3) determine the maximal number of prostate biopsy cores allowable within a specimen jar which would not preclude accurate histological evaluation of the tissue. A bibliographic search using PubMed® covering the period up to July 2012 yielded approximately 550 articles. Articles were reviewed and categorized based on which of the 3 objectives of this review was addressed. Data were extracted, analyzed and summarized. Recommendations are provided based on this literature review and our clinical experience. The use of 10 to 12-core extended sampling protocols increases cancer detection rates compared to traditional sextant sampling methods and reduces the likelihood of repeat biopsy by increasing negative predictive value, ultimately allowing more accurate risk stratification without increasing the likelihood of detecting insignificant cancers. As the number of cores increases above 12, the increase in diagnostic yield becomes marginal. Only limited evidence supports the use of initial biopsy schemes involving more than 12 cores or saturation. Apical and laterally directed sampling of the peripheral zone increases cancer detection rate, reduces the need for repeat biopsies and predicts pathological features on prostatectomy while transition zone biopsies do not. There are little data to suggest that knowing the exact site of an individual positive biopsy core provides meaningful clinical information. However, determining laterality of cancer on biopsy may be helpful for predicting sites of extracapsular extension and therapeutic planning. Placement of multiple biopsy cores in a single container (greater than 2) appears to compromise pathological evaluation, which can reduce cancer detection rate and increase the likelihood of equivocal diagnoses. A 12-core systematic biopsy that incorporates apical and far-lateral cores in the template distribution allows maximal cancer detection, avoids repeat biopsy, and provides information adequate for identifying men who need therapy and planning that therapy while minimizing the detection of occult, indolent prostate cancers. This literature review does not provide compelling evidence that individual site specific labeling of cores benefits clinical decision making regarding the management of prostate cancer. Based on the available literature, we recommend packaging no more than 2 cores in each jar to avoid reduction of the cancer detection rate through inadequate tissue sampling.	f	\N
23494361	Disseminated intravascular coagulation (DIC) is a life-threatening complication, and its control is essential for therapeutic success. Recombinant human soluble thrombomodulin alfa (rTM) is a novel therapeutic agent for DIC. The efficacy of rTM in the treatment of DIC is reportedly superior to that of conventional anti-DIC treatments, such as unfractionated heparin or low molecular weight heparin, but hemorrhagic events occasionally interfere with the therapeutic benefits of rTM. We assessed the clinical features of 20 consecutive patients who were given rTM for DIC associated with various hematologic disorders. Eight patients achieved remission of both primary disease and DIC, eight died due to progression of the primary disease, and four died of various hemorrhagic complications. Assessment of 16 biomarkers for coagulation showed that the four patients who died of hemorrhagic complications despite remission of their primary disease showed lower ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin Type 1 motif, member 13) plasma activity than other patients (P = 0.016). The optimal cut-off level of ADAMTS-13 for predicting risk of hemorrhagic complications was 42 % (P = 0.007). Plasma ADAMTS-13 activity determined at diagnosis of DIC may help predict the risk of hemorrhagic events during and/or following DIC treatment with hematologic disorders.	f	\N
23494513	The use of self-expandable metal stents (SEMS) for the treatment of malignant colorectal obstruction is increasing. However, results of risk factors for its complications are inconsistent. This study aimed to examine the clinical effectiveness of the procedure as well as the complications and risk factors associated with the complications. Medical records of patients with malignant colorectal obstruction who underwent endoscopic placement of covered or uncovered SEMS were reviewed retrospectively. The procedure was performed by two endoscopists with experience in pancreatobiliary endoscopy. A total of 152 patients were included (102 men; mean age, 70 ± 12.5 years). The procedure was performed for palliative management in 83 patients and performed as a bridge to surgery in 69 patients. There were 111 uncovered stents and 41 covered stents. The technical success rate was 100% and the clinical success rate 94.1%. Overall complications were observed in 49 patients (32.2%) during the follow-up period (median, 98 days; interquartile range, 19-302 days). Obstruction (17.1%), migration (7.9%), perforation (5.2%), bleeding (1.3%), and tenesmus (0.7%) were the causes of the complications. Stage IV disease, carcinomatosis peritonei, complete obstruction of the colon, palliative intention, and covered stents increased the complications based on the univariate analysis. Multivariate analysis revealed that complete obstruction of the colon and covered stents were significantly independent risk factors for complications. In the palliative group, Kaplan-Meier analysis showed significantly shorter median duration to the onset of complications in the covered stent group than in the uncovered stent group. Although SEMS in patients with malignant colorectal obstruction is effective both as palliative therapy and as a bridge to surgery, one-third of patients experienced complications. Severity of obstruction and stent type can influence outcomes.	f	\N
23510013	Children with disabilities are two to three times more likely to become overweight or obese than typically developing children. Children with spina bifida (SB) are at particular risk, yet obesity prevalence and weight management with this population are under-researched. This retrospective chart review explored how weight is assessed and discussed in a children's SB outpatient clinic. Height/weight data were extracted from records of children aged 2-18 with a diagnosis of SB attending an outpatient clinic at least once between June 2009-2011. Body mass index was calculated and classified using Centers for Disease Control and Prevention cut-offs. Notes around weight, diet and physical/sedentary activities were transcribed verbatim and analysed using descriptive thematic analysis. Of 180 eligible patients identified, only 63 records had sufficient data to calculate BMI; 15 patients were overweight (23.81%) and 11 obese (17.46%). Weight and physical activity discussions were typically related to function (e.g. mobility, pain). Diet discussions focused on bowel and bladder function and dietary challenges. Anthropometrics were infrequently recorded, leaving an incomplete picture of weight status in children with SB and suggesting that weight is not prioritised. Bowel/bladder function was highlighted over other benefits of a healthy body weight, indicating that health promotion opportunities are being missed. Implications for Rehabilitation It is important to assess, categorise and record anthropometric data for children and youth with spina bifida as they may be at particular risk of excess weight. Information around weight categorisation should be discussed openly and non-judgmentally with children and their families. Health promotion opportunities may be missed by focusing solely on symptom management or function. Healthcare professionals should emphasise the broad benefits of healthy eating and physical activity, offering strategies to enable the child to incorporate healthy lifestyle behaviours appropriate to their level of ability.	f	\N
23511908	Corticostriatal projections are essential components of forebrain circuits and are widely involved in motivated behaviour. These axonal projections are formed by two distinct classes of cortical neurons, intratelencephalic (IT) and pyramidal tract (PT) neurons. Convergent evidence points to IT versus PT differentiation of the corticostriatal system at all levels of functional organization, from cellular signalling mechanisms to circuit topology. There is also growing evidence for IT/PT imbalance as an aetiological factor in neurodevelopmental, neuropsychiatric and movement disorders - autism, amyotrophic lateral sclerosis, obsessive-compulsive disorder, schizophrenia, Huntington's and Parkinson's diseases and major depression are highlighted here.	f	\N
23515578	Disturbances in proteostasis are observed in many neurodegenerative diseases. This leads to activation of protein quality control to restore proteostasis, with a key role for the removal of aberrant proteins by proteolysis. The unfolded protein response (UPR) is a protein quality control mechanism of the endoplasmic reticulum (ER) that is activated in several neurodegenerative diseases. Recently we showed that the major proteolytic pathway during UPR activation is via the autophagy/lysosomal system. Here we investigate UPR induction if the other major proteolytic pathway of the ER -ER associated degradation (ERAD)-is inhibited. Surprisingly, impairment of ERAD results in decreased UPR activation and protects against ER stress toxicity. Autophagy induction is not affected under these conditions, however, a striking relocalization of the lysosomes is observed. Our data suggest that a protective UPR-modulating mechanism is activated if ERAD is inhibited, which involves lysosomes. Our data provide insight in the cross-talk between proteolytic pathways involved in ER proteostasis. This has implications for neurodegenerative diseases like Alzheimer's disease where disturbed ER proteostasis and proteolytic impairment are early phenomena in the pathology.	f	\N
23523498	Unicompartmental knee arthroplasty (UKA) is a less invasive treatment for medial gonarthrosis. However, registry data have demonstrated higher revision and early failure rates. The purpose of this study is to report the early survivorship and failure modes in a series of 1000 consecutive medial mobile bearing UKA. UKA patients with a minimum of 2 year follow-up or those meeting the study endpoint (UKA failure or death) were included. Demographic variables, pre and post-operative clinical variables, and mode of failure were analyzed. Eight hundred and thirty-nine knees were included in the analysis. Forty revisions were performed at an average of 23.1 months (range, 2.3-74.2) following UKA for a survivorship of 95.2%. Indications for revision were aseptic loosening (15), tibial collapse (7), mobile bearing dislocation (2), persistent pain (12), progression of disease (2), infection (1), and tibiofemoral instability (1). These results are from a single center and may not be comparable to those of larger reports such as national registries.	f	\N
23526950	Transformation is a complex process, involving many changes in the cell. In this work, we investigated the transcriptional changes that arose during the development of squamous cell carcinoma (SCC) in mice. Using microarray analysis, we looked at gene expression during different stages in cancer progression in 31 mice. By analyzing tumor progression in each mouse separately, we were able to define the global changes that were common to all 31 mice, as well as significant changes that occurred in fewer individuals. We found that different genes can contribute to the tumorigenic process in different mice, and that there are many ways to acquire the malignant properties defined by Hanahan and Weinberg as "hallmarks of cancer". Eventually, however, all these changes lead to a very similar cancerous phenotype. The finding that gene expression is strongly heterogeneous in tumors that were induced by a standardized protocol in closely related mice underscores the need for molecular characterization of human tumors and personalized therapy.	f	\N
23528171	Surgical resection of lung metastases of epithelial and mesenchymal tumors has an irreplaceable position in the complex treatment of advanced stages of these malignancies. Among the most significant prognostic factors affecting longterm survival of these patients are: parameter of complete resection, number and size of metastases, histological type of primary tumor, lymph node involvement, DFI (Disease Free Interval) and biological aggressiveness of the tumor or TDT (Tumor Doubling Time). retrospective analysis of patients with lung metastases of epithelial and mesenchymal tumors operated on at the I. Department of Surgery from 2005 to 2011. The authors present a set of 50 patients and evaluation of their age, gender, type of primary tumor, number of metastases, occurrence of bilateral metastases, repeat metastasectomies, duration of DFI, type of operation and selected approach and performance of mediastinal lymphadenectomy. The probability of five-year survival, relationship between survival on DFI, difference in survival between metastases of colorectal cancer versus renal cancer and the influence of repeated metastasectomies and number of metastases on survival were statistically analyzed. Sixty operations were performed on a set of 50 patients (average age 61.2 years). Forty-two procedures were performed by thoracotomic approach. A solitary metastasis was discovered in 43 patients; in 8 patients, more than 3 metastases were resected. Repeated metastasectomies were performed 10 times. Mediastinal lymphadenectomy was performed in 21 cases. The most frequent procedure was extraanatomic resection (28×). Fourteen patients had DFI < 12 months, 19 patients had DFI 12-36 months and 17 patients had DFI > 36 months. Average survival was 66.9 months; the probability of five-year survival was 0.549 (54.9%). A relationship between DFI and survival was not discovered. There was no statistically significant difference in survival after metastasectomy for colorectal cancer and renal cancer. A relationship between survival interval and number of metastases and repeated metastasectomies was not discovered. Surgical resection of lung metastases plays an important role in multidisciplinary care, assuming a precise selection of patients indicated for this treatment. When properly adhering to the indication criteria, very positive results of long-term survival may be expected.	f	\N
23537409	Nitric oxide (NO) is involved in the regulation of several physiological processes such as vascular homeostasis. Exogenous NO supply offers major therapeutic interest, especially in the treatment of coronary artery disease, ischemic syndromes and other cardiovascular pathologies. Nevertheless, the administration of NO itself is limited by its short half-life. NO prodrugs have been marketed for decades, e.g. organic nitrates for angina pectoris. These prodrugs display undeniable advantages such as angina crisis relief and preconditioning effect. Nevertheless, they suffer from several drawbacks: toxicity, tolerance, endothelial dysfunction exacerbation. These negative effects are related to massive production of reactive species derived from oxygen or nitrogen, which trigger oxidative and nitrosative stress. New NO donors are under development to overcome those disadvantages, among which the S-nitrosothiols family seems especially promising.	f	\N
23539255	Laparoscopy-assisted total gastrectomy (LATG) has been used more frequently despite the associated technical difficulty and concerns over oncological safety. This study was undertaken to compare the short- and long-term surgical outcomes following either LATG or open total gastrectomy (OTG) for gastric cancer. A total of 120 LATG and 228 OTG were retrospectively matched with respect to sex, age (±5 years), and pathological tumor-node-metastasis stage for comparison of the clinical outcomes. The total complication rate among 120 LATG and 228 OTG was 18.3 % (22/120) and 16.2 % (37/228), respectively. The most common complication after LATG was anastomotic-related complication (6.7 %); five anastomotic leakages (4.2 %) and three anastomotic strictures were reported (2.5 %). That after OTG was wound complication (3.5 %), including seroma or infection. Matched patients analysis: Time to first gas passing and time to the resumption of a soft diet were significantly shorter in the LATG group than in the OTG group. The postoperative hospital stay of LATG was shorter in the LATG group (9.3 ± 4.2 days) than in the OTG group (11.7 ± 7.3 days; p = 0.057). Among matched patients, there was no significant difference between complication rate (24 vs. 32 %; p = 0.504) or leakage rate (6 vs. 4 %). During median follow-up of 50 (range, 10-92) months, there was no significant difference in the disease-free survival rate between the matched groups, respectively (94.5 vs. 87.1 %: p = 0.148). As for patients with TNM stage I gastric cancer, the disease-free survival rate (100 vs. 90.9 %; p = 0.5) and the cumulative survival rate (91.5 vs. 95.2 %; p = 0.618) did not differ significantly between the LATG and OTG groups. LATG for gastric cancer has the advantage over an OTG in terms of better short-term outcomes and similar long-term outcome. LATG is an acceptable alternative to OTG for the treatment of gastric cancer.	f	\N
23541879	This consensus document was prepared by an expert panel of the Grupo de Estudio de Sida (GESIDA [Spanish AIDS Study Group]) and the Plan Nacional sobre el Sida (PNS [Spanish National AIDS Plan]). The document updates current guidelines on the treatment of tuberculosis (TB) in HIV-infected individuals contained in the guidelines on the treatment of opportunistic infections published by GESIDA and PNS in 2008. The document aims to facilitate the management and treatment of HIV-infected patients with TB in Spain, and includes specific sections and recommendations on the treatment of drug-sensitive TB, multidrug-resistant TB, and extensively drug-resistant TB, in this population. The consensus guidelines also make recommendations on the treatment of HIV-infected patients with TB in special situations, such as chronic liver disease, pregnancy, kidney failure, and transplantation. Recommendations are made on the timing and initial regimens of antiretroviral therapy in patients with TB, and on immune reconstitution syndrome in HIV-infected patients with TB who are receiving antiretroviral therapy. The document does not cover the diagnosis of TB, diagnosis/treatment of latent TB, or treatment of TB in children. The quality of the evidence was evaluated and the recommendations graded using the approach of the Grading of Recommendations Assessment, Development and Evaluation Working Group.	f	\N
23542225	BM failure (BMF) is a major and frequent complication of dyskeratosis congenita (DKC). Allogeneic hematopoietic SCT (allo-HSCT) represents the only curative treatment for BMF associated with this condition. Transplant-related morbidity/mortality is common especially after myeloablative conditioning regimens. Herein, we report nine cases of patients with DKC who received an allo-SCT at five different member centers within the Eastern Mediterranean Blood and Marrow Transplantation Registry. Between October 1992 and February 2011, nine DKC patients (male, 7 and female, 2), with a median age at transplantation of 19.1 (4.9-31.1) years, underwent an allo-HSCT from HLA-matched, morphologically normal-related donors (100%). Preparative regimens varied according to different centers, but was reduced intensity conditioning (RIC) in eight patients. Graft source was unstimulated BM in five cases (56%) and G-CSF-mobilized PBSCs in four (44%) cases. The median stem cell dose was 6.79 (2.06-12.4) × 10(6) cells/kg body weight. GVHD prophylaxis consisted of CsA in all nine cases; MTX or mycophenolate mofetil were added in five (56%) and two (22%) cases, respectively. Anti-thymocyte globulin was administered at various doses and scheduled in four (44%) cases. Median time-to-neutrophil engraftment was 21 (17-27) days. In one case, late graft failure was noted at 10.4 months post allo-HSCT. Only one patient developed grade II acute GVHD (11%). Extensive chronic GVHD was reported in one case, whereas limited chronic GVHD occurred in another four cases. At a median follow-up of 61 (0.8-212) months, seven (78%) patients were still alive and transfusion independent. One patient died of metastatic gastric adenocarcinoma and graft failure was the cause of death in another patient. This study suggests that RIC preparative regimens are successful in inducing hematopoietic cell engraftment in patients with BMF from DKC. Owing to the limited sample size, the use of registry data and heterogeneity of preparative as well as GVHD prophylaxis regimens reported in this series, we are unable to recommend a particular regimen to be considered as the standard for patients with this disease.	f	\N
23544766	To evaluate chemotherapy regimen utilization in patients with non-small cell lung cancer (NSCLC) treated in US community oncology practices, to examine the relationship between evidence-based guideline adherence and the follow-up monitoring period (FUMP) over 1.5 years, and to understand the relative costs of commonly administered chemotherapy regimens. Retrospective data analysis. Using a large US medical oncology clinical database derived from a proprietary web-based drug dispensing technology, we identified adult patients with NSCLC who started adjuvant therapy for early-stage disease or first-line therapy for advanced and metastatic disease from July 1, 2009, through June 30, 2010. Adjuvant or first-line regimen utilization and the FUMP within 1.5 years were analyzed with respect to national evidence-based guideline adherence. Costs for commonly administered regimens based on 2010 Medicare reimbursement were compared. A total of 3505 patient treatment regimens were included in this study. Rates of guideline adherence were 75.0% and 61.3% for the first-line and the adjuvant treatment groups, respectively (P < .0001). Treatment with guidelinebased regimens correlated with a significantly longer FUMP in the first-line treatment groupcompared with non-guideline-based regimens (P = .005). Regimen costs for the top 11 regimens in the adjuvant and first-line treatment settings varied greatly. Low-cost regimens were prescribed more commonly. Rates of guideline adherence were significantly higher in the first-line than in the adjuvant NSCLC treatment group. First-line treatment with guideline-based regimens correlated with an extended FUMP for advanced NSCLC patients.	f	\N
23544828	Osteoporosis is a systemic disease that affects millions of people worldwide. It is estimated that 50% of women and approximately 20% of men more than 50 years of age will sustain a fragility fracture. The cause of nonunion in patients with osteoporosis is likely multifactorial, and includes age-related changes in fracture repair as well as challenges in achieving stable internal fixation. This article discusses fracture healing in patients with osteoporosis and the principles of fixation. Pharmacotherapy for the patient with osteoporosis is also discussed.	f	\N
23547660	Tiotropium bromide is an effective therapy for COPD patients. Comparing across programs tiotropium Respimat Soft Mist inhaler was at least as efficacious as tiotropium HandiHaler, however, concerns have been raised about tiotropium's safety when given via Respimat. The TIOSPIR trial (NCT01126437) compares the safety and efficacy of tiotropium Respimat 5 μg once daily (marketed) and 2.5 μg once daily (investigational) with tiotropium HandiHaler 18 μ once daily (marketed). The hypotheses to be tested are 1). that tiotropium Respimat 5 μg once daily and Respimat 2.5 μg once daily are non-inferior to HandiHaler in terms of all-cause mortality, and 2). that tiotropium Respimat 5 μg once daily is superior to HandiHaler in terms of time to first exacerbation. A spirometry substudy evaluates the bronchodilator efficacy. The trial is a randomized, double-blind, double dummy, event-driven, parallel group study. Participants can use any background treatment for COPD except inhaled anticholinergic agents. The study encompasses a wide range of COPD patients, e.g. patients with stable cardiac diseases including arrhythmia can be included. Clinical sites are international and include both primary care as well as specialists. To date, over 17,000 participants have been randomized from over 1200 sites in 50 countries with an anticipated treatment duration of 2-3 years. TIOSPIR will provide precise estimates of the relative safety and efficacy of the Respimat and HandiHaler formulations of tiotropium, assess potential dose-dependence of important outcomes and provide information on the clinical epidemiology of COPD in a large international patient cohort.	f	\N
23549020	Metastatic prostate carcinoma commonly involves bones and extrapelvic lymph nodes, with occasional visceral deposits. Central nervous system involvement is unusual and particularly the occurrence of leptomeningeal metastasis (LM) is extremely rare, with few cases described in the medical literature. The clinical presentation is characterized by multifocal neurological deficit and the prognosis is generally dismal, with survival ranging between 3 and 6 months. We report on a patient affected by LM due to prostate cancer who was treated with a combined-modality approach consisting of sequential chemotherapy and radiotherapy. A 70-year-old man was referred to our group for cognitive mental disorder, left-sided frontal headache and nausea; the patient had a previous history of metastatic prostate cancer. LM was diagnosed neuroradiologically with brain MRI and evidence of a detectable level of PSA in the cerebrospinal fluid. He was treated with docetaxel and prednisone for 3 cycles followed by external beam radiotherapy (EBRT) to the whole brain to a total dose of 30 Gy in 10 fractions with a simultaneous integrated boost to the macroscopic disease (total dose of 35 Gy in 10 fractions). No acute toxicity was observed. A substantial clinical response was obtained after EBRT with neurological improvement and radiologically stable disease at post-treatment imaging until 10 weeks after radiation. The patient died of sudden general condition deterioration 3 months after EBRT. Since LM derived from prostate cancer is likely to become a more common clinical event, such patients would need to be included in clinical trials evaluating new therapeutic approaches, considering that the current treatment strategies have been shown to be rather ineffective.	f	\N
23549631	The prognosis of thrombotic thrombocytopenic purpura (TTP) has considerably improved since the introduction of plasma exchange (PEX) therapy. However, unresponsive thrombotic thrombocytopenic purpura (Un-TTP) still carries high morbidity and mortality rates, indicating a need for early specific treatments. In a retrospective study including consecutive adults with TTP admitted between January 1997 and January 2011 in a teaching hospital intensive care unit (ICU), our objective here is to identify early clinical and laboratory features predicting Un-TTP. Patients who responded to plasma exchange and steroids (N = 49) were compared with patients with unresponsive TTP defined as requirement for other treatments, protracted course, or death (N = 37, 43 %). Hospital mortality was 24.3 % in the Un-TTP group. Variables associated with Un-TTP on univariate logistic regression were older age, cardiac involvement, neurological involvement, higher anti-a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS13) immunoglobulin G (IgG) titer, lower platelet counts starting on day 2, higher Sequential Organ Failure Assessment (SOFA) scores starting on day 3, need for higher plasma volumes to obtain remission, and greater use of adjuvant treatments and life-sustaining interventions. Multivariate logistic regression identified four factors independently associated with Un-TTP: age over 60 years [odds ratio (OR) 7.90; 95 % confidence interval (95 % CI) 1.06-78.34], cardiac (OR 5.17; 95 % CI 1.63-16.39) or neurological (OR 8.04; 95 % CI 1.27-51.03) manifestations at diagnosis, and day 2 platelet count less than 15 G/l (OR 3.88; 95 % CI 1.30-11.62). Therapeutic intensification starting on day 3 or even earlier in patients with the independent risk factors for unresponsive TTP identified in our study deserves evaluation in a multicenter prospective study.	f	\N
23554958	Intracranial Artery Stenosis (ICAS) is one of the most common causes of ischemic stroke in Asia. Previous studies have shown the number of ideal cardiovascular health (CVH) metrics was associated with lower risk of stroke. This study aimed to investigate the relationship between ideal CVH metrics and prevalence of ICAS. A random sample of 5,412 participants (selected from Kailuan Study as a reference population) aged 40 years or older (40.10% women), free of stroke, transient ischemic attack, and coronary disease, were enrolled in the Asymptomatic Polyvascular Abnormalities Community study from 2010 to 2011. We collected information on the seven CVH metrics (including smoking, body mass index, dietary intake, physical activity, blood pressure, total cholesterol and fasting blood glucose); and assessed ICAS by transcranial Doppler. The relationship between the ideal CVH metrics and prevalence of ICAS was analyzed using the multivariate logistic regression. After adjusting for age, sex, and other potential confounders, the adjusted odds ratios(95% confidence interval) for ICAS were 0.76(0.58-0.99), 0.55(0.43-0.72), 0.49(0.37-0.65), 0.43(0.31-0.61), and 0.36(0.22-0.62), respectively, for those having 2, 3, 4, 5, and 6-7 ideal CVH metrics compared with those having 0-1 ideal metric(p-trend<0.0001). Similar inverse associations were observed in different age and gender groups (all p-trends<0.05). We found a clear gradient relationship between the number of ideal CVH metrics and lower prevalence of ICAS in a Chinese population, which supports the importance of ideal health behaviors and factors in the prevention of ICAS.	f	\N
23557197	Human leukocyte antigen matching at allelic resolution is proven clinically significant in hematopoietic stem cell transplantation, lowering the risk of graft-versus-host disease and mortality. However, due to the ever growing HLA allele database, tissue typing laboratories face substantial challenges. In light of the complexity and the high degree of allelic diversity, it has become increasingly difficult to define the classical transplantation antigens at high-resolution by using well-tried methods. Thus, next-generation sequencing is entering into diagnostic laboratories at the perfect time and serving as a promising tool to overcome intrinsic HLA typing problems. Therefore, we have developed and validated a scalable automated HLA class I and class II typing approach suitable for diagnostic use. A validation panel of 173 clinical and proficiency testing samples was analysed, demonstrating 100% concordance to the reference method. From a total of 1,273 loci we were able to generate 1,241 (97.3%) initial successful typings. The mean ambiguity reduction for the analysed loci was 93.5%. Allele assignment including intronic sequences showed an improved resolution (99.2%) of non-expressed HLA alleles. We provide a powerful HLA typing protocol offering a short turnaround time of only two days, a fully integrated workflow and most importantly a high degree of typing reliability. The presented automated assay is flexible and can be scaled by specific primer compilations and the use of different 454 sequencing systems. The workflow was successfully validated according to the policies of the European Federation for Immunogenetics. Next-generation sequencing seems to become one of the new methods in the field of Histocompatibility.	f	\N
23557266	Adhesion molecules play a key role in the pathogenetic mechanisms of inflammatory bowel disease (IBD), both in Crohn's disease (CD) and ulcerative colitis (UC). In the last decade, some progress has been made in understanding their key role in leukocyte trafficking control in terms of basic research, but evidence of clinical efficacy is lacking. In the last 2 years, new molecules directed against integrins and integrin receptors have been developed and investigated in clinical trials, showing that anti-α4β7 integrin agents can be effective and safe for the induction and maintenance of remission in active CD and UC. Preliminary data show that anti-MAdCAM, anti-β7 and anti-integrin receptor agents are not all effective in IBD. Such results open new perspectives on clinical management of IBD, and new directions in understanding the role of adhesion molecules and leukocyte recruitment both in CD and UC.	f	\N
23578358	Angiogenic stimulation is a promising new strategy for treating patients with arteriosclerotic coronary artery disease. This strategy aims to ameliorate cardiac function by improving myocardial perfusion and lowering the risk of myocardial infarction. However, angiogenesis may contribute to the growth of atherosclerotic lesions. Atherogenesis is also a potential side effect of angiogenic therapy. Early clinical trials were performed using fibroblast growth factor 2 (FGF2) protein, which enhances the formation of new collateral vessels to reduce ischaemic symptoms. Conversely, angiogenic stimulation by FGF2 is a dilemma because it could cause negative angiogenic effects, such as atherosclerosis. Thus far, clinical trials in patients with recombinant FGF2 protein therapy have not yet yielded undisputable beneficial effects. Future trials should determine whether an improvement can be obtained in patients with coronary artery disease using a combination of FGF2 and other growth factors or a combination of the FGF2 gene and stem cell therapy. This review summarises the multiple roles of FGF2 in the progression of atherosclerosis, its effect on pro-angiogenesis and improvement of cardiac function in coronary artery disease, and the potentially unfavourable effect of angiogenesis on the prevention and treatment of atherogenesis.	f	\N
23581956	To review cases of nosocomial influenza and compare the epidemiology, clinical characteristics and outcomes with community-acquired cases. Prospective case series of adults hospitalised with influenza during April - November of 2010 and 2011 using a hospital-based sentinel surveillance system. A nosocomial case was defined as polymerase chain reaction-confirmed influenza where symptom onset was more than 2 15s after admission or, if this was not known, where the date of the positive test was more than 7 15s after admission. Demographic, clinical and outcome measures for patients with nosocomial influenza compared with patients admitted with community-acquired influenza. In 2010-2011, 598 cases of influenza were detected, of which 26 (4.3%) were nosocomial. All patients with nosocomial influenza had chronic comorbidities, compared with 71.7% of patients (410/572) with community-acquired influenza (P = 0.001). Similar proportions of community-acquired (32.5%) and nosocomial (36.4%) cases occurred in patients vaccinated in the current season. Clinical findings at time of enrollment did not differ between the two groups, with similar rates of fever, cough, chest pain and dyspnoea. Compared with community-acquired cases, a higher proportion of patients with nosocomial influenza received neuraminidase inhibitors within 2 15s of symptom onset (38.5% v 15.9%; P = 0.003). Admission to intensive care took place in 21.3% and 23.1% of community-acquired and nosocomial cases, respectively. One death from nosocomial influenza occurred in a patient with end-stage respiratory disease. Nosocomial influenza is uncommon but may be associated with severe disease. It may be partially preventable as patients frequently have comorbidities for which influenza vaccination is recommended. Patients, particularly those at high risk of complications, and their contacts (including health care workers) should be vaccinated to prevent severe disease.	f	\N
23591331	Self-expandable metal stents (SEMSs) are used to relieve malignant biliary obstruction. To compare outcomes between covered self-expandable metal stents (CSEMSs) and uncovered self-expandable metal stents (USEMSs) in malignant biliary obstruction. Retrospective cohort study. Tertiary cancer center. Patients with malignant biliary obstruction. Placement of CSEMS or USEMS. Time to recurrent biliary obstruction (TRO), overall survival (OS), and adverse events. From January 2000 to June 2011, 749 patients received SEMSs: 171 CSEMSs and 578 USEMSs. At 1 year, there was no significant difference in the percentage of patients with recurrent obstruction (CSEMSs, 35% vs USEMSs, 38%) and survival (CSEMSs, 45% vs USEMSs, 49%). There was no significant difference in the median OS (CSEMSs, 10.4 months vs USEMSs, 11.8 months; P = .84) and the median TRO (CSEMSs, 15.4 months vs USEMSs, 26.3 months; P = .61). The adverse event rate was 27.5% for the CSEMS group and 27.7% for the USEMS group. Although tumor ingrowth with recurrent obstruction was more common in the USEMS group (76% vs 9%, P < .001), stent migration (36% vs 2%, P < .001) and acute pancreatitis (6% vs 1%, P < .001) were more common in the CSEMS group. Retrospective study. There was no significant difference in the patency rate or overall survival between CSEMSs and USEMSs for malignant distal biliary strictures. The CSEMS group had a significantly higher rate of migration and pancreatitis than the USEMS group. No significant SEMS-related adverse events were observed in patients undergoing neoadjuvant chemoradiation or surgical resection.	f	\N
23594492	To detect fully penetrant rare recessive variants that could constitute Mendelian subentities of complex diseases, we propose a novel strategy, the HBD-GWAS strategy, which can be applied to genome-wide association study (GWAS) data. This strategy first involves the identification of inbred individuals among cases using the genome-wide SNP data and then focuses on these inbred affected individuals and searches for genomic regions of shared homozygosity by descent that could harbor rare recessive disease-causing variants. In this second step, analogous to homozygosity mapping, a heterogeneity lod-score, HFLOD, is computed to quantify the evidence of linkage provided by the data. In this paper, we evaluate this strategy theoretically under different scenarios and compare its performances with those of linkage analysis using affected sib-pair (ASP) data. If cases affected by these Mendelian subentities are not enriched in the sample of cases, the HBD-GWAS strategy has almost no power to detect them, unless they explain an important part of the disease prevalence. The HBD-GWAS strategy outperforms the ASP linkage strategy only in a very limited number of situations where there exists a strong allelic heterogeneity. When several rare recessive variants within the same gene are involved, the ASP design indeed often fails to detect the gene, whereas, by focusing on inbred individuals using the HBD-GWAS strategy, the gene might be detected provided very large samples of cases are available.	f	\N
23594728	The presence of baseline proteinuria predicts the outcome in patients with chronic kidney disease and in the general population, independent of renal function. However, the predictive value of proteinuria during an episode of acute illness has not been reported yet. Therefore, we investigated the incidence and predictive value of proteinuria in patients with community-acquired pneumonia. An analysis of prospectively collected data, obtained from patients >18 years of age, was performed. Patients were hospitalized with community-acquired pneumonia in two hospitals in the Netherlands and participated in two consecutive clinical trials. A total protein/creatinine (P/C) ratio was measured in a urine sample from the day of admission. Patients were categorized in quartiles of P/C ratio. Primary outcome was length of hospital stay. 198/319 patients (62%) had a P/C ratio >23 mg/mmol creatinine. In multivariate analysis, proteinuria turned out to be an independent predictor for length of stay and admission to the intensive care unit. The incidence of proteinuria during pneumonia is high and proteinuria is an independent predictor for length of hospital stay and admission to the intensive care unit. Proteinuria is a cheap and easily accessible marker for outcome and might be used to assess the severity of pneumonia.	f	\N
23602249	Obesity is associated with elevated risk of heart disease. A solid understanding of the safety and potential adverse effects of high-fat, low-carbohydrate diet (HFLCD) similar to that used by humans for weight loss on the heart is crucial. High fat intake is known to promote increases in reactive oxygen species and mitochondrial damage. We hypothesized that there would be adverse effects of HFLCD on myocardial ischemia/reperfusion injury through enhancing oxidative stress injury and impairing mitochondrial biogenesis in a nongenetic, diet-induced rat model of obesity. To test the hypothesis, 250-g male Sprague-Dawley rats were fed an obesity-promoting diet for 7 weeks to induce obesity, then switched to HFLCD or a low-fat control diet for 2 weeks. Isolated hearts underwent global low flow ischemia for 60 minutes and reperfusion for 60 minutes. High-fat, low-carbohydrate diet resulted in greater weight gain and lower myocardial glycogen, plasma adiponectin, and insulin. Myocardial antioxidant gene transcript and protein expression of superoxide dismutase and catalase were reduced in HFLCD, along with increased oxidative gene NADPH oxidase-4 transcript and xanthine oxidase activity, and a 37% increase in nitrated protein (nitrotyrosine) in HFLCD hearts. The cardiac expression of key mitochondrial regulatory factors such as nuclear respiratory factor-1 and transcription factor A-mitochondrial were inhibited and myocardial mitochondrial DNA copy number decreased. The cardiac expression of adiponectin and its receptors was down-regulated in HFLCD. High-fat, low-carbohydrate diet impaired recovery of left ventricular rate-pressure product after ischemia/reperfusion and led to 3.5-fold increased injury as measured by lactate dehydrogenase release. In conclusion, HFLCD leads to increased ischemic myocardial injury and impaired recovery of function after reperfusion and was associated with attenuation of mitochondrial biogenesis and enhanced oxidative stress in obese rats. These findings may have important implications for diet selection in obese patients with ischemic heart disease.	f	\N
23607333	Genetic polymorphism studies of cytokines may provide an insight into the understanding of acute kidney injury (AKI) and death in intensive care unit (ICU) patients. The aim of this study was to investigate whether the genetic polymorphisms of -308 G < A tumour necrosis factor (TNF)-α, -174 G > C interleukin (IL)-6 and -1082 G > A IL-10 may predispose ICU patients to the development of AKI and/or death. In a prospective nested case-control study, 303 ICU patients and 244 healthy individuals were evaluated. The study group included ICU patients who developed AKI (n = 139) and 164 ICU patients without AKI. The GG genotype of TNF-α (low producer phenotype) was significantly lower in the with AKI than without AKI groups and healthy individuals (55 versus 62 versus 73%, respectively; P = 0·01). When genotypes were stratified into four categories of TNF-α/IL-10 combinations, it was observed that low TNF-α plus low IL-10 producer phenotypes were more prevalent in patients with AKI, renal replacement therapy and death (P < 0·05). In logistic regression analysis, low TNF-α producer plus low IL-10 producer phenotypes remained as independent risk factors for AKI and/or death [odds ratio (OR) = 2·37, 95% confidence interval (CI): 1·16-4·84; P = 0·02] and for renal replacement therapy (RRT) and/or death (OR = 3·82, 95% CI: 1·19-12·23; P = 0·02). In this study, the combination of low TNF-α plus low IL-10 producer phenotypes was an independent risk factor to AKI and/or death and RRT and/or death in critically ill patients. Our results should be validated in a larger prospective study with long-term follow-up to emphasize the combination of these genotypes as potential risk factors to AKI in critically ill patients.	f	\N
23613224	High-intensity interval training (HIT) as exercise therapy is gradually implemented in cardiac rehabilitation as the cardiovascular benefits from exercise is intensity dependent. However, in previous studies, HIT has been performed with strict supervision. The aim of the study was to assess the feasibility and effectiveness of different modes of HIT in cardiac rehabilitation. a randomized clinical study. Ninety participants with coronary artery disease (80 men/10 women, mean age 57 ± 8 years) were randomly assigned to one of three exercise modes: group exercise (GE), treadmill exercise (TE), or home-based exercise (HE). HIT was performed twice a week for 12 weeks with an exercise intensity of 85-95% of peak heart rate. The primary outcome measure was change in peak oxygen uptake (peak VO2). Eighty-three participants (92%) completed the intervention without any severe adverse events. Peak VO2 increased from 34.7 ± 7.3 to 39.0 ± 8.0 ml/kg/min, 32.7 ± 6.5 to 36.0 ± 6.2 ml/kg/min, and 34.4 ± 4.8 to 37.2 ± 5.2 ml/kg/min in TE, GE, and HE, respectively. Mean group difference for TE vs. HE was 1.6 ml/kg/min (95% confidence interval, CI, 0.7 to 3.1, p = 0.02), TE vs. GE 1.1 ml/kg/min (95% CI-0.5 to 2.5, p = 0.27), and GE vs. HE 0.6 ml/kg/min (95% CI -1.0 to 2.1, p = 1). However, on-treatment analysis showed no significant difference between groups. HIT was efficiently performed in three settings of cardiac rehabilitation, with respect to target exercise intensity, exercise attendance, and increase in peak VO2. Exercise mode was not essential for exercise capacity.	f	\N
23613636	To investigate the significance of Twist2 for colorectal cancer (CRC). In this study, 93 CRC patients were included who received curative surgery in Eastern Hepatobiliary Surgery Hospital from January 1999 to December 2010. Records of patients' clinicopathological characteristics and follow up data were reviewed. Formalin-fixed, paraffin-embedded tissue blocks were used to observe the protein expression of Twist2 and E-cadherin by immunohistochemistry. Two independent pathologists who were blinded to the clinical information performed semiquantitative scoring of immunostaining. A total score of 3-6 (sum of extent + intensity) was considered as Twist2-positive expression. The expression of E-cadherin was divided into two levels (preserved and reduced). An exploratory statistical analysis was conducted to determine the association between Twist2 expression and clinicopathological parameters, as well as E-cadherin expression. Furthermore, the variables associated with prognosis were analyzed by Cox's proportional hazards model. Kaplan-Meier analysis was used to plot survival curves according to different expression levels of Twist2. Twist2-positive expression was observed in 66 (71.0%) samples and mainly located in the cytoplasm. Forty-three (46.2%) samples showed reduced expression of E-cadherin. There were no significant correlations between Twist2 expression and any of the clinicopathological parameters. However, Twist2-positive expression was significantly associated with reduced expression of E-cadherin (P = 0.040). Multivariate analysis revealed that bad M-stage [hazard ratio (HR) = 7.694, 95%CI: 2.927-20.224, P < 0.001] and Twist2-positive (HR = 5.744, 95%CI: 1.347-24.298, P = 0.018) were the independent risk factors for poor overall survival (OS), while Twist2-positive (HR = 3.264, 95%CI: 1.455-7.375, P = 0.004), bad N-stage (HR = 2.149, 95%CI: 1.226-3.767, P = 0.008) and bad M-stage (HR = 10.907, 95%CI: 4.937-24.096, P < 0.001) were independently associated with poor disease-free survival (DFS). Survival curves showed a definite trend for Twist2-negative patients to have longer OS and DFS than Twist2-negative patients, not only overall, but also for patients in different stages, especially for DFS of patients in stage III (P = 0.033) and IV (P = 0.026). Our data suggests, for the first time, that Twist2 is a valuable prognostic biomarker for CRC, particularly for patients in stage III and IV.	f	\N
23617953	By definition, a generic product is considered interchangeable with the innovator brand product. Controversy exists about interchangeability, and attention is predominantly directed to contaminants. In particular for chronic, degenerative conditions such as in Parkinson's disease (PD) generic substitution remains debated among physicians, patients and pharmacists. The objective of this study was to compare the pharmaceutical quality of seven generic levodopa/benserazide hydrochloride combination products marketed in Germany with the original product (Madopar® / Prolopa® 125, Roche, Switzerland) in order to evaluate the potential impact of Madopar® generics versus branded products for PD patients and clinicians. Madopar® / Prolopa® 125 tablets and capsules were used as reference material. The generic products tested (all 100 mg/25 mg formulations) included four tablet and three capsule formulations. Colour, appearance of powder (capsules), disintegration and dissolution, mass of tablets and fill mass of capsules, content, identity and amounts of impurities were assessed along with standard physical and chemical laboratory tests developed and routinely practiced at Roche facilities. Results were compared to the original "shelf-life" specifications in use by Roche. Each of the seven generic products had one or two parameters outside the specifications. Deviations for the active ingredients ranged from +8.4% (benserazide) to -7.6% (levodopa) in two tablet formulations. Degradation products were measured in marked excess (+26.5%) in one capsule formulation. Disintegration time and dissolution for levodopa and benserazide hydrochloride at 30 min were within specifications for all seven generic samples analysed, however with some outliers. Deviations for the active ingredients may go unnoticed by a new user of the generic product, but may entail clinical consequences when switching from original to generic during a long-term therapy. Degradation products may pose a safety concern. Our results should prompt caution when prescribing a generic of Madopar®/Prolopa®, and also invite to further investigations in view of a more comprehensive approach, both pharmaceutical and clinical.	f	\N
23620363	The number of missense mutations being identified in cancer genomes has greatly increased as a consequence of technological advances and the reduced cost of whole-genome/whole-exome sequencing methods. However, a high proportion of the amino acid substitutions detected in cancer genomes have little or no effect on tumour progression (passenger mutations). Therefore, accurate automated methods capable of discriminating between driver (cancer-promoting) and passenger mutations are becoming increasingly important. In our previous work, we developed the Functional Analysis through Hidden Markov Models (FATHMM) software and, using a model weighted for inherited disease mutations, observed improved performances over alternative computational prediction algorithms. Here, we describe an adaptation of our original algorithm that incorporates a cancer-specific model to potentiate the functional analysis of driver mutations. The performance of our algorithm was evaluated using two separate benchmarks. In our analysis, we observed improved performances when distinguishing between driver mutations and other germ line variants (both disease-causing and putatively neutral mutations). In addition, when discriminating between somatic driver and passenger mutations, we observed performances comparable with the leading computational prediction algorithms: SPF-Cancer and TransFIC. A web-based implementation of our cancer-specific model, including a downloadable stand-alone package, is available at http://fathmm.biocompute.org.uk.	f	\N
23620431	To report the findings of en face adaptive optics (AO) near infrared (NIR) reflectance fundus flood imaging in eyes with geographic atrophy (GA). Observational clinical study of AO NIR fundus imaging was performed in 12 eyes of nine patients with GA, and in seven controls using a flood illumination camera operating at 840 nm, in addition to routine clinical examination. To document short term and midterm changes, AO imaging sessions were repeated in four patients (mean interval between sessions 21 days; median follow up 6 months). As compared with scanning laser ophthalmoscope imaging, AO NIR imaging improved the resolution of the changes affecting the RPE. Multiple hyporeflective clumps were seen within and around GA areas. Time-lapse imaging revealed micrometric-scale details of the emergence and progression of areas of atrophy as well as the complex kinetics of some hyporeflective clumps. Such dynamic changes were observed within as well as outside atrophic areas. in eyes affected by GA, AO nir imaging allows high resolution documentation of the extent of RPE damage. this also revealed that a complex, dynamic process of redistribution of hyporeflective clumps throughout the posterior pole precedes and accompanies the emergence and progression of atrophy. therefore, these clumps are probably also a biomarker of rpe damage. AO NIR imaging may, therefore, be of interest to detect the earliest stages, to document the retinal pathology and to monitor the progression oF GA. (ClinicalTrials.gov number, NCT01546181.).	f	\N
23625177	Expression and function of the immunoregulatory molecule HLA-E was investigated in patients with relapsing-remitting (RR) multiple sclerosis (MS). Serum and cerebrospinal fluid (CSF) soluble (s)HLA-E and -G levels were measured by ELISA in 80 RRMS patients. Controls were patients with other inflammatory neurological disorders (OIND, n = 81) and noninflammatory neurological disorders (NIND, n = 86). Serum sHLA-E concentrations were higher in RRMS than in NIND patients only. CSF sHLA-E concentrations were higher in RRMS than controls. Increased CSF sHLA-E levels were detected in MRI inactive and clinically stable RRMS patients. sHLA-E intrathecal synthesis (ITS) was higher in RRMS than controls, and the number of patients with sHLA-E ITS above cut-off was higher i) in MS than controls, and ii) in clinically stable than clinically active MS patients. sHLA-E CSF levels and ITS correlated with i) the same sHLA-G parameters, and ii) disease duration. HLA-E expression and co-expression with CD markers were investigated in MS plaques from three different cases by immunohistochemistry and confocal microscopy, respectively. Infiltrating T lymphocytes and macrophages, as well as resident microglial cells and astrocytes expressed HLA-E. CSF samples from MS patients were finally tested for inhibitory activity of in vitro CTL and NK cell mediated cytotoxicity. sHLA-E⁺ were more effective than sHLA-E⁻ CSF samples in such inhibition. Maximum inhibition was achieved with sHLA-E⁺/sHLA-G⁺ CSF samples In conclusion, increased sHLA-E CSF levels may play an immunomodulatory role in MS, contributing to the inhibition of intrathecal inflammatory response. The potential of sHLA-E as biomarker of MS activity warrants further investigation.	f	\N
23628099	The apex is a particular region of the prostate in its surgical dissection and pathological analysis. We sought to evaluate the prognostic value of the apical localization of prostate tumors. From 1988 to 2010, data pre- (age, clinical stage, preoperative PSA, biopsy Gleason score) and postoperative (prostate weight, pathologic stage TNM 2010, Gleason score, margin status) of 2765 total prostatectomies were collected prospectively. These data were compared according to existence or absence of tumor at the apex. The prognostic impact of tumor at the apex on biochemical recurrence-free survival (PSA>0.2 ng/mL) has been studied in univariate and multivariate models. One thousand eight hundred seventeen tumors had a location at the apex (65.7%). In univariate analysis, there was a significant difference in the clinical stage, the biopsy and pathological Gleason score, the result of curage, the pathological stage and the margin status between apical tumors and others. With a mean decline of 34.6 months, 502 patients had a biochemical recurrence (18.1%). Disease-free survival at 10 years was 60.7% for tumor at the apex versus 65.9% in other cases. The location at the apex was significantly associated with biochemical recurrence on univariate analysis (P=0.01). After adjustment for clinical and pathological stage, PSA level, Gleason score and surgical margins, the apex was not anymore a pejorative independent predictor (P=0.0087). The existence of tumor in the prostatic apex was associated with more aggressive tumoral criteria and was an independent and pejorative predictor of biochemical recurrence-free survival at 10 years in univariate analysis. The apical localization could be an additional argument in the decision of adjuvant therapy after prostatectomy.	f	\N
23638302	Immune cells called mast cells can hinder rather than help the body's response to dengue virus, which suggests that mast cell products could be used as biomarkers to identify severe forms of the disease.	f	\N
23644526	Vertebral metastases affect 20 to 50% of cancer patients and represent a major turning point in the disease from the functional impact they generate. Early treatment is mandatory to prevent or treat any neurological compression. Due to the high variability of clinical and radiological presentations, best care requires a multidisciplinary team, involving oncologists, radiation oncologists, interventional radiologists and spine surgeons. Recent advances in radiotherapy and interventional radiology have offered various efficient therapeutic solutions with relatively low morbidity rate in the management of symptomatic spine metastases. However, surgery remains the standard treatment for patients with rapidly progressive spinal cord compression or significant osteolytic lesion leading to a high risk of fracture. However, conventional surgical strategies are associated with significant morbidity and contraindicated in patients in poor general condition. In addition, postoperative complications are likely to affect patient's quality of life and delay the initiation of anticancer therapies. In order to reduce iatrogenic lesions, new "minimally invasive" techniques were developed to achieve immediate stabilisation and decompression while reducing the morbidity of the approach. We aim to inform the reader of the existence of these techniques so that each patient can benefit from treatment best suited to their situation.	f	\N
23645623	Weight gain increases the prevalence of obesity, a risk factor for cardiovascular disease. Nevertheless, unintentional weight loss can be a harbinger of health problems. The Atherosclerosis Risk in Communities Study (1987-2009) included 15,792 US adults aged 45-64 years at baseline and was used to compare associations of long-term (30 years) and short-term (3 years) weight change with the risks of coronary heart disease (CHD) and ischemic stroke. Age-, gender-, and race-standardized incidence rates were 4.9 (95% confidence interval (CI): 4.6, 5.2) per 1,000 person-years for CHD and 2.5 (95% CI: 2.3, 2.8) per 1,000 person-years for stroke. After controlling for baseline body mass index and other covariates, long-term weight gain (since age 25 years) of more than 2.7% was associated with elevated CHD risk, and any long-term weight gain was associated with increased stroke risk. Among middle-aged adults, short-term (3-year) weight loss of more than 3% was associated with elevated immediate CHD risk (hazard ratio = 1.46, 95% CI: 1.18, 1.81) and stroke risk (hazard ratio = 1.45, 95% CI: 1.10, 1.92). Risk tended to be larger in adults whose weight loss did not occur through dieting. Avoidance of weight gain between early and middle adulthood can reduce risks of CHD and stroke, but short-term, unintentional weight loss in middle adulthood may be an indicator of immediate elevated risk that has not previously been well recognized.	f	\N
23649916	CD146 is an adhesion molecule localized at endothelial cell junctions and facilitates cell-cell interactions. The circulating soluble form (sCD146) lacks both the intracellular and the transmembrane domains. In this study we show that CD146 expression was significantly decreased in the lung tissue of smokers with chronic obstructive pulmonary disease (COPD) and also in rats exposed to second-hand smoke (SHS). Concurrently, levels of sCD146 were increased in both the plasma and bronchoalveolar lavage fluid (BALF) of COPD patients as well as in BALF from rats exposed to SHS. Decreased or abolished CD146 protein expression in rat pulmonary micro- and macrovascular endothelial cells was found after treatment with cigarette smoke extract (CSE), proinflammatory cytokine interleukin 18 (IL-18) or after silencing CD146 expression with siRNA. The decrease in CD146 protein was accompanied by increased endothelial monolayer permeability and enhanced macrophage infiltration in vitro. In CD146 knockout (KO) mice, distinct perivascular oedema was seen and increased numbers of inflammatory cells, along with increased protein levels in BALF. Increased sCD146 was found in BALF and plasma from patients with COPD. The circulating plasma levels of sCD146 correlated positively with the presence of anti-endothelial cell antibodies (AECAs). sCD146 in combination with AECAs may be useful markers for early detection of COPD. Our study indicates that loss of CD146 function damages pulmonary endothelial integrity. This damage may represent part of the pathophysiological processes that are involved in the basic aetiology of COPD/emphysema.	f	\N
23653428	Colistin is increasingly used as the last-resort treatment option against infections caused by multidrug-resistant (MDR) Gram-negative pathogens, but its nephrotoxicity is of concern, especially in severely ill patients. The aim of this study was to analyze the toxicity of colistin therapy in adults and children with hematological malignancies (HM) and hematopoietic stem cell transplantation (HSCT) recipients. Data on HSCT recipients and HM patients, treated with intravenous colistin (2.5-5 mg/kg/day in children and 3-6 million international units (IU) in adults, adjusted to renal function) during the period 2008-2011 in our center, were retrospectively collected and analyzed. Nephrotoxicity was defined according to the RIFLE criteria (Risk, Injury, Failure, Loss, and End-stage kidney disease). Twenty-nine children and adults received 38 courses of intravenous colistin (2.5-5 mg/kg/day in children and 3-6 × 10(6) IU in adults, adjusted to renal function) [allogeneic HSCT (22 courses) and HM (16 courses)] for 3-28 days (median 10 days) for empirical therapy for nosocomial clinical sepsis (28) or local infection (6), and bacteremia with MDR Gram-negative rods (4). Nephrotoxicity was observed at the end of 4 (10.5%) courses. In 32 (84%) courses, nephrotoxic medications were concomitantly administered. Two patients had convulsions, probably unrelated to colistin. Seven patients (18%) died while on colistin therapy. No death was attributed to an adverse effect of colistin. Treatment with intravenous colistin, with dosage adjusted to renal function, was relatively safe for HM/HSCT patients, even with concomitantly administered nephrotoxic medications. Concern about nephrotoxicity should not justify a delay in initiating empirical colistin treatment in situations where infection with MDR Gram-negative rods is likely.	f	\N
23658247	The implementation of national estimated glomerular filatration rate reporting and the inclusion of renal-specific indicators in a primary care pay for performance (P4P) system since April 2006 has promoted identification and better management of risk factors related to chronic kidney disease (CKD). In the UK, the P4P framework is known as the Quality and Outcomes Framework (QOF). One of the key targets for intervention in primary care was hypertension. It is clear that hypertension is a major predictor of development and progression of CKD; thus, targeting better blood pressure control is likely to have a positive impact on outcomes in CKD. The aim of this study was to evaluate the effectiveness of renal indicators outlined in P4P on the management of hypertension in primary care. To estimate the cost implications of the resulting changes in prescribing patterns of antihypertensive medication following introduction of such indicators. We performed a prospective cohort study using a large primary care database. This cohort was taken from a database collated as part of a clinical decision support system used to assist the management of CKD in primary care. We investigated a total population of 90 250 individuals on general practitioner (GP) registers with a valid serum creatinine estimation in the 6-year study period. A total of 10 040 patients had confirmed stage 3-5 CKD in the 2 years pre-QOF and formed the study cohort. Patients were studied over three time periods, pre-QOF (1 April 2004 to 31 March 2006), 2 years post-QOF (1 April 2006 to 31 March 2008) and finally the two subsequent years (1 April 2008 to 31 March 2010). The mean systolic and diastolic blood pressures (BP) together with antihypertensive medication were analysed over the three time periods. Cost calculation was based on 2009 British National Formulary list prices for antihypertensives. The mean age of the cohort at the start of the study period was 64.8 years, 55% were female. In those patients with stage 3-5 CKD 83.9% were hypertensive, defined by a pre-P4P BP of >140/85 or currently taking antihypertensive medication. The proportion of patients with CKD 3-5 attaining the BP target of 145/80 increased from 41.5% in the pre-QOF period to 50.0% in the post-QOF period. This increase was even more marked for those with hypertension in the pre-QOF period (28.8-45.1%). In the hypertensive patients, mean BP fell from 146/79 mmHg to 140/76 in the first 2 years post-P4P [P < 0.01, analysis of variance (ANOVA)]. This BP reduction was sustained in the last 2 years of the study, 139/75 (P < 0.01, ANOVA). The proportion of hypertensive patients taking angiotensin-converting enzyme inhibitors or angiotensin blockers increased, this was also sustained in the third time period. An increase in the prescribing of diuretics, calcium channel blockers and β-blockers was also observed. The additional cost of increased prescribing was calculated to be €25.00 per hypertensive patient based on GP prescription data. Population BP control has improved since the introduction of P4P renal indicators, and this improvement has been sustained. This was associated with a significant increase in the use of antihypertensive medication, resulting in increased prescription cost. Longer-term follow-up will establish whether or not this translates to improved outcomes in terms of progression of CKD, cardiovascular disease and patient mortality.	f	\N
23662931	An intradural somatic-to-autonomic anastomosis, or Xiao procedure, has been described to create a "skin-CNS-bladder" reflex that improves bladder and bowel function in patients with neurogenic bladder and bowel dysfunction. The authors present their experience with a 10-year-old boy with chronic neurogenic bladder and bowel dysfunction related to spinal cord injury who underwent the Xiao procedure. After undergoing a left L-5 ventral root to left S2-3 intradural anastomosis, the patient reported that his bladder and bowel dysfunction improved between 6 and 12 months. Two years after the procedure, however, he reported that there was no change in his bladder or bowel dysfunction as compared with his condition prior to the procedure. Frequent, systematic multidisciplinary evaluations produced conflicting data. Electrophysiological and histological evaluation of the previously performed anastomosis during surgical reexploration 3 years after the Xiao procedure revealed that the anastomosis was in anatomical continuity but neuroma formation had prevented reinnervation. Nerve action potentials were not demonstrable across the anastomosis, and stimulation of the nerve above and below the anastomosis created no bladder or perineal contractions. This is the first clinical report on the outcome of the Xiao procedure in a child with spinal cord injury outside of China. It is impossible to draw broad conclusions about the efficacy of the procedure based on a single patient with no demonstrable benefit. However, future studies should carefully interpret transient improvements in bladder function, urodynamic findings, and the patient's ability to void in response to scratching after the Xiao procedure. The authors' experience with the featured patient, in whom reinnervation could not be demonstrated, suggests that such changes could be related to factors other than the establishment of a skin-CNS-bladder reflex as a result of a somatic-to-autonomic anastomosis.	f	\N
23664519	In the field of emerging innovative therapies, such as thrombopoietin mimetics, the question of who needs splenectomy remains highly relevant. Removal of the spleen is an accepted and potentially curative treatment of immune thrombocytopenia (ITP) after decades with a favorable economical-effect ratio but with relevant morbidity particularly in the young patients. ITP is rare and splenectomy is performed in a minority of children, which makes its research almost impossible, resulting in a poor standardization of the procedure. Hence, in children, recommendation and decision for splenectomy is individually based and rests on expert opinions. Furthermore, local practice and availability of health products affect the frequency of splenectomy. Current guidelines agree on one point: splenectomy should be postponed for at least 12 months after the initial diagnosis of ITP, due to the high probability of improvement or even spontaneous remission. However, evidence-based data are lacking and splenectomy remains controversial. This article reviews the current literature and delineates controversies and complexities of splenectomy in children with ITP. There is an urgent need for consensus of this procedure in pediatric patients.	f	\N
23668671	Recent genome-wide association studies have identified multiple loci associated with BMI or the waist:hip ratio (WHR). However, evidence on gene-lifestyle interactions is still scarce, and investigation of the effects of well-documented dietary and other lifestyle data is warranted to assess whether genetic risk can be modified by lifestyle. We assessed whether previously established BMI and WHR genetic variants associate with obesity and weight change in the Finnish Diabetes Prevention Study, and whether the associations are modified by dietary factors or physical activity. Individuals (n 459) completed a 3 d food record and were genotyped for twenty-six BMI- and fourteen WHR-related variants. The effects of the variants individually and in combination were investigated in relation to obesity and to 1- and 3-year weight change by calculating genetic risk scores (GRS). The GRS were separately calculated for BMI and the WHR by summing the increasing alleles weighted by their published effect sizes. At baseline, the GRS were not associated with total intakes of energy, macronutrients or fibre. The mean 1- and 3-year weight changes were not affected by the BMI or WHR GRS. During the 3-year follow-up, a trend for higher BMI by the GRS was detected especially in those who reported a diet low in fibre (P for interaction=0·065). Based on the present findings, it appears unlikely that obesity-predisposing variants substantially modify the effect of lifestyle modification on the success of weight reduction in the long term. In addition, these findings suggest that the association between the BMI-related genetic variants and obesity could be modulated by the diet.	f	\N
23669496	We evaluated the prevalence of chronotropic incompetence (CI), a marker of autonomic dysfunction, and its prognostic value in patients with chronic obstructive pulmonary disease (COPD). We performed a retrospective analysis of 449 patients with severe COPD who underwent a cardiopulmonary exercise test, after excluding patients with lung volume reduction surgery, left ventricular dysfunction and those not in sinus rhythm. CI was defined as percent predicted heart rate reserve (%HRR). Events were defined as death or lung transplant during a median follow-up of 68 months. Median age was 61 years; median percent predicted forced expiratory volume in one second (%FEV1) of 25% and median %HRR of 33%. The hazard ratio for an event in the lowest quartile of %HRR, taking the highest quartile as reference, was of 3.2 (95% confidence interval: 2.1-4.8; p<0.001). In a multivariate regression model, %HRR was an independent predictor of events. In conclusion, CI was an independent and powerful outcome predictor in patients with severe COPD.	f	\N
23669598	Although human papillomavirus (HPV) infections have been causally linked to oral cavity squamous cell carcinoma (OSCC), the potential role of low-risk HPV (LR-HPV) types in the pathogenesis of this malignancy remains unclear. We sought to investigate the distribution of HPV genotypes and their prognostic significance in OSCC patients treated by radical surgery, either with or without adjuvant therapy. We studied two non-overlapping OSCC cohorts for the periods 2005-2006 (2005 cohort, n = 204) and 2010-2011 (2010 cohort, n = 206). Paraffin-embedded tissue blocks were collected, and the HPV genotype was determined using PCR plus HPV blot tests. The primary study endpoint was the prevalence of HPV genotypes. The secondary endpoints were the 2-year therapeutic outcomes. The overall prevalence of HPV infections did not differ significantly in the two study cohorts. However, the prevalence of LR-HPV was significantly higher in the 2010 cohort than in the 2005 cohort (p = 0.002). The overall prevalence of HPV infections was not significantly associated with the 2-year outcomes. However, multivariate analysis demonstrated that LR-HPV infection was a predictor of poor 2-year disease-free survival (p = 0.036, hazard ratio [HR] = 3.1), disease-specific survival (p = 0.014, HR = 3.8), and overall survival (p = 0.016, HR = 3.2) in the subgroups of OSCC patients with poor differentiation, pN2 lymph node metastases, or extracapsular spread (n = 150). LR-HPV infections may have an important role in determining the clinical outcomes of certain OSCC patients bearing specific risk factors.	f	\N
23670309	It is a matter of debate whether increased brain iron levels are the cause or only the consequence of neurodegenerative process in degenerative parkinsonism. The aim of this study is to characterize disease-related changes in volumes and iron-related R2 values of basal ganglia and thalamus. 13 patients with progressive supranuclear palsy (PSP), 15 with a parkinsonian variant of multiple system atrophy (MSA-p), 29 with Parkinson's disease (PD), and 21 age-matched controls underwent 3-Tesla MRI. The R2 values and volumes were calculated for the selected subcortical structures (caudate nucleus, putamen, globus pallidus, and thalamus) using an automated region-based analysis. Voxel-based analysis was also performed to visualize a topographical correlation of R2 value and volume. The PSP group had significantly higher R2 values in globus pallidus and caudate nucleus (p < 0.05), whereas the MSA-p group had higher R2 values in putamen (p < 0.001) than PD and controls. The globus pallidus in PSP and the putamen in MSA-p were the most significant areas of atrophy to differentiate PSP, MSA-p and PD (AUC = 0.856, 0.832, respectively, p < 0.001). The R2 values in both structures increased in parallel with the extent of atrophy. They were negatively correlated with volumes in putamen (r = -0.777, p < 0.001) and globus pallidus (r = -0.409, p = 0.025) of MSA-p, and globus pallidus (r = -0.4, p = 0.043) of PSP. Voxel-based analysis identified higher R2 values in more severely atrophic sub-regions in these structures. We observed topographical differences of iron deposition as well as atrophy between MSA-p and PSP. Increased iron levels were related to the structural atrophy in basal ganglia. Our results imply that iron accumulation is likely an epiphenomenon of the degenerative process.	f	\N
23682773	Some studies have shown differences in specific cognitive ability domains between the sexes at 60 years-of-age. However is important to analyze whether the rate of cognitive decline is also similar between the sexes after this age. The present study examined previously published literature to investigate whether cognitive decline is distinct between men and women after the age of 60 years. A systematic review was carried out with the PubMed, LILACS and PsycINFO databases (2001-2011) using the following search terms: aging, aged, cognitive function, mild cognitive impairment, mental health and cognition. We analyzed longitudinal research that used neuropsychological tests for evaluating cognitive function, showed results separated by sex and that excluded participants with dementia. Elderly women showed better performance in tests of episodic memory, whereas elderly men had a better visuospatial ability. Only one study detected distinct rates of cognitive decline in specific tests between the sexes. Despite differences observed in some domains, most of the studies showed that this rate is similar between the sexes until the age of 80 years. It is unclear whether sex influences the rate of cognitive decline after the age of 80 years. The present review observed that sex does not determine the rate of cognitive decline between 60 and 80 years-of-age. The contextual and cultural factors that involve men and women might determine a distinct decline between them, rather than sex alone.	f	\N
23683938	The serum level of LOX-1 ligand containing ApoB (LAB) may reflect atherogenicity better than LDL cholesterol (LDLC), total LDL particles and usual measurement of oxidized LDL. The association between LAB and intima-media thickness (IMT) of carotid artery was investigated by ultrasound in US and Japan men. Participants were 297 US Caucasian and 310 Japanese men, aged 40-49 years without past history of cardiovascular disease. Serum LAB levels were measured by ELISAs with recombinant LOX-1 and monoclonal anti-apolipoprotein B antibody. Serum LAB levels [median (interquartile range), μg/L] were 1321 (936, 1730) in US Caucasians and 940 (688, 1259) in Japanese. For Caucasian men, average IMT was higher in higher LAB quartile, which was 0.653, 0.667, 0.688, and 0.702 mm, respectively (p for trend = 0.02). Linear regression analysis showed serum LAB was significantly associated with IMT after adjustment for LDLC or total LDL particles in addition to other traditional or novel risk factors for atherosclerosis such as C-reactive protein. However, there was no significant relationship between LAB and IMT in Japanese men. Serum LAB, a new candidate biomarker for residual risk, was associated with an increased carotid IMT in US Caucasian men independently of various risk factors; however, ethnic difference should be clarified in the future.	f	\N
23685553	Current guidelines do not support the use of genetic profiles in risk assessment of coronary heart disease (CHD). However, new single nucleotide polymorphisms associated with CHD and intermediate cardiovascular traits have recently been discovered. We aimed to compare several multilocus genetic risk score (MGRS) in terms of association with CHD and to evaluate clinical use. We investigated 6 Swedish prospective cohort studies with 10 612 participants free of CHD at baseline. We developed 1 overall MGRS based on 395 single nucleotide polymorphisms reported as being associated with cardiovascular traits, 1 CHD-specific MGRS, including 46 single nucleotide polymorphisms, and 6 trait-specific MGRS for each established CHD risk factors. Both the overall and the CHD-specific MGRS were significantly associated with CHD risk (781 incident events; hazard ratios for fourth versus first quartile, 1.54 and 1.52; P<0.001) and improved risk classification beyond established risk factors (net reclassification improvement, 4.2% and 4.9%; P=0.006 and 0.017). Discrimination improvement was modest (C-index improvement, 0.004). A polygene MGRS performed worse than the CHD-specific MGRS. We estimate that 1 additional CHD event for every 318 people screened at intermediate risk could be saved by measuring the CHD-specific genetic score in addition to the established risk factors. Our results indicate that genetic information could be of some clinical value for prediction of CHD, although further studies are needed to address aspects, such as feasibility, ethics, and cost efficiency of genetic profiling in the primary prevention setting.	f	\N
23685743	We evaluate sex-based differences in the effectiveness of early cardiac computed tomographic angiography (CCTA) and standard emergency department (ED) evaluation in patients with acute chest pain. In the Rule-Out Myocardial Infarction With Computer-Assisted Tomography (ROMICAT)-II multicenter, controlled trial, we randomized 1000 patients (47% women) 40 to 74 years of age with symptoms suggestive of acute coronary syndrome to an early CCTA or standard ED evaluation. In this prespecified analysis, women in the CCTA arm had a greater reduction in length of stay, lower hospital admission rates, and lesser increased cumulative radiation dose than men in a comparison of ED strategies (P for interaction ≤0.02). Although women had lower acute coronary syndrome rates than men (3% versus 12%; P<0.0001), sex differences in length of stay persisted after adjustment for baseline differences, including acute coronary syndrome rate (P for interaction <0.03). Length of stay was similar between sexes with normal CCTA findings (P=0.11). There was no missed acute coronary syndrome for either sex. No difference was observed in major adverse cardiac events between sexes and ED strategies (P for interaction =0.39). Women had more normal CCTA examinations than men (58% versus 37%; P<0.0001), less obstructive coronary disease by CCTA (5% versus 17%; P=0.0001), but similar normalcy rates for functional testing (P=0.65). Men in the CCTA arm had the highest rate of invasive coronary angiography (18%), whereas women had comparable low 5% rates regardless of ED strategy. This trial provides data supporting an early CCTA strategy as an attractive option in women presenting to the ED with symptoms suggestive of acute coronary syndrome. The findings may be explained by lower CAD prevalence and severity in women than men. http://www.clinicaltrials.gov. Unique identifier: NCT01084239.	f	\N
23689410	Coronary heart disease and ischemic stroke are frequent coexistent conditions that share risk factors and pose major burdens to global health. Even though a clear relation has been established between extracranial internal carotid artery atherosclerosis and symptomatic or asymptomatic coronary heart disease, there is a gap in knowledge about the association between intracranial atherosclerosis and coronary heart disease. Intracranial atherosclerosis is associated with high risks of stroke recurrence and vascular death. More research and clinical trials are needed to answer whether early diagnosis of asymptomatic coronary heart disease and aggressive treatment can decrease the risk of vascular death in patients with ischemic stroke caused by intracranial atherosclerosis.	f	\N
23698559	Animal models will be critical for preclinical evaluations of novel HIV eradication and/or functional cure strategies in the setting of suppressive combination antiretroviral therapy (cART). Here, the strengths, limitations, and challenges of recent efforts to develop nonhuman primate (NHP) models of cART-mediated suppression for use in studies of persistent virus and curative approaches are discussed. Several combinations of NHP species and viruses that recapitulate key aspects of human HIV infection have been adapted for cART-mediated suppression studies. Different cART regimens incorporating drugs targeting multiple different steps of the viral replication cycle have provided varying levels of virologic suppression, dependent in part upon the host species, virus, drug regimen and timing, and virologic monitoring assay sensitivity. New, increasingly sensitive virologic monitoring approaches for measurements of plasma viral RNA, cell-associated and tissue-associated viral RNA and DNA, and the replication-competent residual viral pool in the setting of cART in NHP models are being developed to allow for the assessment of persistent virus on cART and to evaluate the impact of viral induction/eradication strategies in vivo. Given the vagaries of each specific virus and host species, and cART regimen, each model will require further development and analysis to determine their appropriate application for addressing specific experimental questions.	f	\N
23700280	Lymphoma-associated hemophagocytic lymphohistiocytosis (HLH) is a rare but fatal disease. Differences between B cell and T cell lymphoma-associated HLH remain unclear, specifically clinical characteristics and survival. We retrospectively analyzed 30 lymphoma-associated HLH patients from July 2004 to October 2012. Patients were divided into B cell (n = 13) and T cell (n = 17) lymphoma groups. Patients' age, performance status, presence of Epstein-Barr virus infection, international prognostic index, presence of disseminated intravascular coagulopathy, serum triglyceride, fibrinogen, and lactate dehydrogenase levels were not significantly different between B cell and T cell lymphoma groups. HLH was an indicator for treatment resistance in patients with B cell (p = 0.048), but not T cell (p = 0.217), lymphoma. Patients in the T cell lymphoma group, however, had higher serum ferritin levels than patients in the B cell lymphoma group (11,525.6 versus 3,790.6 ng/mL; p = 0.043). The median survival time for patients in the B cell and T cell lymphoma groups was 330 and 96 days, respectively. Although the difference was not statistically significant (p = 0.273), our results suggested a trend toward a better overall survival time in patients with B cell lymphoma. This survival advantage could be at least partially due to use of rituximab (p = 0.045) for the treatment of patients with B cell lymphoma. Our results also suggested that allogeneic hematopoietic stem cell transplantation could possibly provide survival benefits to T cell lymphoma-associated HLH by graft-versus-lymphoma effect.	f	\N
23701659	Reduced endogenous pain inhibition, as part of the degenerative process, is presumed to be the mechanism underlying the common presence of pain in patients with Parkinson's disease (PD). The present study aimed to assess an endogenous pain inhibitory system in PD using the conditioned pain modulation paradigm. Twenty-six predominantly unilateral PD patients and 19 controls underwent psychophysical pain assessment before and after patients' morning dopaminergic medication. An unexpected increase in several parameters of pain perception for PD patients was found after dopaminergic medication (e.g. for 49°C noxious heat stimulation an increase from 70.6 ± 4.0 to 77.6 ± 4.0 on the numerical pain scale, P < 0.001). This increase was seen in patients with predominantly left-sided PD, regardless of the stimulated side (for 49°C noxious heat stimulation, predominantly left-sided PD patients, pain perception increased from 73.5 ± 6.8 to 85.0 ± 6.8, P < 0.001, whereas predominantly right-sided PD patients did not show a significant increase, 68.3 ± 6.8 to 70.4 ± 6.5, P = 0.777). Baseline efficiency of conditioned pain modulation inversely correlated with age at disease onset (r = -0.522; P = 0.009) and disease severity (Unified PD Rating Scale, r = 0.447; P = 0.032) but did not differ between patients and controls. Increased sensory response causing hyperalgesia occurs after dopaminergic medication in patients with predominantly left-sided PD.	f	\N
23704428	Human monocytic ehrlichiosis (HME) is a tick-born disease that presents predominantly as a mild to moderate acute illness. Severe life-threatening disease has been reported with a case death rate of approximately 3%, often in immunosuppressed persons. A delay in therapy initiation has been proven to increase the morbidity of the disease. We report a case of an elderly immunocompetent man with severe HME disease and multiorgan failure to emphasise on the severity of this disease in the elderly, as well as the importance of early therapy for overall favourable prognosis.	f	\N
23706729	The health of the tens of millions of street children globally is understudied. We undertook a systematic review of the existing quantitative literature regarding the health status of street children and youth in low- and middle-income countries to summarize available knowledge, identify underexplored areas of research, and inform the future research agenda regarding the health of this population. A total of 108 articles met our inclusion criteria. Demographic data and structural factors associated with street life are summarized. Although data in specific regions or diseases are sparse, the literature review illustrates that youth's survival behaviors and the exposures associated with poor shelter have resulted in disproportionate morbidity in the areas of infectious illness, psychiatric disease, reproductive health, and perhaps to a lesser extent, growth. Vast areas of health that may disproportionately affect street children in childhood or later on as adults have not been investigated, including chronic diseases and cognitive deficits. Studies of specific diseases or conditions vary considerably by region. Strengths and limitations of the literature are discussed and principles for future research in this area are proposed.	f	\N
23709100	This multicenter analysis evaluated patient outcome and clinical pathologic features of thymic epithelial tumors after complete surgical resection and adjuvant treatment. Histologic classification and clinical staging were performed according to WHO classification and Masaoka staging system, respectively. We analyzed 62 patients, 20 (32%) of whom had myasthenia at diagnosis. Clinical and pathologic staging was as follows: 31 (50%) and 30 (48%) patients had stage I disease, 19 (30%) and 22 (35%) stage II, 5 (8%) and 3 (6%) stage III, 2 (4%) and 2 (3%) stage IVa, and 5 (8%) and 5 (8%) stage IVb, respectively. Histologic examination revealed 11 (19%) type A tumors, 19 (30%) type AB tumors, 7 (12%) type B1 tumors, 11 (17%) type B2 tumors, 11 (17%) type B3 tumors, and 3 (5%) type C tumors. Adjuvant therapies comprised chemotherapy in 3 (5%) patients and radiotherapy in 16 (26%) patients. Median follow-up was 71 months (range 1-145). DFS and OS at 48, 60, and 72 months were 89 and 89%, 86 and 97%, and 95% and 92%, respectively. Myasthenia at the onset of disease (P=0.18 for DFS; P=0.97) and tumor size>5 cm (P=0.94 for DFS; P=0.56) were not prognostic factors. TETs are rare and indolent tumors. Complete surgical resection followed by adjuvant therapies, such as chemotherapy and/or radiotherapy, in patients at risk of recurrence show very good DFS and OS results, even in cases with radically resected pleural-pulmonary metastases.	f	\N
23712633	Ticagrelor, a recently approved platelet antagonist indicated for the reduction of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS), has been reported to cause dyspnea in more than 13% of patients. Dyspnea is not a clinically relevant adverse event with other medications indicated for ACS. One suggested mechanism of ticagrelor-induced dyspnea involves an increase in systemic adenosine concentrations through adenosine deaminase inhibition. Dyspnea, a subjective finding resulting from physiologic and sensory mechanisms, may be a consequence of increased systemic adenosine concentrations, leading to amplified and prolonged receptor activity. Current literature suggests, however, that pulmonary status is not compromised, with no reduction of efficacy seen in patients with ticagrelor-induced dyspnea, thus allowing clinicians to continue therapy without reservation. Still, patients with a history of asthma and chronic obstructive pulmonary disease may be more susceptible to ticagrelor-induced dyspnea, potentially leading to nonadherence and exacerbations of morbidity. Therefore, it is paramount that health care providers continually monitor these patients with the aims of maintaining medication therapy adherence and providing relevant options if dyspnea becomes intolerable.	f	\N
23723040	We previously identified a four-generation family with medullary thyroid cancer (MTC) and a germline p.Y791F RET mutation whose cancer lacked a strong genotype-phenotype correlation. The entire gene coding region of the RET gene should be sequenced when genotype-phenotype discrepancies are observed in patients with multiple endocrine neoplasia type 2 (MEN 2), even if a RET hotspot mutation has been identified. A new genetic test was performed in the index case of this family with the p.Y791F RET germline mutation. The entire coding region of the RET gene was investigated by direct sequencing of PCR products. Once a mutation was identified, the target exon was sequenced in all at-risk relatives. An additional p.C634Y germline mutation in the RET gene was identified in the reported family. The double mutation occurred in cis and segregated with the phenotype. Through the Brazilian Genetic Screening Program developed at our institution, we additionally report the combination of these two mutations (p.C634Y/p.Y791F) in the RET gene in four other unrelated families. The overall penetrance of MTC and pheochromocytoma in patients with the p.C634Y/p.Y791F mutations was 79% and 13%, respectively. Our data emphasises that a comprehensive analysis of the RET gene may reveal multiple germline mutations in MEN 2 patients who exhibit an atypical clinical course of the disease.	f	\N
23725082	To examine the effect of hypertensive disease of pregnancy (HDP) on the development of respiratory distress syndrome (RDS) in preterm neonates. A retrospective cohort study. All neonatal intensive care units in New South Wales and the Australian Capital Territory. A total of 18,845 preterm neonates aged between 24 and 36 weeks gestation admitted to the units from 1998 to 2006 were included for study purpose. Exclusion criteria were multiple pregnancies, chorioamnionitis, antepartum hemorrhage and neonates who developed respiratory diagnoses other than RDS. Effect of HDP on the development of RDS was measured. A total of 1093 neonates from hypertensive and 2274 from normotensive pregnancies with complete datasets were included. The association between HDP and the development of RDS was modified by gestational age (HDP-by-gestational age interaction p value <0.0001). Therefore the cohort was divided into extreme (24-28 weeks gestation, n = 752), severe (29-32 weeks gestation, n = 1448) and moderate (33-36 weeks gestation, n = 1167) preterm groups. HDP was associated with a decreased risk of RDS in the moderate preterm group (OR: 0.68; 95% CI: 0.48-0.98, p = 0.04) and a non-significant change in risk for the severe preterm group. Almost all neonates in the extreme preterm group experienced RDS. HDP is associated with a lower risk of developing RDS in moderate preterm neonates. This could have clinical implications in terms of risk stratification for this group of neonates.	f	\N
23726393	The balance of risk and benefit from early neurosurgical intervention for conscious patients with superficial lobar intracerebral haemorrhage of 10-100 mL and no intraventricular haemorrhage admitted within 48 h of ictus is unclear. We therefore tested the hypothesis that early surgery compared with initial conservative treatment could improve outcome in these patients. In this international, parallel-group trial undertaken in 78 centres in 27 countries, we compared early surgical haematoma evacuation within 12 h of randomisation plus medical treatment with initial medical treatment alone (later evacuation was allowed if judged necessary). An automatic telephone and internet-based randomisation service was used to assign patients to surgery and initial conservative treatment in a 1:1 ratio. The trial was not masked. The primary outcome was a prognosis-based dichotomised (favourable or unfavourable) outcome of the 8 point Extended Glasgow Outcome Scale (GOSE) obtained by questionnaires posted to patients at 6 months. Analysis was by intention to treat. This trial is registered, number ISRCTN22153967. 307 of 601 patients were randomly assigned to early surgery and 294 to initial conservative treatment; 298 and 291 were followed up at 6 months, respectively; and 297 and 286 were included in the analysis, respectively. 174 (59%) of 297 patients in the early surgery group had an unfavourable outcome versus 178 (62%) of 286 patients in the initial conservative treatment group (absolute difference 3·7% [95% CI -4·3 to 11·6], odds ratio 0·86 [0·62 to 1·20]; p=0·367). The STICH II results confirm that early surgery does not increase the rate of death or disability at 6 months and might have a small but clinically relevant survival advantage for patients with spontaneous superficial intracerebral haemorrhage without intraventricular haemorrhage. UK Medical Research Council.	f	\N
23731266	Existing nutritional guidelines suggest that protein requirements of adults with stage five chronic kidney disease undergoing haemodialysis (HD) or peritoneal dialysis (PD) are increased as a result of protein losses during dialysis. The present review aimed to update previous guidance and develop evidence-based practice guidelines on the protein requirements of adults undergoing maintenance dialysis. Following a PICO approach (Participants or Population, Intervention or Exposure, Comparison and Outcome), four research questions were formulated to investigate the total protein requirement and protein quality required by adults undergoing HD and PD. A comprehensive, systematic review was undertaken using the databases Medline, EMBASE and the Cochrane Library from 2005 to September 2009 for HD studies and from 1997 to September 2009 for PD studies. The literature search yielded 2931 studies, which were assessed for inclusion. Following appraisal, 19 studies in HD and 18 studies in PD met the inclusion criteria and were systematically reviewed. Limited good quality evidence supports the recommendations that: (i) adults undergoing maintenance HD require a minimum protein intake of 1.1 g kg(-1) ideal body weight (IBW) per day; and (ii) adults undergoing maintenance PD require a minimum protein intake of 1.0-1.2 kg(-1) IBW per day, in conjunction with an adequate energy intake. There were no studies that addressed the quality of protein for either HD or PD. Evidence suggests that nutritional status may be maintained with lower protein intakes than previously recommended. However, the evidence base is limited and further randomised controlled trials are required to establish the optimal protein intake for dialysis patients.	f	\N
23742957	To determine the prevalence and persistence of new-onset clinical remission in rheumatoid arthritis (RA) patients. The Consortium of Rheumatology Researchers of North America (CORRONA) cohort was used to examine the prevalence of remission and associated comorbidities and RA therapies according to the 2011 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) remission criteria. Factors influencing the likelihood of remaining in remission were identified by logistic regression with generalized estimating equations. Analysis of variance and Tukey's test were used to determine differences in disability according to whether RA patients had been in remission or only low disease activity (LDA). A total of 2105 individuals met ACR/EULAR remission criteria at the most recent visit within CORRONA, yielding an 8% point prevalence of remission. Patients with certain comorbidities (e.g., heart failure) were significantly less likely to achieve or remain in remission compared to those without these conditions (p < 0.001 for each). Among prednisone users, the prevalence of remission was 1-6% (depending on dose) higher compared to those not on prednisone (10%). More than 50% of patients who had consistently been in remission for ≥1 year were able to remain in remission over the next year. Patients consistently in remission had less disability than patients who achieved LDA or who fluctuated between remission and LDA. Patients consistently in remission for at least 1 year had a high likelihood to remain in remission. These individuals might be considered the most likely candidates for de-escalation or withdrawal of RA treatments.	f	\N
23745323	The GOLD 2011 recommendations for chronic obstructive pulmonary disease (COPD) introduce a new classification system to optimize treatment in individual patients. Except for FEV,, this classification incorporates breathlessness measurement using modified medical research council questionnaire (mMRC) or the COPD assessment Test (CAT) and the number of exacerbations. The aim of our study was to compare the GOLD 2010 and GOLD 2011 COPD. The study group consisted of 143 patients. Based on the post-bronchodilator FEV, only, as recommended in the GOLD 2010 report, there were 24 patients in stage I, 57patients in II, 43 in Ill and 19 in IV, respectively. In all patients, the number of exacerbations per year was noted and dyspnea was assessed with the modified MRC scale. The patients were subsequently graded to group A,B,C,D as proposed in the combined COPD assessment in GOLD 2011. Grading of 51 (35,7%) patients according to the GOLD 2011 criteria was difficult; there were 22 patients in GOLD stage I/II with > or =2 exacerbations per year and 29 patients in GOLD stage Ill/IV with < 2 exacerbations per year. They were grading to more risk group. The new classification according to GOLD 2011 lets on optimizations of the treatment, in most cases of COPD patients but in clinical practice, there may be problems with the classification of the patients with severe airway obstruction without frequent exacerbations and especially those with mild/moderate airflow limitation and frequent exacerbations.	f	\N
23750230	All non-human great apes are endangered in the wild, and it is therefore important to gain an understanding of their demography and genetic diversity. Whole genome assembly projects have provided an invaluable foundation for understanding genetics in all four genera, but to date genetic studies of multiple individuals within great ape species have largely been confined to mitochondrial DNA and a small number of other loci. Here, we present a genome-wide survey of genetic variation in gorillas using a reduced representation sequencing approach, focusing on the two lowland subspecies. We identify 3,006,670 polymorphic sites in 14 individuals: 12 western lowland gorillas (Gorilla gorilla gorilla) and 2 eastern lowland gorillas (Gorilla beringei graueri). We find that the two species are genetically distinct, based on levels of heterozygosity and patterns of allele sharing. Focusing on the western lowland population, we observe evidence for population substructure, and a deficit of rare genetic variants suggesting a recent episode of population contraction. In western lowland gorillas, there is an elevation of variation towards telomeres and centromeres on the chromosomal scale. On a finer scale, we find substantial variation in genetic diversity, including a marked reduction close to the major histocompatibility locus, perhaps indicative of recent strong selection there. These findings suggest that despite their maintaining an overall level of genetic diversity equal to or greater than that of humans, population decline, perhaps associated with disease, has been a significant factor in recent and long-term pressures on wild gorilla populations.	f	\N
23752073	Several studies have indicated that plasma citrulline levels reflect the extent of mucosal injury of the small intestine. This study was performed to determine whether plasma citrulline levels correlate with the disease activity in pediatric patients with Crohn disease (CD). A total of 63 CD and 23 ulcerative colitis (UC) patients were included in this study. Disease severity was assessed by pediatric CD activity index (PCDAI), pediatric UC activity index, simplified endoscopic activity score for CD, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR). The correlations among these variables and plasma citrulline levels were evaluated. We performed subgroup analysis whether correlations between plasma citrulline levels and disease activity depend on small bowel involvement in patients with CD. The plasma citrulline levels correlated negatively with CRP (r = -0.332, P = 0.008), ESR (r = -0.290, P = 0.022), and PCDAI (r = -0.424, P = 0.001) in patients with CD. The plasma citrulline levels were significantly lower in patients with jejunal involvement than in those without (P = 0.027). In subgroup analysis, patients with CD with jejunal involvement showed significantly negative correlations of plasma citrulline levels with CRP (r = -0.628, P = 0.016) and PCDAI (r = -0.632, P = 0.015); however, patients with CD without jejunal involvement revealed no correlations of plasma citrulline levels with CRP and PCDAI. There were no significant correlations between plasma citrulline levels and simplified endoscopic activity score for CD. There were no significant correlations of plasma citrulline levels with CRP, ESR, and pediatric UC activity index in patients with UC. Plasma citrulline levels correlated with disease severity as measured by PCDAI, CRP, and ESR in pediatric patients with CD with jejunal involvement.	f	\N
23756272	To assess the effectiveness of a multidisciplinary team approach to reduce severe maternal morbidity in women with invasive placenta previa. We conducted a prospective study of 33 women with placenta previa and increta-percreta (diagnosed by ultrasound and/or magnetic resonance imaging) delivering at Mount Sinai Hospital, Toronto, following the introduction in January 2008 of a team-based approach to women with this condition. We included women who delivered by June 2012. We reviewed antenatal outpatient and inpatient records for use of six pre-defined team components by the attending staff obstetrician: (1) antenatal maternal-fetal medicine consultation, (2) surgical gynaecology consultation, (3) antenatal MRI, (4) interventional radiology consultation and preoperative placement of balloon catheters in the anterior divisions of the internal iliac arteries, (5) pre-planned surgical date, and (6) surgery performed by members of the invasive placenta surgical team. Antenatal course, delivery, and postpartum details were recorded to derive a five-point composite severe maternal morbidity score based on the presence or absence of: (1) ICU admission following delivery, (2) transfusion > 2 units of blood, (3) general anaesthesia start or conversion, (4) operating time in highest quartile (> 125 minutes), and (5) significant postoperative complications (readmission, prolonged postpartum stay, and/or pulmonary embolism). All 33 women survived during this time period. Two thirds (22/33) had either five or six of the six components of multidisciplinary care. Increasing use of multidisciplinary team components was associated with a significant reduction in composite morbidity (R2 = 0.228, P = 0.005). Team-based assessment and management of women with invasive placenta previa is likely to improve maternal outcomes and should be encouraged on a regional basis.	f	\N
23774792	Both genetic inactivation and pharmacological inhibition of the cholesteryl ester synthetic enzyme acyl-CoA:cholesterol acyltransferase 1 (ACAT1) have shown benefit in mouse models of Alzheimer's disease (AD). In this study, we aimed to test the potential therapeutic applications of adeno-associated virus (AAV)-mediated Acat1 gene knockdown in AD mice. We constructed recombinant AAVs expressing artificial microRNA (miRNA) sequences, which targeted Acat1 for knockdown. We demonstrated that our AAVs could infect cultured mouse neurons and glia and effectively knockdown ACAT activity in vitro. We next delivered the AAVs to mouse brains neurosurgically, and demonstrated that Acat1-targeting AAVs could express viral proteins and effectively diminish ACAT activity in vivo, without inducing appreciable inflammation. We delivered the AAVs to the brains of 10-month-old AD mice and analyzed the effects on the AD phenotype at 12 months of age. Acat1-targeting AAV delivered to the brains of AD mice decreased the levels of brain amyloid-β and full-length human amyloid precursor protein (hAPP), to levels similar to complete genetic ablation of Acat1. This study provides support for the potential therapeutic use of Acat1 knockdown gene therapy in AD.	f	\N
23782739	Shewanella spp. is infrequently recovered from clinical specimens. Following two outbreaks of food poisoning, eight Shewanella spp. strains were obtained from the fecal specimens of patients, food and food processing-related materials. Tetrodotoxin (TTX) was identified in the culture supernatants of these strains, and the toxin's biological activity was detected using a mouse bioassay. This study suggested that Shewanella strains can colonize and survive in human intestines. The study also raises the issues of the accumulation of TTX produced by Shewanella in food and the possible role of TTX-producing Shewanella in food poisoning.	f	\N
23793899	Middle East Respiratory Syndrome coronavirus (MERS CoV) came to attention as an emerging pathogen causing severe respiratory illness in patients from the Middle East in September 2012. As of 14 June 2013, 58 human cases of MERS CoV infection have been confirmed, including 33 deaths (case fatality rate of 57%). MERS CoV is a beta-coronavirus, in the same family as SARS-CoV, and shares a probable origin from bats. No animal reservoir or intermediates have been definitely implicated in transmission. Limited human-to-human transmission has occurred within several clusters, as individuals without a recent travel history have become infected after exposure to an ill returned traveler.	f	\N
23811578	Acute thallium poisoning rarely occurs but is a serious and even fatal medical condition. Currently, patients with acute thallium poisoning are usually treated with Prussian blue and blood purification therapy. However, there are few studies about these treatments for acute thallium poisoning. Nine patients with acute thallium poisoning from 1 family were treated successfully with Prussian blue and different types of blood purification therapies and analyzed. Prussian blue combined with sequential hemodialysis, hemoperfusion and/or continuous veno-venous hemofiltration were effective for the treatment of patients with acute thallium poisoning, even after delayed diagnosis. Blood purification therapies help in the clearance of thallium in those with acute thallium poisoning. Prussian blue treatment may do the benefit during this process.	f	\N
23815257	A hallmark of acute inflammation involves the recruitment of polymorphonuclear leukocytes (neutrophils) to infected or injured tissues. The processes underlying this recruitment are complex, and include multiple mechanisms of intercellular communication between neutrophils and the inflamed tissue. In recent studies of the systemic and pulmonary vasculature, interest has increased in novel forms of intercellular communication, such as microparticle exchange and gap junctional intercellular communication. To understand the roles of these novel forms of communication in the onset, progression, and resolution of inflammatory lung injury (such as acute respiratory distress syndrome), we review the literature concerning the contributions of microparticle exchange and gap junctional intercellular communication to neutrophil-alveolar crosstalk during pulmonary inflammation. By focusing on these cell-cell communications, we aim to demonstrate significant gaps of knowledge and identify areas of considerable need for further investigations of the processes of acute lung inflammation.	f	\N
23817139	Animal models of chronic kidney disease (CKD) approximate the human condition and are keys to understanding its pathogenesis and to developing rational treatment strategies. The ethical use of animals requires a detailed understanding of the strengths and limitations of each species and the disease model, and the way in which findings can be translated from animals to humans. While not perfect, the careful use of animal experiments offers the opportunity to examine individual mechanisms in an accelerated time frame.	f	\N
23830210	Postoperative chylothorax is a frequently encountered pathology occurring in up to 4% of patients undergoing surgery for repair of congenital heart disease. Symptomatic thrombosis is associated with chylothorax and may contribute to its severity and duration. Furthermore, vessel thrombosis resulting in persistent vessel occlusion may impede future treatments, diagnostic studies and cardio-surgical interventions. The objective of this study was to determine the incidence of upper system thrombosis in pediatric congenital heart patients with confirmed chylothorax with ultrasound screening of all patients diagnosed with chylothorax. All pediatric patients with confirmed with chylothorax underwent doppler ultrasound of the upper venous system as per hospital standard. This retrospective cohort study enrolled all children between February 1, 2010-August 2012, post cardiac surgery with confirmed chylothorax to determine the incidence of all thrombosis. There were 1396 children who underwent 1396 cardiac surgical procedures during the study time with 760 undergoing cardiopulmonary bypass. Development of chylothorax occurred in 54 of 1396, 3.9% (95%CI 3.0;5.0) procedures in all children. In those children with chylothorax, 28 of 54 episodes, 51.8% (95%CI 38.9;64.6) had confirmed VTE. The 51.8% incidence in this study demonstrates a 2.6 fold increase in risk of thrombosis compared to 20% in children with heart disease and central venous lines and may result in serious clinical consequences. The contribution of upper venous system thrombosis to chylothorax is unknown. Often, clinical suspicion of chylothorax exists, however the lack of a standardized approach to objective diagnosis results in delayed confirmation. Approaches to therapy either treatment of confirmed thrombosis or prevention of thrombosis in patients with chylothorax require formal evaluation. Future studies are urgently needed.	f	\N
23832758	Kallikrein 6 (KLK6) is a secreted serine protease preferentially expressed by oligodendroglia in CNS white matter. Elevated levels of KLK6 occur in actively demyelinating multiple sclerosis (MS) lesions and in cases of spinal cord injury (SCI), stroke, and glioblastoma. Taken with recent evidence establishing KLK6 as a CNS-endogenous activator of protease-activated receptors (PARs), we hypothesized that KLK6 activates a subset of PARs to regulate oligodendrocyte physiology and potentially pathophysiology. Here, primary oligodendrocyte cultures derived from wild type or PAR1-deficient mice and the murine oligodendrocyte cell line, Oli-neu, were used to demonstrate that Klk6 (rodent form) mediates loss of oligodendrocyte processes and impedes morphological differentiation of oligodendrocyte progenitor cells (OPCs) in a PAR1-dependent fashion. Comparable gliopathy was also elicited by the canonical PAR1 agonist, thrombin, as well as PAR1-activating peptides (PAR1-APs). Klk6 also exacerbated ATP-mediated oligodendrogliopathy in vitro, pointing to a potential role in augmenting excitotoxicity. In addition, Klk6 suppressed the expression of proteolipid protein (PLP) RNA in cultured oligodendrocytes by a mechanism involving PAR1-mediated Erk1/2 signaling. Microinjection of PAR1 agonists, including Klk6 or PAR1-APs, into the dorsal column white matter of PAR1(+/+) but not PAR1(-/-) mice promoted vacuolating myelopathy and a loss of immunoreactivity for myelin basic protein (MBP) and CC-1(+) oligodendrocytes. These results demonstrate a functional role for Klk6-PAR1 signaling in oligodendroglial pathophysiology and suggest that antagonists of PAR1 or its protease agonists may represent new modalities to moderate demyelination and to promote myelin regeneration in cases of CNS white matter injury or disease.	f	\N
23838529	Classical multiple sclerosis (CMS) and neuromyelitis optica spectrum disorders (NMOSD) are distinct central nervous system inflammatory demyelinating disorders (CNS IDD). Early diagnosis of CNS IDD is important as appropriate immunotherapies to optimize prognosis. We studied the diagnoses of CNS IDD among Hong Kong Chinese in a hospital-based setting. Consecutive Chinese patients who presented to our hospital with clinically isolated syndrome and subsequently diagnosed to have CNS IDD from 1980 to 2010 were reviewed. Patients with known diagnosis of CNS IDD referred for further care were excluded. Serial sera were assayed for aquaporin-4 autoantibodies (AQP4 Ab), at least 3 assays within 2-5years. A total of 210 patients diagnosed to have CNS IDD with disease duration of at least 2years were studied. Among 198 patients with serial sera available, 40 (20.2%, 20 had NMO and 20 other NMOSD) were AQP4 Ab-positive. Four patients who were AQP4 Ab-negative on the initial assay converted to AQP4 Ab-positive on repeated assays. The diagnoses of 210 patients were CMS in 88 (41.9%), NMOSD 47 (22.4%, 27 NMO, 20 other NMOSD), single attack of myelitis 23 (11.0%), single attack of optic neuritis 21 (10.0%), relapsing myelitis 10 (4.8%), acute disseminated encephalomyelitis (ADEM) 9 (4.3%), relapsing optic neuritis in 6 (2.9%), opticospinal multiple sclerosis 3 (1.4%) and single attack of brainstem encephalitis 3 (1.4%). Compared to CMS, NMOSD patients had older onset age, lower frequencies of brain MRI abnormalities and CSF OCB, higher frequency of LETM, higher CNS inflammation attack frequency in the first 2years, worse clinical outcome with higher EDSS score and mortality rate. This hospital-based study suggests that CMS (41.9%) and NMOSD (22.4%) are the most common CNS IDD among Hong Kong Chinese. NMOSD has worse clinical outcome than CMS. Detection of AQP4 Ab facilitates early diagnosis and prompts immunotherapies of NMOSD.	f	\N
23846297	Decoy receptor 3 (DcR3) is abundantly expressed in human tumors and protects cells from a wide range of apoptotic stimuli. In this study, we demonstrate that DcR3 is overexpressed in pancreatic carcinoma cells, and that the pancreatic carcinoma cell lines, Panc-1 and SW1990, are resistant to Fas ligand (FasL)-mediated apoptosis. To further define the function of DcR3 in cell growth and apoptosis, we used small interfering RNA (siRNA) to knockdown the expression of the DcR3 gene in Panc-1 and SW1990 cells. Our results revealed that the silencing of DcR3 expression enhanced the inhibitory effects of FasL and reduced the capabiltiy of the cells for proliferation and colony formation in vitro. In addition, the downregulation of DcR3 modulated the cell apoptotic regulators, Fas-associated death domain (FADD), caspase‑3 and caspase‑8, thus triggering cell apoptosis. Furthermore, the knockdown of DcR3 inhibited the growth of Panc-1 tumor xenografts. Taken together, our findings indicate that DcR3 is important in cancer progression and may be a used as a potential therapeutic target for the gene therapy of pancreatic carcinoma.	f	\N
23849416	Abiraterone, an androgen synthesis inhibitor, has been successfully used in the treatment of castration-resistant prostate cancer (CRPC) for 2 yr. Enzalutamide is a second-generation nonsteroidal antiandrogen that has recently been approved for the same indication. This is the first study to evaluate the effectiveness of enzalutamide after failure of abiraterone. Thirty-five patients were identified as having received sequential therapy with abiraterone followed by enzalutamide. All patients had undergone prior docetaxel chemotherapy, and no patient had received ketoconazole. Posttreatment changes in prostate-specific antigen (PSA) were used to determine the activity of enzalutamide in patients who had received prior abiraterone. The median duration of abiraterone treatment was 9.0 mo (range: 2.0-19.0 mo). Of the 35 patients, 16 (45.7%) achieved a >50% decline in PSA, and 14 (40%) had a rising PSA as the best response. The median duration of subsequent enzalutamide treatment was 4.9 mo (Kaplan-Meier estimate; 95% confidence interval [CI], 2.4-7.4). Seven of 16 CRPC patients who were initially abiraterone-sensitive (43.8%) and 3 of 19 CRPC patients who were initially abiraterone-insensitive (15.8%) showed a >50% PSA decline while taking enzalutamide. Of the 35 patients, 17 (48.6%) were primarily enzalutamide-resistant and showed a rising PSA as the best response. Median time to progression was 4.0 mo (95% CI, 2.0-6.0) for 18 of 35 patients with at least one declining PSA value while taking enzalutamide (51.4%). Of the 17 patients who were assessable radiologically, only 1 (2.9%) attained a confirmed partial response. Small sample size was the major limitation. Enzalutamide treatment achieved only a modest response rate in patients progressing after abiraterone. Although cross-resistance between abiraterone and enzalutamide was a common phenomenon, it was not inevitable, and a small but significant number of patients showed significant benefit from sequential treatment.	f	\N
23850538	A few years ago, Anisakis infection was almost unknown. Since the first observation in the Netherlands in 1960, several cases of gastrointestinal infections due to a zoonosis sustained by this nematode have been described in countries in which the consumption of raw or uncooked fish (e.g., marinated or salted) is common. Japan alone accounts for 90% of all cases of anisakiasis described in the literature because of the widespread use of raw fish in traditional Japanese cuisine, with sushi and sashimi. Nonetheless, other cases have been reported in Europe, North and South America, and Asia. In Italy, this zoonosis is rare and mostly transmitted by the ingestion of marinated anchovies in coastal areas, or fashion foods (sushi, sashimi, etc.) in inland areas. Once eaten, this parasite can cause an acute form of disease characterized by severe abdominal pain, and for this reason many patients receive the final diagnosis only on obtaining the surgical specimen. Since conservative medical treatment for acute anisakiasis relies on endoscopic removal of the nematode from the gastrointestinal wall if performed within 12h from the ingestion of contaminated fish, it should be compulsory to consider this parasitosis in the accident and emergency department. Here we describe two cases of infection by Anisakis simplex due to ingestion of marinated anchovies in a coastal area of the Tyrrhenian Sea and discuss the types and varieties of Anisakis infection in humans.	f	\N
23861956	Severe stress experienced in early life may have long-term effects on adult physiological and psychological health and well-being. We studied physical and psychosocial functioning in late adulthood in subjects separated temporarily from their parents in childhood during World War II. The 1803 participants belong to the Helsinki Birth Cohort Study, born 1934-44. Of them, 267 (14.8%) had been evacuated abroad in childhood during WWII and the remaining subjects served as controls. Physical and psychosocial functioning was assessed with the Short Form 36 scale (SF-36) between 2001 and 2004. A test for trends was based on linear regression. All analyses were adjusted for age at clinical examination, social class in childhood and adulthood, smoking, alcohol intake, physical activity, body mass index, cardiovascular disease and diabetes. Physical functioning in late adulthood was lower among the separated men compared to non-separated men (b = -0.40, 95% confidence interval [95% CI]: -0.71 to -0.08). Those men separated in school age (>7 years) and who were separated for a duration over 2 years had the highest risk for lower physical functioning (b = -0.89, 95% CI: -1.58 to -0.20) and (b = -0.65, 95% CI: -1.25 to -0.05), respectively). Men separated for a duration over 2 years also had lower psychosocial functioning (b = -0.70, 95% CI: -1.35 to -0.06). These differences in physical and psychosocial functioning were not observed among women. Early life stress may increase the risk for impaired physical functioning in late adulthood among men. Timing and duration of the separation influenced the physical and psychosocial functioning in late adulthood.	f	\N
23866601	The lecture considers a number of molecular and cellular mechanisms underlying the structural and functional rearrangement and development of renal and cardiac fibrosis in chronic kidney disease (CKD). It details the key component of disadaptative organ remodeling (the formation of myofibroblasts via epithelial-mesenchymal and endothelial-mesenchymal transdifferentiation) and the role of leading angiofibrogenic mediators (angiotensin II, transforming growth factor-beta type 1, a plasminogen activator inhibitor type 1, etc.) in the regulation of these processes. Investigation of the molecular and cellular bases of organ fibrosis, including the factors of dysregulated activation, differentiation and survival of microfibroblasts, makes it possible to specify the mechanisms of action of traditional nephro- and cardioprotective agents, to offer a possibility for a goal-oriented (target) effect on individual fibrogenic components, and to expand the arsenal of medications suppressing renal and cardiac remodeling.	f	\N
23868901	Dabigatran is an oral direct thrombin inhibitor widely used to prevent and treat various thromboembolic complications. An advantage of this agent over other anticoagulants is that routine laboratory monitoring and related dose adjustments are considered unnecessary. A major disadvantage is the absence of a reliable means of reversing its anticoagulant effect. After U.S. Food and Drug Administration approval, recently emerged data suggest a higher bleeding risk with dabigatran, especially in the elderly. Clinicians are thus faced with caring for patients with serious bleeding events without readily available tests to measure drug levels or the anticoagulant effects of dabigatran and without effective antidotes to rapidly reverse the anticoagulant effect. On the basis of dabigatran's pharmacokinetic profile, hemodialysis and continuous renal replacement therapy have been used to remove dabigatran with the hope, still unproven, that this would rapidly reverse the anticoagulant effect and reduce bleeding in patients with normal and those with reduced kidney function. However, the best clinical approach to the patient with serious bleeding is not known, and the risks of placing a hemodialysis catheter in an anticoagulated patient can be substantial. This article reviews this issue, addressing clinical indications, drug pharmacokinetics, clinical and laboratory monitoring tests, and dialytic and nondialytic approaches to reduce bleeding in dabigatran-treated patients.	f	\N
23871729	Acute ischemic stroke is a major cerebrovascular disease with potential morbidity and mortality. Despite the availability of thrombolytic therapy in some centers, risk factor modification and rehabilitation therapy are the mainstays of stroke management. There is supporting evidence that Ginkgo biloba may afford neuroprotection and improve the outcomes of patients with acute ischemic stroke. In a double-blind, placebo-controlled, randomized controlled trial, we assessed the efficacy of G biloba on functional outcome in patients with acute stroke. The National Institutes of Heath Stroke Scale (NIHSS) was used to measure functional outcome. A total of 102 patients with acute ischemic stroke were studied. All patients received either G biloba or placebo tablets for 4 months. This trial was registered to the Iranian Registry of Clinical Trials (www.irct.ir; trial IRCT138804212150N1). There were 52 patients who received G biloba and 50 patients who were in the placebo group. Age, sex distribution, previous medical condition, and laboratory data did not have any significant difference between the 2 groups (P>.05). The mean difference of 4-month follow-up NIHSS scores and NIHSS scores at admission was 4.7±2.7 and 4.1±3.0 in the G biloba and placebo groups, respectively (P>.05). The primary outcome-a 50% reduction in the 4-month follow-up NIHSS score compared to the baseline NIHSS score-was reached in 17 patients (58.6%) and 5 patients (18.5%) in the G biloba and placebo groups, respectively (P<.05). The risk ratio and number needed to treat were 3.16 (confidence interval 1.35-7.39) and 2.50 (confidence interval 1.58-5.90), respectively. In addition, multivariate regression adjusted for age and sex revealed a significant NIHSS decline in the G biloba group compared to the placebo group (P<.05). Our data suggest that G biloba may have protective effects in ischemic stroke. Therefore, the administration of G biloba is recommended after acute ischemic stroke.	f	\N
23872666	Sequences of human endogenous retroviruses (HERVs) are members of the long terminal repeat (LTR) retrotransposon family. Although the expression of HERV has long been a topic of investigation, HERV-insertion polymorphisms are not well known, and a genetic association between HERV-insertion polymorphisms and cancer has never been reported. To identify novel HERV loci in the genome from cancer tissues, we carried out the inverse PCR method targeting a conserved LTR region of HML-2, which is the most recently acquired HERV group. Novel two insertions, HML-2_sLTR(1p13.2) and HML-2_sLTR(19q12), were identified as insertionally polymorphic solo LTRs. Furthermore, a significant prevalence of HML-2_sLTR(1p13.2) homozygosity was detected in female never-smoking patients aged 60 years and over who had lung adenocarcinoma [versus the other genotyping; odds ratio (OR): 1.97; 95% confidence interval (CI): 1.01-3.81]. In another cohort consisting of female never-smoking patients with lung adenocarcinoma, a prevalence of HML-2_sLTR(1p13.2) homozygosity tended to be high in patients aged 60 years and over (versus the other genotyping; OR: 2.03; 95% CI: 0.96-4.29), whereas a low prevalence of HML-2_sLTR(1p13.2) homozygosity was detected in patients <60 years old (versus the other genotyping; OR: 0.31; 95% CI: 0.11-0.94). Our results suggest that HML-2_sLTR(1p13.2) is involved with the susceptibility to lung adenocarcinoma in female never-smokers in an age-dependent manner and that other HERV polymorphisms related to human diseases might remain to be identified in the human genome.	f	\N
23874931	The HIV-1 characteristics associated with mother to child transmission (MTCT) are still poorly understood and if known would indicate where intervention strategies should be targeted. In contrast to horizontally infected individuals, exposed infants possess inherited antibodies (Abs) from their mother with the potential to protect against infection. We investigated the HIV-1 gp160 envelope proteins from seven transmitting mothers (TM) whose children were infected either during gestation or soon after delivery and from four non-transmitting mothers (NTM) with similar viral loads and CD4 counts. Using pseudo-typed viruses we tested gp160 envelope glycoproteins for TZM-bl infectivity, CD4 and CCR5 interactions, DC-SIGN capture and transfer and neutralization with an array of common neutralizing Abs (NAbs) (2F5, 2G12, 4E10 and b12) as well as mother and infant plasma. We found no viral correlates associated with HIV-1 MTCT nor did we find differences in neutralization with the panel of NAbs. We did, however, find that TM possessed significantly higher plasma neutralization capacities than NTM (P = 0.002). Furthermore, we found that in utero (IU) TM had a higher neutralization capacity than mothers transmitting either peri - partum (PP) or via breastfeeding (BF) (P = 0.002). Plasma from children infected IU neutralized viruses carrying autologous gp160 viral envelopes as well as those from their corresponding mothers whilst plasma from children infected PP and/or BF demonstrated poor neutralizing capacity. Our results demonstrate heightened autologous NAb responses against gp120/gp41 can associate with a greater risk of HIV-1 MTCT and more specifically in those infants infected IU. Although the number of HIV-1 transmitting pairs is low our results indicate that autologous NAb responses in mothers and infants do not protect against MTCT and may in fact be detrimental when considering IU HIV-1 transmissions.	f	\N
23876833	Tyrosine kinase inhibitors treatment in responding chronic myeloid leukaemia (CML) patients is generally continued indefinitely. In this randomised phase II trial, we investigated whether CML patients in molecular response(4.5) (MR(4.5), quantitative reverse-transcription polymerase chain reaction (RQ-PCR)) after previous combination therapy with imatinib and cytarabine may discontinue imatinib treatment safely. Thirty-three patients from the HOVON 51 study with an MR(4.5) for at least 2 years who were still on imatinib treatment were randomised between continuation of imatinib (arm A, n=18) or discontinuation of imatinib (arm B, n=15). After a median follow up of 36 months since randomisation, 3 patients (17%) in arm A and 10 patients (67%) in arm B had a molecular relapse. All 3 relapsing patients in arm A had also stopped imatinib after randomisation. All but one relapsing patient relapsed within 7 months after discontinuation of imatinib. The molecular relapse rate at 12 and 24 months after randomisation was 0% and 6% (arm A) and 53% and 67% (arm B) respectively. As-treated analysis revealed 56% and 61% relapses at 1 and 2 years since cessation in patients who discontinued imatinib, in contrast to 0% of patients who continued imatinib. All evaluable patients remained sensitive to imatinib after reinitiation and regained a molecular response. Our data suggest that discontinuation of imatinib is safe in patients with durable MR(4.5).	f	\N
23877014	This study aimed to evaluate the efficacy of radiation therapy for pelvic lymph node metastasis from uterine cervical cancer and identify an optimal radiation regimen. A total of 111 metastatic pelvic lymph nodes, ranging from 11 to 56 mm (median, 25 mm) on CT/MRI, in 62 patients with uterine cervical cancer were treated initially with curative radiation therapy, with 46 patients receiving concurrent chemotherapy. Total radiation doses ranged from 45 to 61.2 Gy (median, 50.4 Gy) in 1.8-2 Gy (median, 1.8 Gy) fractions. At a median follow-up of 33 months, 46 of the 62 patients survived. Only 2 irradiated lymph nodes, 24 and 28 mm in diameter, in 1 patient progressed after irradiation alone with 50.4 Gy in 1.8 Gy fractions. All 33 metastatic lymph nodes ≥ 30 mm in diameter were controlled by irradiation at a median dose of 55.8 Gy. The 3-year lymph node-progression free rates were 98.2% in all 62 patients and 98.0% in all 111 metastatic lymph nodes. Except for transient hematologic reactions, 2 patients developed grade ≥ 3 therapy-related toxicities, 1 with an ulcer and the other with perforation of the sigmoid colon. In addition, 2 patients experienced ileus after irradiation. Radiation therapy effectively controlled pelvic lymph node metastases in patients with uterine cervical cancer, with most nodes <24 mm in diameter controlled by total doses of 50.4 Gy in 1.8 Gy fractions and larger nodes controlled by 55.8 Gy, particularly with concurrent chemotherapy. Higher doses to metastatic lymph nodes may increase intestinal toxicities.	f	\N
23880785	The most abundant urinary protein, Tamm-Horsfall protein, later renamed uromodulin, is expressed exclusively by the thick ascending limb cells of the kidney and released into urine from the apical cell membrane. Uromodulin is believed to protect against urinary tract infections and stones, but its other physiologic functions have remained obscure until recently. Renewed interest in uromodulin has been brought about by the identification of uromodulin mutations as causes of a discrete group of diseases that are distinct from nephronophthisis. The three overlapping clinical uromodulin-associated kidney diseases (UAKD) are medullary cystic disease type 2, familial juvenile hyperuricemic nephropathy and glomerulocystic kidney disease. Previously thought of as "adult diseases", it is now recognized that they may also present in childhood and even in infancy. Common characteristics of all three diseases are autosomal dominant inheritance, unremarkable urine sediment and slow progression to end-stage renal disease (ESRD). They are frequently associated with hyperuricemia and gout. These diseases appear to result from failure of the mutant uromodulin to be incorporated into the apical cilium, thereby placing UAKD in the category of "ciliopathies". In addition to causing specific UAKD, certain uromodulin gene polymorphisms have been linked to ESRD in general, suggesting that uromodulin plays a modulatory role in kidney disease progression.	f	\N
23886073	Influenza A and B viruses form different genera, which were originally distinguished by antigenic differences in their nucleoproteins and matrix 1 proteins. Cross-protection between these two genera has not been observed in animal experiments, which is consistent with the low homology in viral proteins common to both viruses except for one of three polymerase proteins, polymerase basic 1 (PB1). Recently, however, antibody and CD4+ T cell epitopes conserved between the two genera were identified in humans. A protective antibody epitope was located in the stalk region of the surface glycoprotein, hemagglutinin, and a CD4+ T cell epitope was located in the fusion peptide of the hemagglutinin. The fusion peptide was also found to contain antibody epitopes in humans and animals. A short stretch of well-conserved peptide was also identified in the other surface glycoprotein, neuraminidase, and antibodies binding to this peptide were generated by peptide immunization in rabbits. Although PB1, the only protein which has relatively high overall sequence homology between influenza A and B viruses, is not considered an immunodominant protein in the T cell responses to influenza A virus infection, amino acid sequence comparisons show that a considerable number of previously identified T cell epitopes in the PB1 of influenza A viruses are conserved in the PB1 of influenza B viruses. These data indicate that B and T cell cross-reactivity exists between influenza A and B viruses, which may have modulatory effects on the disease process and recovery. Although the antibody titers and the specific T cell frequencies induced by natural infection or standard vaccination may not be high enough to provide cross protection in humans, it might be possible to develop immunization strategies to induce these cross-reactive responses more efficiently.	f	\N
23894446	A prostacyclin analogue, ONO-1301, is reported to upregulate beneficial proteins, including stromal cell derived factor-1 (SDF-1). We hypothesized that the sustained-release delivery of ONO-1301 would enhance SDF-1 expression in the acute myocardial infarction (MI) heart and induce bone marrow cells (BMCs) to home to the myocardium, leading to improved cardiac function in mice. ONO-1301 significantly upregulated SDF-1 secretion by fibroblasts. BMC migration was greater to ONO-1301-stimulated than unstimulated conditioned medium. This increase was diminished by treating the BMCs with a CXCR4-neutralizing antibody or CXCR4 antagonist (AMD3100). Atelocollagen sheets containing a sustained-release form of ONO-1301 (n = 33) or ONO-1301-free vehicle (n = 48) were implanted on the left ventricular (LV) anterior wall immediately after permanent left-anterior descending artery occlusion in C57BL6/N mice (male, 8-weeks-old). The SDF-1 expression in the infarct border zone was significantly elevated for 1 month in the ONO-1301-treated group. BMC accumulation in the infarcted hearts, detected by in vivo imaging after intravenous injection of labeled BMCs, was enhanced in the ONO-1301-treated hearts. This increase was inhibited by AMD3100. The accumulated BMCs differentiated into capillary structures. The survival rates and cardiac function were significantly improved in the ONO-1301-treated group (fractional area change 23±1%; n = 22) compared to the vehicle group (19±1%; n = 20; P = 0.004). LV anterior wall thinning, expansion of infarction, and fibrosis were lower in the ONO-1301-treated group. Sustained-release delivery of ONO-1301 promoted BMC recruitment to the acute MI heart via SDF-1/CXCR4 signaling and restored cardiac performance, suggesting a novel mechanism for ONO-1301-mediated acute-MI heart repair.	f	\N
23899604	In the mammalian nervous system, axons are commonly surrounded by myelin, a lipid-rich sheath that is essential for precise and rapid conduction of nerve impulses. In the peripheral nervous system (PNS), myelin sheaths are formed by Schwann cells which wrap around individual axons. While the tyrosine kinase receptors ERBB2 and ERBB3 are established mediators of peripheral myelination, less is known about the functions of the related epidermal growth factor receptor (EGFR) in the regulation of PNS myelination. Here, we report a peripheral neurodegenerative disease caused by increased EGFR activation. Specifically, we characterize a symmetric and distally pronounced, late-onset muscular atrophy in transgenic mice overexpressing the EGFR ligand epigen. Histological examination revealed a demyelinating neuropathy and axon degeneration, and molecular analysis of signaling pathways showed reduced protein kinase B (PKB, AKT) activation in the nerves of Epigen-tg mice, indicating that the muscular phenotype is secondary to PNS demyelination and axon degeneration. Crossing of Epigen-tg mice into an EGFR-deficient background revealed the pathology to be completely EGFR-dependent. This mouse line provides a new model for studying molecular events associated with early stages of peripheral neuropathies, an essential prerequisite for the development of successful therapeutic interventions.	f	\N
23902839	To explore the value of sentinel lymph nodes (SLN) metastasis status in predicting the presence of residual disease in non-sentinel lymph nodes (nSLN) and the feasibility of avoiding or reducing the scope of axillary lymph node dissection (ALND) for patients with single positive SLN. A retrospective study was conducted for 2265 patients with invasive breast carcinomas undergoing sentinel lymph nodes biopsy (SLNB) at Shandong Cancer Hospital between November 1999 and December 2011. And 1228 patients with axillary dissection were screened and divided into 5 groups of (-), (1/n), (1/1), (n/N), (n/n) (n ≥ 2, N ≥ 3, N > n) according to the status of SLN metastasis. The nSLN metastasis rate of SLN(-), (1/n), (1/1), (n/N) and (n/n) groups was 11.8%(73/618), 25.2%(65/258), 49.6%(67/135), 48.4%(60/124)and 65.6%(61/93)respectively. A comparison of SLN(-), (1/n), (1/1), (n/N), and (n/n) groups of nSLN metastasis showed a significant difference (P = 0.000). The differences of nSLN metastasis between SLN(-) and other groups (including 1/n, 1/1, n/N, n/n group) were significant (P = 0.000). This difference was also significant between SLN (1/n) and other positive groups (include 1/1, n/N, n/n group) (P = 0.000), but not significant between SLN(1/1), (n/N) and (n/n) groups (P = 0.842, 0.017, 0.042 respectively, Chi-square segmentation). No significant difference existed between axillary lymph node metastasis on Level II and III of SLN 1/n group and SLN(-) group (P = 0.012, 0.570,χ(2) segmentation). The status of SLN metastasis is one of influencing factors for the nSLN metastasis of patients with invasive breast cancer. The possibility of non-sentinel lymph node involvement for patients with single SLN metastasis was smaller than that of other SLN-positive patients. It is safe for some SLN 1/n patients to undergo low lymph node dissection. But ALND is not avoided for patients with single positive SLN (SLN 1/n n ≥ 2). Their clinicopathological variables should be also considered.	f	\N
23905909	Peripheral arterial diseases associated with an increased risk of death in kidney transplant patients. Natriuretic peptide has anti-atherosclerotic effects. We sought to evaluate the relation between ankle-brachial index and fasting serum long-acting natriuretic peptide concentrations in kidney transplant patients. Fasting blood samples were obtained from 69 kidney transplant patients. Serum long-acting natriuretic peptide concentrations were measured using a commercially available enzyme immunoassay kit. Left or right ankle-brachial index values that were < 0.9 were included in the low ankle-brachial index group. Fifteen patients (21.7%) were enrolled in the low ankle-brachial index group. Increased waist circumference (P = .013), higher serum total cholesterol levels (P = .019), higher triglyceride levels (P = .002), and decreased serum long-acting natriuretic peptide concentrations (P = .006) were noted in the low ankle-brachial index group. Univariate linear regression analysis indicated that the left/right ankle-brachial index values of the subjects were negatively correlated with serum triglycerides (P = .008 or P < .001) and fasting glucose levels (P = .034 or P = .012), but were positively correlated with long-acting natriuretic peptide concentrations (P = .011 or P = .011). Multivariate forward stepwise linear regression analyses of the significant variables revealed that serum triglycerides and long-acting natriuretic peptide levels were independent predictors of the left/right ankle-brachial index values of kidney transplant patients. Serum long-acting natriuretic peptide concentrations correlate positively with ankle-brachial index values among the kidney transplant patients.	f	\N
23908572	To evaluate the clinical usefulness of binocular multifocal electroretinography (mfERG) by comparing results with conventional monocular mfERG in patients with monocular macular disease. mfERG testing was conducted on 32 patients with monocular macular disease and 30 normal subjects. An initial mfERG was simultaneously recorded from both eyes with two recording electrodes under binocular stimulation. A second mfERG was subsequently recorded with conventional monocular stimulation. Amplitudes and implicit times of each ring response of the binocular and monocular recordings were compared. Ring ratios of the binocular and monocular recording were also compared. In the macular disease group, there were no statistical differences in amplitude or implicit time for each of the five concentric rings between the monocular and binocular recordings. However, with binocular simulation, the ring ratios (ring 1 / ring 4, ring 1 / ring 5) were significantly reduced in the affected eye. In the normal control group, there were no statistical differences in any parameters between the monocular and binocular recordings. Binocular mfERG could be a good alternative to the conventional monocular test. In addition, given that the test needs stable fixation of the affected eye during the binocular test, the reliability of the test results could be improved, especially for patients with monocular macular disease.	f	\N
23934213	Human Nijmegen breakage syndrome, caused by the hypomorphic mutation of Nbn gene, is a hereditary instability disease, characterized by chromosomal instability, immunodeficiency, radiosensitivity, cancer predisposition and microcephaly. To study the roles of Nbn protein in microcephaly, Nbn gene was specifically deleted in the central nervous system of mice by nestin-Cre targeting gene system (Frappart et al. in Nat Med 11:538-544, 2005). Strikingly, newborn Nbn-deficient mice exhibit the evident microcephalic cerebellum, which contributes to severe ataxia and balance deficiency. In this study, we first report that PI3K/AKT/mTOR signaling pathway that performs neurotrophic-protecting role in neuronal growth is significantly inhibited in newborn Nbn-deficient cortex and cerebellum. In addition, JNK signaling and ATR signaling are likely to converge to regulate the cerebellar apoptosis of newborn Nbn-deficient mice.	f	\N
23935207	This Phase II trial was designed to evaluate the safety and efficacy of neoadjuvant oxaliplatin and capecitabine and bevacizumab without radiotherapy in patients with poor-risk rectal cancer. Patients with magnetic resonance imaging-defined poor-risk rectal cancer received neoadjuvant oxaliplatin and capecitabine and bevacizumab followed by total mesorectal excision or more extensive surgery. Between February 2010 and December 2011, 32 patients were enrolled in this study. The completion rate of the scheduled chemotherapy was 91%. Reasons for withdrawal were refusal to continue therapy in two patients and disease progression in one, with two of these three patients not undergoing surgery. Among the 29 patients who completed the scheduled chemotherapy, one refused surgery within 8 weeks after the completion of chemotherapy, which was the period stipulated by the protocol, and another had rectal perforation, requiring urgent laparotomy. As a result, the completion rate of this experimental treatment was 84%. Of the 30 patients who underwent surgery, the R0 resection rate was 90% and a postoperative complication occurred in 43%. A pathological complete response was observed in 13% and good tumor regression was exhibited in 37%. Neoadjuvant oxaliplatin and capecitabine plus bevacizumab for poor-risk rectal cancer caused a high rate of anastomotic leakage and experienced a case with perforation during chemotherapy, both of which were bevacizumab-related toxicity. Although the short-term results with the completion rate of 84.4% and the pathological complete response rate of 13.3% were satisfactory, we have to reconsider the necessity of bevacizumab in neoadjuvant chemotherapy (UMIN number, 000003507).	f	\N
23955530	Type 1 diabetes (T1D) is one of the most common chronic diseases with childhood onset, and the disease incidence has increased two to fivefold over the past half century by as yet unknown means. T1D occurs when the body's immune system turns against itself, destroying in a very specific and targeted way-the pancreatic β-cells. T1D results from poorly defined interactions between susceptibility genes and environmental determinants. In contrast to the rapid progress in finding T1D genes, identification and confirmation of environmental determinants remain a formidable challenge. This review article will give an overview of ongoing prospective cohort studies aiming to identify the environmental trigger(s) causing T1D.	f	\N
23956301	Human papillomavirus 16 (HPV16) infection causes 50 % or more of cervical cancers in women. The HPV16 E7 oncogene is continuously expressed in infected epithelium with its oncogenicity linked to cervical cancer. The E7 protein is an ideal target in control of HPV infection through T-cell-mediated immunity. Using HPV16 E7-transgenic mouse keratinocytes (KCs-E7) to investigate T-cell-mediated immune responses, we have shown previously that HPV16-encoded E7 protein inhibits IFN-γ-mediated enhancement of MHC class I antigen processing and T-cell-induced target cell lysis. In this study, we found that HPV16 E7 suppresses IFN-γ-induced phosphorylation of STAT1((Tyr701)), leading to the blockade of interferon regulatory factor-1 (IRF-1) and transporter associated antigen processing subunit 1 (TAP-1) expression in KCs-E7. The results of a (51)Cr release assay demonstrated that IFN-γ-treated KCs-E7 escaped from CTL recognition because HPV16 E7 downregulated MHC class I antigen presentation on KCs. Restoration of IRF-1 expression in KCs-E7 overcame the inhibitory effect of E7 protein on IFN-γ-mediated CTL lysis and MHC class I antigen presentation on KCs. Our results suggest that HPV16 E7 interferes with the IFN-γ-mediated JAK1/JAK2/STAT1/IRF-1 signal transduction pathway and reduces the efficiency of peptide loading and MHC class I antigen presentation on KCs-E7. These results may reveal a new mechanism whereby HPV16 escapes from immune surveillance in vivo.	f	\N
23962064	Understanding how alveoli and the underlying capillary network develop and how these mechanisms are disrupted in disease states is critical for developing effective therapies for lung regeneration. Recent evidence suggests that lung angiogenesis promotes lung development and repair. Vascular endothelial growth factor (VEGF) preserves lung angiogenesis and alveolarization in experimental O2-induced arrested alveolar growth in newborn rats, but combined VEGF+angiopoietin 1 treatment is necessary to correct VEGF-induced vessel leakiness. Hypoxia-inducible factors (HIFs) are transcription factors that activate multiple O2-sensitive genes, including those encoding for angiogenic growth factors, but their role during postnatal lung growth is incompletely understood. By inducing the expression of a range of angiogenic factors in a coordinated fashion, HIF may orchestrate efficient and safe angiogenesis superior to VEGF. We hypothesized that HIF inhibition impairs alveolarization and that HIF activation regenerates irreversible O2-induced arrested alveolar growth. HIF inhibition by intratracheal dominant-negative adenovirus (dnHIF-1α)-mediated gene transfer or chetomin decreased lung HIF-1α, HIF-2α, and VEGF expression and led to air space enlargement and arrested lung vascular growth. In experimental O2-induced arrested alveolar growth in newborn rats, the characteristic features of air space enlargement and loss of lung capillaries were associated with decreased lung HIF-1α and HIF-2α expression. Intratracheal administration of Ad.HIF-1α restored HIF-1α, endothelial nitric oxide synthase, VEGF, VEGFR2, and Tie2 expression and preserved and rescued alveolar growth and lung capillary formation in this model. HIFs promote normal alveolar development and may be useful targets for alveolar regeneration.	f	\N
23962825	G protein-mediated signal transduction is essential for the regulation of cardiovascular function, including heart rate, growth, contraction, and vascular tone. Regulators of G protein Signaling (RGS proteins) fine-tune G protein-coupled receptor-induced signaling by regulating its magnitude and duration through direct interaction with the α subunits of heterotrimeric G proteins. Changes in the RGS protein expression and/or function in the heart often lead to pathophysiological changes and are associated with cardiac disease in animals and humans, including hypertrophy, fibrosis development, heart failure, and arrhythmias. This article focuses on Regulator of G protein Signaling 2 (RGS2), which is widely expressed in many tissues and is highly regulated in its expression and function. Most information to date has been obtained in biochemical, cellular, and animal studies, but data from humans is emerging. We review recent advances on the functional role of cardiovascular RGS2 and the mechanisms that determine its signaling selectivity, expression, and functionality. We highlight key unanswered questions and discuss the potential of RGS2 as a therapeutic target.	f	\N
23968196	Actinic prurigo (AP) is an idiopathic photodermatosis that usually onsets during childhood and predominates in women. It is characterized by the symmetrical involvement of sun-exposed areas of the skin, lips, and conjunctiva. This study aimed to analyze the risk factors associated with AP using a case-control design. All patients diagnosed with AP during 1990-2006 at Dr. Manuel Gea González General Hospital in Mexico City were included. Respective controls were recruited. Race, demographic, geographic, socioeconomic, environmental, clinical, and nutritional risk factors were assessed. A total of 132 persons were enrolled. These included 44 cases and two control groups comprising, respectively, dermatology and non-dermatology outpatients without AP or any autoimmune disease. Distribution by gender, age, place of birth, place of residence, and economic status did not differ significantly among the three groups. A total of 256 variables were analyzed. Only 19 variables were found to be statistically significant (P < 0.05). These were: use of a boiler; use of firewood; car ownership; use of earthenware; mixed material housing; socioeconomic level 1; sun exposure; use of soap; lemon consumption; use of moisturizing hair cream; living with pets in the house; living with farm animals; age; having a family member with AP; having had surgery; having had trauma; having been hospitalized; use of oral medication; and use of herbal medication. Of 40 macro- and micronutrients analyzed, 11 were found to have statistically significant effects (P < 0.05). Multiple epidemiologic, geographic, clinical, and immunologic factors are involved in the etiology of AP. This study proposes a clear line for research directed at specific risk factors that refer to an individual's clinical, allergic, health, and socioeconomic status. Further study should also investigate the etiologic role of diet in AP and the molecular mechanisms behind the development of AP to establish whether AP is caused by exposure to polycyclic aromatic hydrocarbons.	f	\N
23982030	To determine the rate of unplanned PICU readmissions, examine the characteristics of index admissions associated with readmission, and compare outcomes of readmissions versus index admissions. Retrospective cohort analysis. Ninety North American PICUs that participated in the Virtual Pediatric Intensive Care Unit Systems. One hundred five thousand four hundred thirty-seven admissions between July 2009 and March 2011. None. Unplanned PICU readmission within 48 hours of index discharge was the primary outcome. Summary statistics, bivariate analyses, and mixed-effects logistic regression model with random effects for each hospital were performed.There were 1,161 readmissions (1.2%). The readmission rate varied among PICUs (0-3.3%), and acute respiratory (56%), infectious (35%), neurological (28%), and cardiovascular (20%) diagnoses were often present on readmission. Readmission risk increased in patients with two or more complex chronic conditions (adjusted odds ratio, 1.72; p < 0.001), unscheduled index admission (adjusted odds ratio, 1.37; p < 0.001), and transfer to an intermediate unit (adjusted odds ratio, 1.29; p = 0.004, compared with ward). Trauma patients had a decreased risk of readmission (adjusted odds ratio, 0.67; p = 0.003). Gender, race, insurance, age more than 6 months, perioperative status, and nighttime transfer were not associated with readmission. Compared with index admissions, readmissions had longer median PICU length of stay (3.1 vs 1.7 d, p < 0.001) and higher mortality (4% vs 2.5%, p = 0.002). Unplanned PICU readmissions were relatively uncommon, but were associated with worse outcomes. Several patient and admission characteristics were associated with readmission. These data help identify high-risk patient groups and inform risk-adjustment for standardized readmission rates.	f	\N
23983044	To determine the differences in carotid intima-media thickness (CIMT) between patients with psoriatic diseases with and without metabolic syndrome. Eligible patients from the Cardiometabolic Outcome Measures in Psoriatic Arthritis Study database, which is comprised of both psoriasis and psoriatic arthritis (PsA) patients enrolled at 2 academic medical centers, were included. Detailed cardiovascular (CV) risk factors, including metabolic syndrome profiles, medication use, disease activity, and CIMT, were examined. A total of 343 patients with psoriatic disease were evaluated (42.28% with psoriasis and 57.72% with PsA). PsA patients were significantly older, with longer disease duration and higher blood pressure, body mass index, and C-reactive protein (CRP) level. PsA patients took more disease-modifying antirheumatic drugs (DMARDs) and corticosteroids and underwent more CV procedures. There were no differences in prior CV events, family history of CV risk, and Framingham/Adult Treatment Panel III Risk Score. PsA patients had a higher risk of metabolic syndrome (univariate odds ratio [OR] 1.78 [95% confidence interval (95% CI) 1.08-2.95], P = 0.025). Even after adjusting for age, CRP level, and diastolic blood pressure, PsA patients not taking DMARDs were twice as likely to have metabolic syndrome compared to psoriasis patients (adjusted OR 2.09 [95% CI 0.78-5.59], P = 0.049). PsA patients with metabolic syndrome had the thickest CIMT compared to any other group (P < 0.001). PsA patients had an increased prevalence of metabolic syndrome with significantly greater CIMT measurements compared to patients with psoriasis. Furthermore, PsA patients with metabolic syndrome had the greatest CIMT measurements compared to PsA patients without metabolic syndrome and psoriasis patients with or without metabolic syndrome. Incremental increases in inflammatory pathways in PsA may contribute to a higher CV risk as compared to psoriasis patients.	f	\N
23987905	This study evaluated effectiveness of three different surgical strategies for treating ascending aorta aneurysm, with or without involvement of the aortic root, associated with bicuspid aortic valve (BAV). Between 2005 and 2011, 150 consecutive patients underwent a Bentall operation in the presence of ascending aorta and aortic root dilation exceeding 45 mm in diameter and malfunctioning BAV (n = 46, group 1); separate aortic valve and ascending aorta replacement in presence of ascending aorta dilation exceeding 45 mm, aortic root of less than 45 mm, and malfunctioning BAV (n = 77, group 2); or ascending aorta replacement, with or without BAV repair, in the presence of ascending aorta dilation exceeding 45 mm, aortic root of less than 45 mm, and normally functioning or mildly insufficient BAV (n = 27, group 3). Compared with groups 2 and 3, group 1 patients were younger and affected by more severe BAV insufficiency and worse left ventricular function. In groups 1, 2, and 3, respectively, operative mortality was 2.1%, 1.3%, and 0%, and 5-year survival was 94% ± 4%, 92% ± 3.4%, and 100%. At 5 years, no patient in any group required reoperation on the ascending aorta or experienced aortic complications. In groups 2 and 3, root dimensions did not increase and were also significantly smaller compared with preoperative measurements (p < 0.05). Aortic regurgitation grade in group 3 (0.5 ± 0.8/4+) did not increase compared with the preoperative grade (0.8 ± 0.9/4+). At midterm follow-up, the Bentall operation remains associated with optimal results for the treatment of BAV, despite a worse preoperative presentation. In presence of a mildly diseased or normal aortic root and normal BAV function at the time of operation, less invasive surgical procedures, BAV-sparing, or repair procedures, appear to offer gratifying results.	f	\N
23993863	Despite extensive study, few therapeutic targets have been identified for glioblastoma (GBM). Here we show that patient-derived glioma sphere cultures (GSCs) that resemble either the proneural (PN) or mesenchymal (MES) transcriptomal subtypes differ significantly in their biological characteristics. Moreover, we found that a subset of the PN GSCs undergoes differentiation to a MES state in a TNF-α/NF-κB-dependent manner with an associated enrichment of CD44 subpopulations and radioresistant phenotypes. We present data to suggest that the tumor microenvironment cell types such as macrophages/microglia may play an integral role in this process. We further show that the MES signature, CD44 expression, and NF-κB activation correlate with poor radiation response and shorter survival in patients with GBM.	f	\N
24010694	Lenalidomide is an immunomodulatory drug approved by the AEMPS and the EMA, in combination with dexamethasone, for the treatment of multiple myeloma in adult patients who have received at least one prior therapy. Moreover, it has recently been approved for the treatment of patients with transfusion-dependent anaemia due to low- or intermediate-1-risk myelodysplastic syndromes associated with an isolated deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate. It has also shown to be active in other hematologic and no hematologic diseases. Growing evidence of its use entails a challenge when situating the drug in a cost-effective way to treat these diseases. On this article we review the available evidence on the use of lenalidomide in the second line treatment of patients with chronic lymphocytic leukemia, primary amyloidosis and primary myelofibrosis, and in the first line treatment of patients with myelodysplastic syndrome, and also the evidence of other immunomodulators. Different clinical practice guidelines and scientific evidence portals consider lenalidomide a valid alternative in the first-line treatment of patients with myelodysplastic syndromes, specially those with the deletion of 5q, and in second line for patients with chronic lymphocytic leukemia. However, the available evidence of lenalidomide in the treatment of patients with primary amyloidosis and primary myelofibrosis is limited, ant thus is not considered as the first choice treatment. In any case, the treatment of choice should consider the safety profile in each patient, the previous treatments that has received and the own therapeutic protocols of each center.	f	\N
24016609	Retinopathy of prematurity (ROP) is a leading cause of childhood blindness. This retrospective study investigated ROP, including incidence, demographic information,risk factors, treatments, and refractive outcomes, in southern Taiwan over a 10-year period. The authors retrieved the National Cheng Kung University Hospital database between the years 2000 and 2009 for newborns with a gestational age less than 32 weeks and/or with a birth weight less than 1500 g who had been screened for ROP. We recorded sex, birth weight, gestational age, in-hospital versus out-of-hospital birth, paternal and maternal ages, whether there were multiple gestations, parity, Apgar scores, length of hospital stay, risk factors, presence and severity of ROP and whether it was treated, and refraction at the last visit. Regression analyses were performed to identify risk factors for ROP. A total of 503 live births were included. ROP was identified in 190 (37.8%) and met criteria for treatment in 59 (11.7%).ROP was diagnosed as stage 1, 2, 3, 4, and 5 in 61 (12.1%), 36 (7.2%), 81 (16.1%), 11 (2.2%), and 1 (0.2%) infant, respectively. Lower birth weight and younger gestational age were risk factors for greater severity of ROP (p < 0.001). Of the 167 with extremely low birth weight (<1000 g), 118 (70.7%) had ROP and 49 (29.3%) required treatment. On univariate analysis, low birth weight, younger gestational age, and risk factors such as respiratory distress syndrome, chronic lung disease, patent ductus arteriosus, surfactant usage, indomethacin usage, sepsis, upper gastrointestinal bleeding, blood transfusion, and necrotizing enterocolitis were associated with ROP. Multivariate logistic regression analysis showed that only lower birth weight was a significant and independent risk factor for ROP. Myopia (76%)and anisometropia (28%)were common in advanced ROP. Low birth weight is a major risk factor for ROP. Infants with extremely low birth weight had a higher risk of severe ROP. Common ocular sequelae of advanced ROP were myopia and anisometropia.	f	\N
24021446	We present two young patients with morphea or localized scleroderma undergoing systemic treatment, who developed papular lesions on pre-existing sclerotic plaques. Histology was compatible with a papular presentation of morphea and other entities in the differential diagnosis were ruled out. We believe this is a very uncommon presentation of activity in lesions of morphea and should be made known to clinicians so that activity and progression of the disease can be recognized and treated to avoid complications.	f	\N
24032423	Spinocerebellar ataxia type 1 (SCA1) is a hereditary, progressive and fatal movement disorder that primarily affects the cerebellum. Non-invasive imaging markers to detect early disease in SCA1 will facilitate testing and implementation of potential therapies. We have previously demonstrated the sensitivity of neurochemical levels measured by (1) H magnetic resonance spectroscopy (MRS) to progressive neurodegeneration using a transgenic mouse model of SCA1. In order to investigate very early neurochemical changes related to neurodegeneration, here we utilized a knock-in mouse model, the Sca1(154Q/2Q) line, which displays milder cerebellar pathology than the transgenic model. We measured cerebellar neurochemical profiles of Sca1(154Q/2Q) mice and wild-type littermates using 9.4T MRS at ages 6, 12, 24, and 39 weeks and assessed the cerebellar pathology of a subset of the mice at each time point. The Sca1(154Q/2Q) mice displayed very mild cerebellar pathology even at 39 weeks, however, were distinguished from wild types by MRS starting at 6 weeks. Taurine and total choline levels were significantly lower at all ages and glutamine and total creatine levels were higher starting at 12 weeks in Sca1(154Q/2Q) mice than controls, demonstrating the sensitivity of neurochemical levels to neurodegeneration related changes in the absence of overt pathology. We measured cerebellar neurochemical alterations in a knock-in mouse model of spinocerebellar ataxia type 1, a hereditary movement disorder, using ultra-high field magnetic resonance spectroscopy (MRS). Very early neurochemical alterations were detectable prior to overt pathology in the volume-of-interest for MRS. Alterations were indicative of osmolytic changes and of disturbances in membrane phospholipid and energy metabolism.	f	\N
24039761	Pig is an important agricultural animal for meat production and provides a valuable model for many human diseases. Functional studies have demonstrated that microRNAs (miRNAs) play critical roles in almost all aspects of skeletal muscle development and disease pathogenesis. To investigate the miRNAs involved in regulating different periods of skeletal muscle development, we herein performed a comprehensive research for porcine microRNAome (miRNAome) during 10 skeletal muscle developmental stages including 35, 49, 63, 77, 91 dpc (days post coitum) and 2, 28, 90, 120, 180 dpn (days postnatal) using Solexa sequencing technology. Our results extend the repertoire of pig miRNAome to 247 known miRNAs processed from 210 pre-miRNAs and 297 candidate novel miRNAs through comparison with known miRNAs in the miRBase. Expression analysis of the 15 most abundant miRNAs in every library indicated that functional miRNAome may be smaller and tend to be highly expressed. A series of muscle-related miRNAs summarized in our study present different patterns between myofibers formation phase and muscle maturation phase, providing valuable reference for investigation of functional miRNAs during skeletal muscle development. Analysis of temporal profiles of miRNA expression identifies 18 novel candidate myogenic miRNAs in pig, which might provide new insight into regulation mechanism mediated by miRNAs underlying muscle development.	f	\N
24050030	To evaluate serum and peritoneal concentrations of amyloid protein A in women with endometriosis and to compare them with those of women without endometriosis. A prospective study evaluated 76 women suspected of having pelvic endometriosis. Fifty-seven women (group A) were confirmed by videolaparoscopy and had their serum and peritoneal amyloid A concentrations measured by ELISA. The average levels from group A were compared to those obtained in group B. Group B was composed of 13 women without endometriosis, submitted to elective laparoscopy for tubal ligation. Peritoneal amyloid A concentrations in group A (310.3 +/- 97.8 ng/mL) were higher than those of group B (53.4 +/- 58.2 ng/mL); p = 0.0. However, serum concentrations in groups A (14.01 +/- 32.3 ng/mL) and B (9.5 +/- 15.9 ng/mL) did not differ significantly; p = 0.35. The peritoneal amyloid A protein concentration in pelvic endometriosis was higher when compared to normal controls, corroborating the inflammatory nature of the disease. This finding suggests that the procedure of evaluating the peritoneal amyloid A concentration in endometriosis merits further investigation.	f	\N
24052521	Resistin, which is derived from the gene of RSTN, belongs to a family of cysteine-rich secretory proteins called resistin-like molecules (RELMs). Increased serum resistin levels are associated with coronary artery disease (CAD) and the risk of cardiovascular death. Patients (n = 214) with an initial diagnosis of stable angina pectoris, unstable angina pectoris, and myocardial infarction without ST-segment elevation and referred to catheter laboratory for coronary angiography were enrolled in the study. We aimed to investigate the relationship between increased serum resistin level and CAD. The severity of CAD was calculated by the Gensini scoring system. In conclusion, we established a significant correlation between serum resistin levels and CAD (P = .010). Also, serum resistin levels correlated with the Gensini score that represents the severity of CAD angiographically (P = .010).	f	\N
24063011	Aspergillus fumigatus is a ubiquitously present respiratory pathogen. The outcome of a pulmonary disease may vary significantly with fungal viability and host immune status. Our objective in this study was (1) to assess the ability of inhaled irradiation-killed or live A. fumigatus spores to induce allergic pulmonary disease and (2) to assess the extent to which inhaled dead or live A. fumigatus spores influence pulmonary symptoms in a previously established allergic state. Our newly developed fungal delivery apparatus allowed us to recapitulate human exposure through repeated inhalation of dry fungal spores in an animal model. We found that live A. fumigatus spore inhalation led to a significantly increased humoral response, pulmonary inflammation, and airway remodeling in naïve mice and is more likely to induce allergic asthma symptoms than the dead spores. In contrast, in allergic mice, inhalation of dead and live conidia recruited neutrophils and induced goblet cell metaplasia. This data suggests that asthma symptoms might be exacerbated by the inhalation of live or dead spores in individuals with established allergy to fungal antigens, although the extent of symptoms was less with dead spores. These results are likely to be important while considering fungal exposure assessment methods and for making informed therapeutic decisions for mold-associated diseases.	f	\N
24064013	Since the publication of the first reports on the efficiency of colchicine in familial Mediterranean fever (FMF), very few randomised studies have investigated issues related to its long-term use. Thus, different approaches taken by physicians involved in FMF care, are exclusively empiric, emulative, and based on case-reports or case-series. Problems such as colchicine intolerance and colchicine resistance have not been solved yet. This paper aims to evaluate trends in colchicine therapy among physicians taking care of FMF patients around the world. We conducted a survey by sending questionnaires to FMF research and treatment centres in Europe and Asia. Many issues (such as dosages, schedules, side effects, interactions, efficacy and toxicity monitoring, definition of colchicine intolerance, colchicine resistance and responsiveness, etc) have been investigated. When more than 70% of physicians responded giving similar answers to an item, the response was considered as a 'trend'. A comparison between answers of physicians from FMF-prevalent and non-prevalent countries was also made. Thirty-five physicians from 11 countries filled the questionnaires, taking care of a total of more than 15000 FMF patients (pts). Different approaches were evident among the various physicians. Statistically significant different approaches between physicians from FMF-prevalent countries with respect to those from non-prevalent countries were found in items like colchicine during pregnancy, severity score and blood tests for disease monitoring. No consensus was found regarding the definition of colchicine resistance. The current study demonstrated significant variations in the strategy of colchicine therapy for FMF around the world and re-emphasised the need for standardised definitions of colchicine resistance and colchicine intolerance.	f	\N
24072601	Increasing evidence suggests low disease activity or remission is achievable in rheumatoid arthritis (RA). Using a treat to target strategy (T2T) has been shown to achieve these targets of remission or low disease activity in RA. In order to successfully treat to target, rheumatologists need reliable measures of disease activity to switch and/or escalate therapy to achieve or maintain therapeutic targets. Multiple disease-activity measures have been developed for both research and clinical practice. For clinical practice, the American College of Rheumatology (ACR) has recommended the PAS, PAS II, RAPID 3, CDAI, DAS 28, and SDAI for measuring disease activity in rheumatoid arthritis. Each of these measures has strengths and limitations, but they all accurately reflect disease activity, discriminate well between disease states, and are feasible to perform in the clinical setting. Implementation in the clinical setting can be optimized through leveraging technology and systems redesign. Tools such as web-based and smartphone applications have been developed to increase the ease with which these measures can be deployed. Disease-activity measurement in rheumatoid arthritis is included in the rheumatoid arthritis quality measures group in the Centers for Medicare and Medicaid Services' incentive-based Physician Quality Reporting System.	f	\N
24098438	Seminoma is one of the most common Testicular Germ Cell Tumours that originates during embryonic development due to an alteration of the local niche that in turn results in a delayed or blocked differentiation of Primordial Germ Cells. The block of differentiation is actually a common way to develop cancer disease as postulated by the "embryonic rest theory of cancer". In agreement with this theory different studies have demonstrated that embryonic cues display the capacity of reprogramming aggressive cancer cells towards a less aggressive phenotype. Herein we investigate the ability of a culture medium added with 10% egg albumen (EW, Egg White) to modulate seminoma cell phenotype and behaviour, by ensuring a proper set of morphogenetic signals. We chose to use the TCam-2 seminoma cell line that has been established as the only available cell line, obtained from a primary testicular seminoma. EW is able to: 1) modify TCam-2 cell spreading rate and cell-substrate adhesion without affecting proliferation and survival indexes; 2) modulate TCam-2 actin distribution pattern increasing cortical localization of actin filaments; 3) increase TCam-2 cell-cell junction capability; 4) decrease both chemo-sensitive and collective TCam-2 migratory behaviour. According to these observations morphometric fractal analysis revealed the ability of EW to increase Circularity and Solidity parameters and, consequently, to decrease Fractal dimension. Prompted by these observations we hypothesize that EW treatment could rescue, at least in part, the neoplastic-metastatic behaviour of seminoma cells.	f	\N
24102319	Transient receptor potential (TRP) channels are important mediators of sensory signals with marked effects on cellular functions and signalling pathways. Indeed, mutations in genes encoding TRP channels are the cause of several inherited diseases in humans (the so-called 'TRP channelopathies') that affect the cardiovascular, renal, skeletal and nervous systems. TRP channels are also promising targets for drug discovery. The initial focus of research was on TRP channels that are expressed on nociceptive neurons. Indeed, a number of potent, small-molecule TRPV1, TRPV3 and TRPA1 antagonists have already entered clinical trials as novel analgesic agents. There has been a recent upsurge in the amount of work that expands TRP channel drug discovery efforts into new disease areas such as asthma, cancer, anxiety, cardiac hypertrophy, as well as obesity and metabolic disorders. A better understanding of TRP channel functions in health and disease should lead to the discovery of first-in-class drugs for these intractable diseases. With this review, we hope to capture the current state of this rapidly expanding and changing field.	f	\N
24107731	The metabolic dysfunction accompanying the polycystic ovary syndrome (PCOS) may increase the risk of hypertension and cardiovascular disease (CVD). Although menopause per se may be an additional risk factor of CVD, the association between PCOS in postmenopausal women and cardiovascular risk has not been adequately investigated. We aimed to evaluate the effect of PCOS on markers of subclinical atherosclerosis in nondiabetic postmenopausal women. This cross-sectional study included 286 postmenopausal women with intact ovaries. PCOS phenotype was defined if three of the following were present: insulin resistance, current hyperandrogenism or history of clinical androgen excess, history of infertility, central obesity and history of irregular menses. Traditional CVD risk factors, as well as indices of arterial structure (intima-media thickness, atheromatous plaques presence) and function [flow-mediated dilation, pulse wave velocity (PWV), augmentation index] were compared between women with a PCOS phenotype and the rest of the sample, who served as controls. Women with the PCOS phenotype (N=43) had higher SBP and triglycerides and lower high-density lipoprotein (HDL)-cholesterol than controls. Mean values of PWV differed significantly between PCOS cases and controls (9.46±1.74 vs. 8.60±1.51 m/s, P=0.001, univariate). Multivariate regression analysis showed that the PCOS phenotype, age and SBP were the only independent predictors of PWV. Arterial stiffness is increased in asymptomatic, nondiabetic women with a putative PCOS phenotype, independently of age, BMI or blood pressure. This might present one mechanism through which PCOS increases the risk of CVD and hypertension later in life.	f	\N
24108471	Brain vasculature is uniquely programmed to protect central nervous system tissues and respond to their metabolic demands. These functions are subverted during the development of primary and metastatic brain tumors, resulting in vascular perturbations that are thought to contribute to progression and comorbidities of the underlying disease, including thrombosis and hemorrhage. Chronic activation of the coagulation system is particularly obvious in glioblastoma multiforme (GBM), where intratumoral vasoocclusive thrombosis may contribute to hypoxia, pseudopalisading necrosis, and angiogenesis. GBM is also associated with spontaneous or iatrogenic bleeding, and the emission of circulating procoagulants implicated in the unusually high risk of peripheral venous thromboembolism. Tissue factor (TF) expression is elevated in several types of brain tumors, including adult and pediatric GBM, as is the production of TF-containing microparticles (TF-MPs). Both TF expression and its vesicular emission are regulated by tumor microenvironment (e.g., hypoxia), in concert with activated oncogenic and growth factor pathways (RAS, EGFR, MET), as well as the loss of tumor suppressor gene activity (PTEN). Discovery of distinct oncogenic networks led to recognition of unique molecular subtypes within brain tumors, of which GBM (proneural, neural, classical, and mesenchymal), and medulloblastoma (SHH, WNT, group 3, and group 4) exhibit subtype-specific composition of the tumor coagulome. It remains to be established whether mechanisms of thrombosis and biological effects of coagulation in brain tumors are also subtype specific. In this regard, TF pathway represents a paradigm, and its impact on tumor dormancy, inflammation, angiogenesis, formation of cancer stem cell niches, and dissemination is a subject of considerable interest. However, establishing the extent to which TF and TF-MPs contribute to pathogenesis and thromboembolic disease in the context of primary and secondary brain tumors may require molecular stratification of patient populations. We suggest that a better understanding of these molecular linkages may pave the way to a more effective (targeted) therapy, prophylaxis, adjunctive use of anticoagulants, and other agents able to modulate interactions between brain tumors and the coagulation system.	f	\N
24124671	To explore the exercise characteristics of patients with idiopathic pulmonary arterial hypertension (IPAH). From November 2010 to September 2012 , 76 consecutive IPAH patients and 24 healthy controls from Fuwai Cardiovascular Hospital were enrolled to undergo cardiopulmonary exercise testing. The exercise parameters were compared. Correlations among peak oxygen consumption, anaerobic threshold, peak oxygen pulse, New York Heart Association (NYHA) class, N-terminal pro-brain natriuretic peptide (NT-proBNP), 6-minute walking distance (6 MWD) and cardiac index are analyzed in IPAH. There were 21 males and 55 females in IPAH and 8 males and 16 females in controls. Their mean ages were (31.5 ± 10.6) and (35.5 ± 6.4) years respectively. Significant differences (P = 0.000) existed between two groups in peak oxygen consumption ((12.7 ± 3.3) vs (25.6 ± 5.8) ml·min(-1)·kg(-1)), anaerobic threshold ((9.8 ± 2.5) vs (16.7 ± 3.9) ml·min(-1)·kg(-1)), peak oxygen pulse ((5.3 ± 1.6) vs (9.9 ± 2.5) ml/bpm) and ventilator efficiency (slope of minute ventilation in relation to CO2 produced) ((42.6 ± 2.0) vs (25.5 ± 3.5)). In IPAH, peak oxygen consumption was significantly correlated with NYHA class (r = -0.509, P = 0.000), 6 MWD (r = 0.443, P = 0.002) and NT-proBNP levels (r = -0.423, P = 0.011). And anaerobic threshold was significantly correlated with NYHA class (r = -0.362, P = 0.002), 6MWD (r = 0.343, P = 0.004) and NT-proBNP levels (r = -0.275, P = 0.017). Peak oxygen pulse and ventilator efficiency were both correlated well with total pulmonary vascular resistance. Partial correlation analysis demonstrated that there were significant correlations among peak oxygen consumption, anaerobic threshold, NYHA class, NT-proBNP levels and 6MWD after adjusting for age, gender and weight. Peak oxygen consumption and anaerobic threshold decrease ventilator efficiency in IPAH patients. Cardiopulmonary exercise testing is an invasive tool of assessing safely the function of IPAH patients.	f	\N
24127735	Knee osteoarthritis (OA) is a major cause of pain, functional limitation, and reduced quality-of-life, particularly in older adults. This study evaluated the 'real world' NSAID-sparing effect of glucosamine (specifically Structoflex®) in patients with knee OA compared with a control population of patients who did not receive a slow-acting symptomatic anti-osteoarthritis agent. This analysis was conducted over a 1-year follow-up period. Data were sourced from the French Disease Analyzer (IMS Lifelink EMR™) database. The primary measure was the NSAID-sparing effect produced by Structoflex® compared with a matched control group. Secondary measures included an evaluation of the change in the number of general practitioner visits and use of other medicinal products related to knee OA. A total of 11,772 patients (67.66% female) were included in the analysis (436 and 11,336 patients in the Structoflex® and control groups, respectively). Most patients were aged 50-65 years (58.72%); 19.5% of patients were aged >76 years. At study inclusion, 51.61% of patients had experienced OA for <1 year. Prior to starting Structoflex®, 51.61% of patients had received an NSAID prescription. Significantly more patients who were receiving an NSAID at the time of starting Structoflex® discontinued their NSAID treatment during the follow-up period compared with patients in the control group (32% vs 23%; p = 0.0452). During the 1-year follow-up period, the total mean duration of NSAID prescription (30.39 ± 38.64 days vs 37.82 ± 54.62 days; p = 0.0109) and the mean number of days (calculated using Defined Daily Dose) on NSAID (45.12 ± 49.03 days vs 53.00 ± 71.14 days; p = 0.0333) was significantly lower in Structoflex®-treated patients compared with control group patients. This large 'real world' analysis demonstrated a significant NSAID-sparing effect of glucosamine in patients with knee OA.	f	\N
24138892	I shall discuss the work of researchers at Harvard Medical School who came together in the early 1990s. Scattered across various Harvard-affiliated hospitals and research centers, these individuals were unified by their interest in ocular neovascularization. Together and separately, they investigated models of ocular neovascularization, exploring tumor angiogenesis in eye development and disease.	f	\N
24141443	To validate the Clinical Gait and Balance Scale (GABS) for a Brazilian population of patients with Parkinson's disease (PD) and to compare it to the Berg Balance Scale (BBS). One hundred and seven PD patients were evaluated by shortened UPDRS motor scale (sUPDRSm), Hoehn and Yahr (HY), Schwab and England scale (SE), Falls Efficacy Scale International (FES-I), Freezing of Gait Questionnaire (FOG-Q), BBS and GABS. The internal consistency of the GABS was 0.94, the intra-rater and inter-rater reliability were 0.94 and 0.98 respectively. The area under the receiver operating characteristic (ROC) curve was 0.72, with a sensitivity of 0.75 and specificity of 0.6, to discriminate patients with a history of falls in the last twelve months, for a cut-off score of 13 points. Our study shows that the Brazilian version of the GABS is a reliable and valid instrument to assess gait and balance in PD.	f	\N
24144148	Pompe disease is a rare, progressive and often fatal neuromuscular disorder. It is caused by a deficiency of the lysosomal alpha-glucosidase. Among glycogen storage disorders, it is one of the most common. Its clinical manifestations can start at any moment of life, with a very variable symptomatology. In this article, we show an extended revision of the literature in regards to the main medical aspects of Pompe disease: etiology, psychopathology, epidemiology, clinical variants, pathological diagnosis, and enzyme replacement therapy. With this information, we created a diagnostic and therapeutic guide, which is addressed to specialists and to first-level physicians, in order to let them identify both the classic and the late forms of this disease. We describe as well the best, timely, multidisciplinary treatment in use. Also, we show some suggestions to the proper functioning of health institutions, and routes to diagnosis. We conclude that Pompe disease may be properly diagnosed and treated if health care professionals follow the internationally approved recommendations.	f	\N
24151631	Cystic echinococcosis (CE) is a chronic, clinically complex, and neglected disease. Its prevalence in Italy, a country of medium to high endemicity, remains poorly defined, as notification has long ceased to be mandatory. We set up a retrospective cohort study involving all CE patients followed at our institute between January 2005 and December 2012. Demographical and clinical features were recorded and analyzed. CE was found in 28 patients (64.3%), mostly Italians from the central regions (50%), followed by subjects from the islands (33.3%) and Southern Italy (16.7%). Their median age was 45 years (IQR: 38.5-66.5), with Eastern Europeans being significantly younger (28 years, IQR: 19-39) than other patients (P ≤ 0.0001). A total of 149 cysts, mostly with hepatic localization (96%), were described. Based on the WHO classification, the cysts were mainly small (80.5%) and active (CE1 (73.8%); CE2 (7.4%)). Active cysts were more common in Eastern Europeans (85.7%) than Italians (66.7%). Our data confirm CE occurrence in Italy. We emphasize the importance to have a national CE registry, opportunely recently introduced. This is essential to assess CE prevalence in this country, implement appropriate control measures, and improve patient management.	f	\N
24152546	Pre-diagnosis oophorectomy and estrogen therapy could impact mortality due to breast cancer and cardiovascular disease (CVD) among breast cancer survivors. Elective bilateral oophorectomy at the time of hysterectomy for benign conditions is not uncommon among US women. We examined the association between pre-diagnosis total abdominal hysterectomy with bilateral salpingooophorectomy (TAHBSO) and both overall and cause-specific mortality in the Collaborative Breast Cancer Studies cohort. Medical history and prior estrogen use were collected during standardized telephone interviews. Vital status, including date and cause of death, was obtained by linkage with the National Death Index. Multivariate hazard ratios (HR) and 95% confidence intervals (CI) for cause-specific mortality were calculated using Cox proportional hazards regression. Seventeen percent (N = 1,778) of breast cancer survivors (mean age at diagnosis = 63.5) reported pre-diagnosis TAHBSO. During follow-up (mean = 9.5 years), 2,856 deaths occurred, including 1,060 breast cancer deaths and 459 CVD deaths. Breast cancer deaths occurred a median of 5.1 years after diagnosis; CVD deaths occurred further from diagnosis (median = 9.7 years). Women who reported pre-diagnosis TAHBSO had a 16% decrease in all-cause mortality (HR = 0.84; 95% CI: 0.76, 0.92) compared to those with an intact uterus and ovaries. This overall decrease reflected a 27% lower breast cancer mortality among women who never used postmenopausal hormones (HR = 0.73; CI: 0.55, 0.96) and 43% lower CVD risk among women who reported using estrogen (HR = 0.57; CI: 0.39, 0.83) after TAHBSO. Information on prior TAHBSO and estrogen use can inform risk of death fromboth breast cancer and cardiovascular disease among breast cancer survivors.	f	\N
24152582	The Ca(2+) channel-binding domain 3 (CBD3) peptide, derived from the collapsin response mediator protein 2 (CRMP-2), is a recently discovered voltage-gated Ca(2+) channel (VGCC) blocker with a preference for CaV2.2. Rodent administration of CBD3 conjugated to cell penetrating motif TAT (TAT-CBD3) has been shown to reduce pain behavior in inflammatory and neuropathic pain models. However, TAT-CBD3 analgesia has limitations, including short half-life, lack of cellular specificity and undesired potential off-site effects. We hypothesized that these issues could be addressed by expressing CBD3 encoded by high-expression vectors in primary sensory neurons. We constructed an adeno-associated viral (AAV) vector expressing recombinant fluorescent CBD3 peptide and injected it into lumbar dorsal root ganglia (DRGs) of rats before spared nerve injury (SNI). We show that selective expression of enhanced green fluorescent protein (EGFP)-CBD3 in lumbar 4 (L4) and L5 DRG neurons and their axonal projections results in effective attenuation of nerve injury-induced neuropathic pain in the SNI model. We conclude that AAV-encoded CBD3 delivered to peripheral sensory neurons through DRG injection may be a valuable approach for exploring the role of presynaptic VGCCs and long-term modulation of neurotransmission, and may also be considered for development as a gene therapy strategy to treat chronic neuropathic pain.	f	\N
24157515	While undernutrition and infectious diseases are still persistent in developing countries, overweight, obesity, and associated comorbidities have become more prevalent. Uganda, a developing sub-Saharan African country, is currently experiencing the public health paradox of undernutrition and overnutrition. We utilized the 2011 Uganda Demographic and Health Survey (DHS) to examine risk factors and hot spots for underweight, overweight, and obesity among adult females (N = 2,420) and their children (N = 1,099) using ordinary least squares and multinomial logit regression and the ArcGIS Getis-Ord Gi* statistic. Overweight and obese women were significantly more likely to have overweight children, and overweight was correlated with being in the highest wealth class (OR = 2.94, 95% CI = 1.99-4.35), and residing in an urban (OR = 1.76, 95% CI = 1.34-2.29) but not a conflict prone (OR = 0.48, 95% CI = 0.29-0.78) area. Underweight clustered significantly in the Northern and Northeastern regions, while overweight females and children clustered in the Southeast. We demonstrate that the DHS can be used to assess geographic clustering and burden of disease, thereby allowing for targeted programs and policies. Further, we pinpoint specific regions and population groups in Uganda for targeted preventive measures and treatment to reduce the burden of overweight and chronic diseases in Uganda.	f	\N
24169298	Morbidity and mortality from preventable, noncommunicable chronic disease (NCD) threatens the health of our populations and our economies. The accumulation of vast amounts of scientific knowledge has done little to change this. New and innovative thinking is essential to foster new creative approaches that leverage and integrate evidence through the support of big data, technology, and design thinking. The purpose of this paper is to summarize the results of a consensus meeting on NCD prevention sponsored by the International Olympic Committee (IOC) in April 2013. Within the context of advocacy for multifaceted systems change, the IOC's focus is to create solutions that gain traction within health care systems. The group of participants attending the meeting achieved consensus on a strategy for the prevention and management of chronic disease that includes the following: 1. Focus on behavioral change as the core component of all clinical programs for the prevention and management of chronic disease. 2. Establish actual centers to design, implement, study, and improve preventive programs for chronic disease. 3. Use human-centered design (HCD) in the creation of prevention programs with an inclination to action, rapid prototyping and multiple iterations. 4. Extend the knowledge and skills of Sports and Exercise Medicine (SEM) professionals to build new programs for the prevention and treatment of chronic disease focused on physical activity, diet, and lifestyle. 5. Mobilize resources and leverage networks to scale and distribute programs of prevention. True innovation lies in the ability to align thinking around these core strategies to ensure successful implementation of NCD prevention and management programs within health care. The IOC and SEM community are in an ideal position to lead this disruptive change. The outcome of the consensus meeting was the creation of the IOC Non-Communicable Diseases ad hoc Working Group charged with the responsibility of moving this agenda forward.	f	\N
24171516	The efficacy of autologous stem-cell transplantation during the first remission in patients with diffuse, aggressive non-Hodgkin's lymphoma classified as high-intermediate risk or high risk on the International Prognostic Index remains controversial and is untested in the rituximab era. We treated 397 patients who had disease with an age-adjusted classification of high risk or high-intermediate risk with five cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP plus rituximab. Patients with a response were randomly assigned to receive three additional cycles of induction chemotherapy (control group) or one additional cycle of induction chemotherapy followed by autologous stem-cell transplantation (transplantation group). The primary efficacy end points were 2-year progression-free survival and overall survival. Of 370 induction-eligible patients, 253 were randomly assigned to the transplantation group (125) or the control group (128). Forty-six patients in the transplantation group and 68 in the control group had disease progression or died, with 2-year progression-free survival rates of 69 and 55%, respectively (hazard ratio in the control group vs. the transplantation group, 1.72; 95% confidence interval [CI], 1.18 to 2.51; P=0.005). Thirty-seven patients in the transplantation group and 47 in the control group died, with 2-year overall survival rates of 74 and 71%, respectively (hazard ratio, 1.26; 95% CI, 0.82 to 1.94; P=0.30). Exploratory analyses showed a differential treatment effect according to risk level for both progression-free survival (P=0.04 for interaction) and overall survival (P=0.01 for interaction). Among high-risk patients, the 2-year overall survival rate was 82% in the transplantation group and 64% in the control group. Early autologous stem-cell transplantation improved progression-free survival among patients with high-intermediate-risk or high-risk disease who had a response to induction therapy. Overall survival after transplantation was not improved, probably because of the effectiveness of salvage transplantation. (Funded by the National Cancer Institute, Department of Health and Human Services, and others; SWOG-9704 ClinicalTrials.gov number, NCT00004031.).	f	\N
24172078	Many symptomatic patients with severe aortic stenosis (AS) and preserved left ventricular ejection fraction (LVEF) are denied surgery and have a grim prognosis with medical management. Between 2003 and 2012, among 550 patients with severe isolated AS and preserved LVEF on transthoracic echocardiography, 241 did not undergo aortic valve replacement (mean age, 83.2±7.6 years; 54% female; aortic valve area index, 0.40±0.13cm(2)/m(2); mean LVEF, 64.8±7.6%) and 67% presented with cardiac symptoms. At a mean follow-up of 25.5±25.1 months, 134 patients (56%) had died. Survival at 1, 5 and 9.5 years was 71%, 28% at 12%, respectively. Median survival was 36.3 months (95% confidence interval [CI]: 27.2-42.4 months). In unadjusted analyses, age, heart failure, hypertension, renal insufficiency, left atrial size, pulmonary artery systolic pressure (PASP), relative wall thickness and LV mass/LV end diastolic volume ratio were associated with mortality. On multivariate analysis adjusted for all significant univariate predictors, age ≥78 years, history of hypertension, left atrial diameter ≥40mm and PASP ≥42mmHg gave a joint area under the curve of 0.80 (95% CI: 0.73-0.86) for mortality. In medically treated patients with severe isolated AS and preserved LVEF, older age, history of hypertension, and echo-Doppler variables reflecting LV diastolic dysfunction are independent predictors of death.	f	\N
24203705	Microbial genome sequencing is one of the longest-standing areas of biological database development, but high-throughput, low-cost technologies have increased its throughput to an unprecedented number of new genomes per year. Several thousand microbial genomes are now available, necessitating new approaches to organizing information on gene function, phylogeny and microbial taxonomy to facilitate downstream biological interpretation. MetaRef, available at http://metaref.org, is a novel online resource systematically cataloguing a comprehensive pan-genome of all microbial clades with sequenced isolates. It organizes currently available draft and finished bacterial and archaeal genomes into quality-controlled clades, reports all core and pan gene families at multiple levels in the resulting taxonomy, and it annotates families' conservation, phylogeny and consensus functional information. MetaRef also provides a comprehensive non-redundant reference gene catalogue for metagenomic studies, including the abundance and prevalence of all gene families in the >700 shotgun metagenomic samples of the Human Microbiome Project. This constitutes a systematic mapping of clade-specific microbial functions within the healthy human microbiome across multiple body sites and can be used as reference for identifying potential functional biomarkers in disease-associate microbiomes. MetaRef provides all information both as an online browsable resource and as downloadable sequences and tabular data files that can be used for subsequent offline studies.	f	\N
24206993	Ulnar impaction syndrome generally occurs with positive ulnar variance. The solution to the problem is to unload the ulnocarpal joint. Effective surgical options include diaphyseal ulnar shortening osteotomy, open wafer osteotomy, and arthroscopic wafer osteotomy. Recently, Slade and Gillon described an open procedure of ulnar shortening in the osteochondral region of the ulnar head. The procedure minimizes the risk of hemarthrosis and does not require hardware removal, which are problems with other surgical options. This article introduces a new arthroscopic technique of distal metaphyseal ulnar shortening osteotomy for ulnar impaction syndrome. This technique offers the advantages of minimizing surgical injury to the dorsal capsule of the distal radoulnar joint and so protects its stability.	f	\N
24211848	Crimean-Congo hemorrhagic fever virus (CCHFV) etiology was detected in a family cluster (nine cases, including two deaths) in the village of Karyana, Amreli District, and also a fatal case in the village of Undra, Patan District, in Gujarat State, India. Anti-CCHFV IgG antibodies were detected in domestic animals from Karyana and adjoining villages. Hyalomma ticks from households were found to be positive for CCHF viral RNA. This confirms the emergence of CCHFV in new areas and the wide spread of this disease in Gujarat State.	f	\N
24218343	Regional body-fat distribution is one of the key variables that explains the metabolic heterogeneity of obesity and its related cardiovascular risks. According to the ectopy concept, the inability of subcutaneous adipose tissue to store surplus triglycerides may lead to the development of fat in ectopic sites, such as the heart. Epicardial adipose tissue is a metabolically active endocrine organ that produces numerous factors that can modulate cardiac structure and function. The development of in vivo noninvasive imaging has made it possible to quantify its thickness and volume with increasing accuracy. In this review, we discuss the local interaction and cross-talk between epicardial fat and neighboring structures, such as coronary arteries and myocardium, and its relevance to cardiac diseases, such as coronary-artery disease or atrial fibrillation. Beneficial and harmful effects of epicardial adipose tissue are described and analyzed. What leads to an imbalance between protective and deleterious actions has to be further explored. We believe that epicardial fat, which has been neglected for years, plays a key role in cardiovascular disease pathophysiology and represents a "new world" exploration for therapeutic targets, which will be addressed in future clinical and research studies. Elucidating the mechanisms that drive the deposition or mobilization of cardiac adiposity between other ectopic-fat stores needs to be accomplished within the next few years.	f	\N
24223459	We evaluated whether the methylenetetrahydrofolate reductase (MTHFR) 677C>T marker influences the risk and severity of Alzheimer's disease (AD) and whether AD is associated with homocysteine, vitamin B12, and cholesterol levels in Egypt. Forty-three Alzheimer's cases and 32 non-AD controls were genotyped for the 677C>T polymorphism. Clinical characteristics and levels of homocysteine, vitamin B12, and cholesterol were assessed. No significant differences in the frequencies of the MTHFR alleles or genotypes between AD cases and controls (P = 0.14) were identified. The 677T mutant allele was significantly overrepresented in AD cases compared to controls (OR = 2.22; P = 0.03). The 677T/T frequency was three times higher in AD patients than in controls, which could increase plasma homocysteine levels. Severe cases of AD were the most frequent in patients with the T/T genotype (11.6%). The effect of the MTHFR polymorphism on the risk of AD may be independent of homocysteine, vitamin B12, or even cholesterol levels. The MTHFR 677C>T polymorphism--especially the presence of one copy of the T allele--appears to confer a potential risk for the development of AD. The T/T genotype may contribute to hypercysteinemia as a sensitive marker.	f	\N
24226095	Sterol 12α-hydroxylase (CYP8B1) is required for cholic acid synthesis and plays a critical role in intestinal cholesterol absorption and pathogenesis of cholesterol gallstone, dyslipidemia, and diabetes. In this study we investigated the underlying mechanism of fasting induction and circadian rhythm of CYP8B1 by a cholesterol-activated nuclear receptor and core clock gene retinoic acid-related orphan receptor α (RORα). Fasting stimulated, whereas restricted-feeding reduced expression of CYP8B1 mRNA and protein. However, fasting and feeding had little effect on the diurnal rhythm of RORα mRNA expression, but fasting increased RORα protein levels by cAMP-activated protein kinase A-mediated phosphorylation and stabilization of the protein. Adenovirus-mediated gene transduction of RORα to mice strongly induced CYP8B1 expression, and increased liver cholesterol and 12α-hydroxylated bile acids in the bile acid pool and serum. A reporter assay identified a functional RORα response element in the CYP8B1 promoter. RORα recruited cAMP response element-binding protein-binding protein (CBP) to stimulate histone acetylation on the CYP8B1 gene promoter. In conclusion, RORα is a key regulator of diurnal rhythm and fasting induction of CYP8B1, which regulates bile acid composition and serum and liver cholesterol levels. Antagonizing RORα activity may be a therapeutic strategy for treating inflammatory diseases such as non-alcoholic fatty liver disease and type 2 diabetes.	f	\N
24226419	IL-32 is a pro-inflammatory cytokine expressed by activated natural killer cells, T cells, keratinocytes, and fibroblasts. In this study, we examined the role of IL-32 in cutaneous T-cell lymphoma (CTCL), including mycosis fungoides (MF) and Sézary syndrome (SS). IL-32 mRNA expression levels in lesional skin of MF patch, plaque, and tumor were increased compared with those of normal skin, which positively correlated with CCL17 and CCL18 mRNA expression levels. Serum IL-32 levels positively correlated with disease activity within each patient. Immunostaining showed that keratinocytes expressed IL-32 in the lesional skin of MF patch and plaque, whereas in MF tumor, atypical T cells in the dermis strongly expressed IL-32. We also showed that IL-32 dose-dependently accelerated the proliferation of MF and SS cell lines in vitro, which was inhibited by blocking mitogen-activated protein kinase and NF-κB-mediated signaling. The addition of anti-IL-32 antibodies in culture decreased the proliferation of SS cells and the viability of MF cells, suggesting that IL-32 serves as an autocrine growth factor. In conclusion, our results suggest that IL-32 has a role in the formation and maintenance of CTCL lesions, providing a possible therapeutic target for patients with this disease.	f	\N
24240787	To assess the efficacy of pirfenidone in patients with advanced-stage idiopathic pulmonary fibrosis (IPF), we conducted a retrospective study of patients who received pirfenidone therapy. In addition, the combined effects of inhaled N-acetylcysteine (NAC) and pirfenidone were evaluated. Eligible patients had a clinical and radiologic diagnosis of advanced-stage IPF (stages of severity III&IV). Patients who exhibited a relative decline in forced vital capacity (FVC) of 10% or more within the preceding six (±2) months were enrolled. The outcome was evaluated from the date of the 6-month follow-up PFT. Relative declines in FVC of more than 10% were defined as progressive disease (ineffective group), while those less than 10% were defined as stable disease (effective group). The clinical features were compared between the two groups. We also compared the efficacy of the combined therapy with inhaled NAC and pirfenidone (n=11) with that of pirfenidone alone (n=7). Eighteen patients 59-82 years of age with IPF who received pirfenidone therapy were reviewed. Pirfenidone stabilized declines in FVC by 10% at six months in eight of the 18 cases (44%). The median changes in FVC at six months were +120 mL in the effective group and -590 mL in the ineffective group. The number of NAC users was significantly higher in the effective group (7/8=87.5%) than in the ineffective group (3/10=30%) (p=0.02). Furthermore, the use of combined NAC therapy was correlated with a favorable outcome. The median change in FVC at six months was 0 mL in the NAC group and -290 mL in the non-NAC group. The median survival period was 557 ± 66 days in the NAC group and 196 ± 57 days in the non-NAC group (p=0.03). Among the advanced-stage IPF patients with a more progressive status, pirfenidone decreased the rate of decline in FVC. In addition, patients treated with pirfenidone combined with NAC therapy exhibited favorable outcomes. Additional studies are needed to confirm the efficacy of this combined therapy for IPF.	f	\N
24246538	The use of "chimney" stents to augment the proximal landing zone for endovascular aneurysm repair has been increasingly reported. Despite mounting enthusiasm for this technique, the durability of this type of repair and capability to preserve perfusion to target branches remains a paramount concern. Here, we report management of a patient presenting with acute bilateral renal chimney stent thrombosis and a type Ia endoleak.	f	\N
24252129	Favre-Racouchot syndrome (FRS) is both disfiguring and difficult to treat. Available medical and surgical therapies are of variable efficacy. Most treatments do not achieve complete resolution and do not show maintenance of therapeutic response. To assess the response to a novel two-step treatment using the CO2 laser in patients with FRS. Seven patients with FRS were treated with the CO2 laser in resurfacing mode with manual expression of comedones under infiltrative local anaesthesia. The procedure was completed in one treatment session lasting 30 min and the wound was left to heal by secondary intention. A topical antibiotic was applied to treated areas, which were covered with a nonadherent dressing. All patients were assessed 3 months postoperatively by the operating laser surgeon and a visual assessment of clinical response to treatment in comparison with pretreatment photographs was made. Patient satisfaction was also recorded. All patients achieved complete resolution of FRS. The follow-up duration for our cohort ranged from 8 months to 3 years. Two patients required further treatment within a 2-3-year period from initial treatment. Disease relapse was noted over 1 year after the primary treatment; both these cases were smokers and repeat treatment with similar laser parameters maintained reproducible results. Our longest disease-free follow-up duration was 3 years postprimary treatment. The laser surgeons and patients reported high levels of therapeutic benefit and satisfaction with the results. This two-step treatment of FRS (CO2 laser resurfacing and manual pressure-induced expression of comedones) is an effective and durable treatment for FRS with an excellent cosmetic outcome. Long-term follow-up beyond 3 years is planned to determine whether later recurrence occurs with this technique.	f	\N
24263779	Over recent decades, the prevalence of high blood pressure (BP) has increased among children. Several risk factors are involved in the genesis of high BP during childhood, and their early identification can prevent the development of that disease. To assess the prevalence of high BP and associated factors in children. Cross-sectional, population-based study, carried out at the household. This study included 276 two- to five-year-old children in the city of Goiânia, state of Goiás, and assessed their BP, sociodemographic characteristics, birth weight, high BP family history, passive smoking, maternal breastfeeding, dietary habits, sedentary lifestyle and nutritional status. Poisson regression was used to assess the association between risk factors and high BP. Their mean age was 3.1 ± 0.79 years, and high BP and overweight were observed in 19.9% and 11.2% of the children, respectively. Direct association of high BP was identified with age [prevalence ratio (PR) = 2.3; 95%CI: 1.2 - 4.8; p = 0.017] and overweight (PR = 2.0; 95%CI: 1.2 - 3.6; p = 0.014). No other variable associated with high BP. The prevalence of high BP in children was high. Overweight and younger children had greater prevalence of high BP.	f	\N
24264509	According to 1981-2009 data, homicide accounts for 16,000-26,000 deaths annually in the United States and ranks within the top four leading causes of death among U.S. residents aged 1-40 years. Homicide can have profound long-term emotional consequences on families and friends of victims and on witnesses to the violence, as well as cause excessive economic costs to residents of affected communities. For years, homicide rates have been substantially higher among certain populations. Previous reports have found that homicides are higher among males, adolescents and young adults, and certain racial/ethnic groups, such as non-Hispanic blacks, non-Hispanic American Indian/Alaska Natives (AI/ANs), and Hispanics. The 2011 CDC Health Disparities and Inequalities Report (CHDIR) described similar findings for the year 2007. For example, the 2011 report showed that the 2007 homicide rate was highest among non-Hispanic blacks (23.1 deaths per 100,000), followed by AI/ANs (7.8 deaths per 100,000), Hispanics (7.6 deaths per 100,000), non-Hispanic whites (2.7 deaths per 100,000), and Asian/Pacific Islanders (A/PIs) (2.4 deaths per 100,000). In addition, non-Hispanic black men aged 20-24 years were at greatest risk for homicide in 2007, with a rate that exceeded 100 deaths per 100,000 population. Other studies have reported that community factors such as poverty and economic inequality and individual factors such as unemployment and involvement in criminal activities can play a substantial role in these persistent disparities in homicide rates. Public health strategies are needed in communities at high risk for homicide to prevent violence and save lives.	f	\N
24269993	To report on unexpected findings in 4 patients with chronic paraplegia who underwent the laparoscopic implantation of neuroprosthesis procedure in the pelvic lumbosacral nerves. Observational case series. Tertiary referral unit specialized in advanced gynecological surgery and neuropelveology. Three patients with incomplete American Spinal Injury Association (ASIA) Impairment Scale (AIS) grade B (n=2) and AIS grade C (n=1) spinal cord injury (SCI) and 1 patient with flaccid complete chronic SCI (AIS grade A) (n=1). Functional electrical stimulation (FES)-assisted locomotor training and continuous low-frequency pelvic-lumbosacral neuromodulation. Change in ASIA Lower Extremity Motor Scores, ASIA sensory scores for light touch and pinprick sensation, and Walking Index for Spinal Cord Injury scores. All 4 patients developed progressive recovery of some sensory and voluntary motor functions below the lesions. Three are currently capable of voluntary weight-bearing standing and walking a few meters with a walker without FES. The first patient with the longest follow-up is even capable of electrically assisted standing/walking with 2 crutches without braces or assistance for a distance of about 900 meters, and of weight-bearing standing and walking for 30 meters with a walker without stimulation. We report unexpected sensory and locomotor recovery in 4 people with paraplegia with SCI. Our findings suggest that FES-assisted locomotor training with continuous low-frequency pelvic nerve stimulation in patients with SCI may induce changes that affect the central pattern generator and allow supra- and infraspinal inputs to engage residual spinal pathways.	f	\N
24274981	DMD gene which is composed of 79 exons is the largest known gene located on X chromosome (Xp21). Point mutations in the dystrophin gene are responsible for 30-35% of cases with DMD/BMD. Mutation analysis of all the exons of the DMD gene is costly in developing countries, therefore, a few of the exons are selected to be analyzed routinely in clinical laboratories. In this study, direct sequencing was used for detection of point mutations in 10 exons of dystrophin gene in patients affected with DMD without detectable large rearrangements. Freely available programs were used to predict the damaging effects of the mutations. Point mutations were successfully detected in three patients. Three novel mutations, two missense mutations located on nonconservative domains and a single nucleotide deletion, were detected. Missense mutations were predicted to change splicing efficiency. Detection of point mutations by DNA analysis followed by prediction of the pathogenecity by using bioinformatic tool might be an asset to provide proper diagnosis or genetic counseling to patients and their family.	f	\N
24276026	Early detection and improved (neo)-adjuvant treatment has extended survival of breast cancer over the last decades. It remains controversial whether a survival benefit is achieved once metastases have occurred. This study investigates survival trends in metastatic breast cancer (MBC) looking at the distribution of prognostic factors and the time period of the diagnosis of the primary and metastatic disease. In this retrospective study, 1635 patients, diagnosed with MBC and treated at three German cancer centers, were included. For the survival analysis, patients were grouped into three time periods [1980-1994 (a), 1995-1999 (b) and 2000-2009 (c)], which were chosen according to the availability of new antineoplastic drugs for the treatment of MBC. Additionally, patients were divided into three risk groups using the simultaneously published prognostic score. The analysis of overall survival according to the date of primary diagnosis demonstrated a significant decline compared with the reference (a): (a versus b) hazard ratio (HR) = 1.37; P < 0.001; (a versus c) HR = 2.45; P < 0.001. Considering the time of first occurrence of metastasis, survival remains unchanged over the three periods (a versus b): HR = 0.94 P = 0.436; (a versus c): HR = 0.95; P = 0.435. However, a significant shift towards more unfavorable risk factors was seen. Although survival in MBC remains unchanged over time, patients developing metastatic disease have a more aggressive disease that is presumably compensated by more effective treatment. This alteration of tumor biology in MBC may be explained by a negative selection of patients with adverse risk profiles due to the advantages of the adjuvant therapy.	f	\N
24280762	Helicobacter pylori infections can induce pathologies ranging from chronic gastritis, peptic ulceration to gastric cancer. Bacterial isolates harbor numerous well-known adhesins, vacuolating cytotoxin VacA, protease HtrA, urease, peptidoglycan, and type IV secretion systems (T4SS). It appears that H. pylori targets more than 40 known host protein receptors on epithelial or immune cells. A series of T4SS components such as CagL, CagI, CagY, and CagA can bind to the integrin α 5β 1 receptor. Other targeted membrane-based receptors include the integrins αvβ 3, αvβ 5, and β 2 (CD18), RPTP-α/β, GP130, E-cadherin, fibronectin, laminin, CD46, CD74, ICAM1/LFA1, T-cell receptor, Toll-like receptors, and receptor tyrosine kinases EGFR, ErbB2, ErbB3, and c-Met. In addition, H. pylori is able to activate the intracellular receptors NOD1, NOD2, and NLRP3 with important roles in innate immunity. Here we review the interplay of various bacterial factors with host protein receptors. The contribution of these interactions to signal transduction and pathogenesis is discussed.	f	\N
24281461	Pediatric-onset Crohn disease is more aggressive than adult-onset disease, has high rates of resistance to existing drugs, and can lead to permanent impairments. Few trials have evaluated new drugs for refractory Crohn disease in children. To determine whether thalidomide is effective in inducing remission in refractory pediatric Crohn disease. Multicenter, double-blind, placebo-controlled, randomized clinical trial of 56 children with active Crohn disease despite immunosuppressive treatment, conducted August 2008-September 2012 in 6 pediatric tertiary care centers in Italy. Thalidomide, 1.5 to 2.5 mg/kg per day, or placebo once daily for 8 weeks. In an open-label extension, nonresponders to placebo received thalidomide for an additional 8 weeks. All responders continued to receive thalidomide for an additional minimum 52 weeks. Primary outcomes were clinical remission at week 8, measured by Pediatric Crohn Disease Activity Index (PCDAI) score and reduction in PCDAI by ≥25% or ≥75% at weeks 4 and 8. Primary outcomes during the open-label follow-up were clinical remission and 75% response. Twenty-eight children were randomized to thalidomide and 26 to placebo. Clinical remission was achieved by significantly more children treated with thalidomide (13/28 [46.4%] vs 3/26 [11.5%]; risk ratio [RR], 4.0 [95% CI, 1.2-12.5]; P = .01; number needed to treat [NNT], 2.86). Responses were not different at 4 weeks, but greater improvement was observed at 8 weeks in the thalidomide group (75% response, 13/28 [46.4%] vs 3/26 [11.5%]; RR, 4.0 [95% CI, 1.2-12.5]; NNT = 2.86; P = .01; and 25% response, 18/28 [64.2%] vs 8/26 [30.8%]; RR, 2.1 [95% CI, 1.1-3.9]; NNT = 2.99; P = .01). Of the nonresponders to placebo who began receiving thalidomide, 11 of 21 (52.4%) subsequently reached remission at week 8 (RR, 4.5 [95% CI, 1.4-14.1]; NNT = 2.45; P = .01). Overall, 31 of 49 children treated with thalidomide (63.3%) achieved clinical remission, and 32 of 49 (65.3%) achieved 75% response. Mean duration of clinical remission in the thalidomide group was 181.1 weeks (95% CI, 144.53-217.76) vs 6.3 weeks (95% CI, 3.51-9.15) in the placebo group (P < .001). Cumulative incidence of severe adverse events was 2.1 per 1000 patient-weeks, with peripheral neuropathy the most frequent severe adverse event. In children and adolescents with refractory Crohn disease, thalidomide compared with placebo resulted in improved clinical remission at 8 weeks of treatment and longer-term maintenance of remission in an open-label follow-up. These findings require replication to definitively determine clinical utility of this treatment. clinicaltrials.gov Identifier: NCT00720538.	f	\N
24284613	The aim of this review was to identify, evaluate and summarize all relevant studies reporting on the clinical response to gluten challenge by adult or pediatric patients with suspected or diagnosed coeliac disease (CD) on a gluten-free diet. We evaluated the effect of gluten challenge on changes in symptoms, intestinal mucosa histology, and serum antibodies. A systematic electronic search was performed for studies published as of 1966 using PubMed and Scopus databases. In the reviewed studies, doses ranged from 0.2 to 30 g/day of wheat gluten or comprised a gluten-containing diet. The onset of symptoms upon gluten intake varied largely from days to months and did not parallel serum antibody or histological changes. Within 3 months of gluten challenge, 70%-100% of pediatric CD patients became positive for AGA-IgA and EMA-IgA antibodies and 50%-70% for AGA-IgG. A limited number of trials suggest that no more than half of adult patients developed positive AGA-IgA, EMA-IgA, tTG-IgA or DGP-IgA/IgG titers. Approximately 50%-100% of pediatric and adult patients experienced mucosal relapse of gluten provocation within 3 months, which was preceded by increased mucosal intra-epithelial lymphocytes within several days of challenge. A 3-month high-dose gluten challenge should be suitable to diagnose the majority of CD patients. In some cases prolonged challenge may be needed to verify diagnosis. Combination testing for antibodies and mucosal histology may fasten the diagnosis.	f	\N
24286024	Brain changes reminiscent of Alzheimer disease (AD) have been previously reported in a substantial portion of elderly cognitive healthy (HC) subjects. The major aim was to evaluate the accuracy of MRI assessed regional gray matter (GM) volume, 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), and neuropsychological test scores to identify those HC subjects who subsequently convert to mild cognitive impairment (MCI) or AD dementia. We obtained in 54 healthy control (HC) subjects a priori defined region of interest (ROI) values of medial temporal and parietal FDG-PET and medial temporal GM volume. In logistic regression analyses, these ROI values were tested together with neuropsychological test scores (free recall, trail making test B (TMT-B)) as predictors of HC conversion during a clinical follow-up between 3 and 4 years. In voxel-based analyses, FDG-PET and MRI GM maps were compared between HC converters and HC non-converters. Out of the 54 HC subjects, 11 subjects converted to MCI or AD dementia. Lower FDG-PET ROI values were associated with higher likelihood of conversion (p = 0.004), with the area under the curve (AUC) yielding 82.0% (95% CI = (95.5%, 68.5%)). The GM volume ROI was not a significant predictor (p = 0.07). TMT-B but not the free recall tests were a significant predictor (AUC = 71% (95% CI = 50.4%, 91.7%)). For the combination of FDG-PET and TMT-B, the AUC was 93.4% (sensitivity = 82%, specificity = 93%). Voxel-based group comparison showed reduced FDG-PET metabolism within the temporo-parietal and prefrontal cortex in HC converters. In conclusion, medial temporal and-parietal FDG-PET and executive function show a clinically acceptable accuracy for predicting clinical progression in elderly HC subjects.	f	\N
24286594	Optimal management of colon cancer (CC) requires detailed assessment of extent of disease. This study prospectively investigates the diagnostic accuracy of 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography/computed tomography (PET/CT) for staging and detection of recurrence in primary CC. PET/CT for preoperative staging was performed in 66 prospectively included patients with primary CC. Diagnostic accuracy for PET/CT and CT was analyzed. In addition to routine follow up, 42 stages I-III CC patients had postoperative PET/CT examinations every 6 months for 2 years. Serological levels of tissue inhibitor of metalloproteinase-1 (TIMP-1), carcinoembryonic antigen, and liberated domain I of urokinase plasminogen activator receptor were analyzed. Accuracy for tumor, nodal, and metastases staging by PET/CT were 82% (95% confidence interval [CI]: 70; 91), 66% (CI: 51; 78), and 89% (CI: 79; 96); for CT the accuracy was 77% (CI: 64; 87), 60% (CI: 46; 73), and 69% (CI: 57; 80). Cumulative relapse incidences for stages I-III CC at 6, 12, 18, and 24 months were 7.1% (CI: 0; 15); 14.3% (CI: 4; 25); 19% (CI: 7; 31), and 21.4% (CI: 9; 34). PET/CT diagnosed all relapses detected during the first 2 years. High preoperative TIMP-1 levels were associated with significant hazards toward risk of recurrence and shorter overall survival. This study indicates PET/CT as a valuable tool for staging and follow up in CC. TIMP-1 provided prognostic information potentially useful in selection of patients for intensive follow up.	f	\N
24292183	Pulmonary arterial hypertension (PAH) is a rare, progressive, and fetal disease. The five-year survival rate after diagnosis is ～50%. In Japan, PAH is listed in the Specified Rare and Intractable Diseases. Pulmonary vascular remodeling and sustained pulmonary vasoconstriction are the major causes for the elevated pulmonary vascular resistance (PVR) in PAH. The pathogenic mechanisms involved in the pulmonary vascular abnormalities in PAH remain unclear. Sustained vasoconstriction and vascular remodeling owing to proliferation of pulmonary arterial smooth muscle cells (PASMCs) are key pathogenic events that lead to early morbidity and mortality. These events have been closely linked to Ca(2+) mobilization and signaling in PASMCs. An increase in cytosolic Ca(2+) concentration ([Ca(2+)]cyt) in PASMCs is an important stimulus for pulmonary vasoconstriction and cell proliferation which subsequently cause pulmonary vascular wall thickening followed by the increase in PVR. Increased resting [Ca(2+)]cyt and enhanced Ca(2+) influx have been implicated in PASMCs from PAH patients, but precise therapeutic targets to interrupt these signal pathways have not been identified. We recently found that the extracellular Ca(2+)-sensing receptor (CaSR), a G protein-coupled receptor (GPCR), is upregulated in PASMCs from patients with idiopathic pulmonary arterial hypertension (IPAH). In addition, blockage of the CaSR with an antagonist (NPS2143) prevents the development of pulmonary hypertension and right ventricular hypertrophy in animal models of pulmonary hypertension. The functionally upregulated CaSR in PASMCs is a novel pathogenic mechanism contributing to the augmented Ca(2+) signaling and excessive cell proliferation in IPAH. Targeting CaSR in PASMCs may help develop novel therapeutic approach for PAH.	f	\N
24298283	In January 2012, Boström and colleagues identified a new muscle tissue secreted peptide, which they named irisin, to highlight its role as a messenger that comes from skeletal muscle to other parts of the body. Irisin is a cleaved and secreted fragment of FNDC5 (also known as FRCP2 and PeP), a member of fibronectin type III repeat containing gene family. Major interest in this protein arose because of its great therapeutic potential in diabetes and perhaps also therapy for obesity. Here we review the most important aspects of irisin's action and discuss its involvement in energy and metabolic homeostasis and whether the beneficial effects of exercise in these disease states could be mediated by this protein. In addition the effects of irisin at the central nervous system (CNS) are highlighted. It is concluded that although current and upcoming research on irisin is very promising it is still necessary to deepen in several aspects in order to clarify its full potential as a meaningful drug target in human disease states.	f	\N
24299152	Patients with systemic lupus erythematosus (SLE) have persistent platelet activation and an increased risk of thrombotic events, which cannot be accounted for by traditional cardiovascular risk factors. Factor (F)XII has a potentially important role in thrombus formation and is triggered by activated platelets. We therefore asked whether the contact system is involved in inflammation and vascular disease (VD) in SLE. Fibrin clots were incubated with purified FXII or whole blood, and the activation and regulation of FXII were studied. Plasma from SLE patients with (n = 31) or without (n = 38) previous VD and from matched healthy controls (n = 68) were analyzed for the presence of complexes formed between contact system enzymes and antithrombin (AT) or C1 inhibitor (C1INH) and evaluated with regard to clinical data and laboratory parameters. Fibrin clots elicited FXII activation and acted as co-factors for AT. In clotting plasma, the levels of FXIIa-AT increased, and FXIIa-C1INH decreased. A similar reciprocal relationship existed in SLE patients. FXIIa-AT was elevated in the SLE patients with a history of VD, while the corresponding levels of factor FXIIa-C1INH were significantly decreased. FXIIa-AT correlated strongly with platelet parameters. The odds ratio for VD among the SLE patients was 8.9 if they had low levels of FXIIa-C1INH, 6.1 for those with high levels of FXIIa-AT, and increased to 23.4 for those with both decreased levels of FXIIa-C1INH and increased levels of FXIIa-AT. Activation of FXII is elicited by fibrin during thrombotic reactions in vitro and in vivo, and fibrin acts as a heparin-like co-factor and regulates AT. Patients with SLE had altered levels of FXIIa-serpin complexes, supporting that the contact system is involved in this disease. FXIIa-serpin complexes are strongly associated with previous VD in SLE patients, suggesting that these complexes are potential biomarkers for monitoring and assessing the risk of thrombotic events in SLE.	f	\N
24305931	Intense postoperative monitoring has resulted in increasing detection of patients with recurrent papillary thyroid cancer (PTC). Our goals included quantifying successful reoperation, and analyzing surgical complications and reasons for relapse. From 1999 to 2008, a total of 410 patients underwent reoperation for PTC relapse. We analyzed post-reoperative disease outcomes, reasons for relapse, and complications. Bilateral reoperative thyroidectomy was performed in 13 (3 %) patients; lobectomy, 34 (8 %); central neck (VI) soft tissue local recurrence excision, 47 (11.5 %); bilateral VI node dissection, 107 (26 %); unilateral VI dissection, 112 (27 %); levels II-V dissection, 93 (23 %); levels III-V, 86 (21 %); lateral single- or two-compartment dissection, 51 (12 %); and node picking, 20 (5 %) of level VI and 53 (13 %) lateral neck. Complications occurred in 6 %; including hypoparathyroidism, 3 %; unintentional recurrent laryngeal nerve (RLN) paralysis, 3 %; phrenic nerve injury, 0.5 %; spinal accessory nerve injury, 0.5 %; and chyle leak in 1.6 %. Of 380 (93 %) patients with follow-up (mean 5.2 years); 274 (72 %) patients are alive with no structural evidence of disease, 38 % developed disease relapse (mean 2.1 years), 42 (11 %) died from PTC, and 55 (14 %) are alive with disease. The reason for relapse was a false negative pre-reoperative ultrasound (US) in 18 (5 %), nodal recurrence in the operative field in 37 (10 %), a combination of these two reasons in 10 (3 %), and disease virulence (local or systemic recurrence) in 81 (21 %). Although 72 % of patients were rendered structurally disease free after reoperation, nearly 40 % suffered additional relapse. Improved surgical technique or preoperative localization might positively affect 15-20 %; at least 20 % reflect the biologic aggressiveness of the disease.	f	\N
24319959	To study the clinical characteristics of pediatric Kawasaki disease complicating mycoplasma pneumoniae pneumonia. Retrospective analysis was conducted on 11 children who had been diagnosed with Kawasaki disease with Mycoplasma pneumoniae pneumonia. The 11 cases presented with varying degrees of fever, conjunctival congestion, skin rashes, lymphadenectasis, distal extremities lesions, heart and lung lesions. 8 of them were standartly treated with azithromycin, while 3 of them were treatad with azithromycin and erythromycin. 2 patients with pleural effusion complicated by lobar pneumonia consolidation were treated with gamma globulin combined aspirin. All of the 11 patients were healed. Infections are common at the diagonosis of KD. Reasonable examination and antibiotics is useful to cure KD with MPP.	f	\N
24321203	Data from surveillance networks help epidemiologists and public health officials detect emerging diseases, conduct outbreak investigations, manage epidemics, and better understand the mechanics of a particular disease. Surveillance networks are used to determine outbreak intensity (i.e., disease burden) and outbreak timing (i.e., the start, peak, and end of the epidemic), as well as outbreak location. Networks can be tuned to preferentially perform these tasks. Given that resources are limited, careful site selection can save costs while minimizing performance loss. We study three different site placement algorithms: two algorithms based on the maximal coverage model and one based on the K-median model. The maximal coverage model chooses sites that maximize the total number of people within a specified distance of a site. The K-median model minimizes the sum of the distances from each individual to the individual's nearest site. Using a ground truth dataset consisting of two million de-identified Medicaid billing records representing eight complete influenza seasons and an evaluation function based on the Huff spatial interaction model, we empirically compare networks against the existing Iowa Department of Public Health influenza-like illness network by simulating the spread of influenza across the state of Iowa. We show that it is possible to design a network that achieves outbreak intensity performance identical to the status quo network using two fewer sites. We also show that if outbreak timing detection is of primary interest, it is actually possible to create a network that matches the existing network's performance using 59% fewer sites. By simulating the spread of influenza across the state of Iowa, we show that our methods are capable of designing networks that perform better than the status quo in terms of both outbreak intensity and timing. Additionally, our results suggest that network size may only play a minimal role in outbreak timing detection. Finally, we show that it may be possible to reduce the size of a surveillance system without affecting the quality of surveillance information produced.	f	\N
24326825	Lymph node metastasis (LNm), local recurrence (LR), and second primary tumor (SPT) after primary surgery for oral squamous cell carcinoma (OSCC) have been considered poor prognostic entities in terms of survival rate. The purpose of this study was to identify the clinicopathologic parameters significantly related to LNm, LR, and SPT. Records from 180 patients who underwent radical surgery for OSCC were retrospectively reviewed. Perineural invasion was significantly related to LNm (18% vs 8%) and LR (15% vs 5%), while the status of the surgical margin (10% in case of clear margins, 18% close margins, and 24% involved margins), namely epithelial precursor lesions (43%) was an independent factor influencing SPT. Perineural invasion proved a good prognostic factor for early events, either LNm or LR, while a surgical margin width less than 5 mm or with epithelial precursor lesions may be considered a risk factor for late events such as SPT.	f	\N
24342581	To evaluate the efficacy of plasma-rich growth factor (PRGF) in improving socket healing after tooth extraction in diabetic patients. This was a split-mouth study in which each patient also served as the control: the study socket was treated with PRGF, whereas the control socket underwent natural healing. The outcome variables were the Healing Index, residual socket volume, visual analog scale score, postsurgical complications, and outcome of a patient questionnaire. The investigation considered the impact of hyperglycemia, glycated hemoglobin, End Organ Disease Score, and smoking habits. Follow-up included 4 postextraction checkups over a 21-day period. Pairs of correlated continuous variables were analyzed with the Wilcoxon test, independent continuous variables with the Mann-Whitney test, and categorical variables with the χ(2) test or Fisher test. From January 2012 to December 2012, 34 patients affected by insulin-dependent diabetes mellitus underwent contemporary bilateral extractions of homologous teeth. The treatment-versus-control postoperative comparison showed that PRGF resulted in significantly smaller residual socket volumes and better Healing Indices from days 3 to 14. The patients' questionnaire outcomes were unanimously in favor of PRGF treatment. The small sample of patients with glycemia values of at least 240 mg/dL showed worse Healing Index and minor socket decreases. PRGF application after extraction improved the healing process in diabetic patients by accelerating socket closure (epithelialization) and tissue maturation, proving the association between PRGF use and improved wound healing in diabetic patients.	f	\N
24349495	Panton-Valentine leukocidin (PVL; gene designation lukF/S-PV) is likely an important virulence factor for Staphylococcus aureus (S. aureus), as qualitative expression of the protein correlates with severity for specific clinical presentations, including skin and soft tissue infections (SSTIs). Development of genetic approaches for risk-assessment of patients with S. aureus infections may prove clinically useful, and whether lukF/S-PV gene expression correlates with specific clinical presentations for S. aureus has been largely unexplored. In the present study, we quantified lukS-PV mRNA among 96 S. aureus isolates to determine whether expression levels correlated with specific clinical presentations in adults and children. Expression level of lukS-PV mRNA among isolates from skin and soft tissue infections (SSTIs) was significantly greater than among isolates from blood stream infection (BSIs), and expression level of lukS-PV mRNA among BSI isolates from children was significantly greater than for BSI isolates among adults. Moreover, expression level of lukS-PV mRNA among community-acquired (CA) isolates was significantly greater than for hospital-acquired (HA) isolates. These data justify additional studies to determine the potential clinical utility for lukS-PV mRNA quantification as a predictive tool for severity of S. aureus infection.	f	\N
24352112	This report contains CDC guidance that augments the 2011 recommendations of the Advisory Committee on Immunization Practices (ACIP) for evaluating hepatitis B protection among health-care personnel (HCP) and administering post-exposure prophylaxis. Explicit guidance is provided for persons working, training, or volunteering in health-care settings who have documented hepatitis B (HepB) vaccination years before hire or matriculation (e.g., when HepB vaccination was received as part of routine infant [recommended since 1991] or catch-up adolescent [recommended since 1995] vaccination). In the United States, 2,890 cases of acute hepatitis B were reported to CDC in 2011, and an estimated 18,800 new cases of hepatitis B occurred after accounting for underreporting of cases and asymptomatic infection. Although the rate of acute hepatitis B virus (HBV) infections have declined approximately 89% during 1990-2011, from 8.5 to 0.9 cases per 100,000 population in the United States, the risk for occupationally acquired HBV among HCP persists, largely from exposures to patients with chronic HBV infection. ACIP recommends HepB vaccination for unvaccinated or incompletely vaccinated HCP with reasonably anticipated risk for blood or body fluid exposure. ACIP also recommends that vaccinated HCP receive postvaccination serologic testing (antibody to hepatitis B surface antigen [anti-HBs]) 1-2 months after the final dose of vaccine is administered (CDC. Immunization of health-care personnel: recommendations of the Advisory Committee on Immunization Practices [ACIP]. MMWR 2011;60 [No. RR-7]). Increasing numbers of HCP have received routine HepB vaccination either as infants (recommended since 1991) or as catch-up vaccination (recommended since 1995) in adolescence. HepB vaccination results in protective anti-HBs responses among approximately 95% of healthy-term infants. Certain institutions test vaccinated HCP by measuring anti-HBs upon hire or matriculation, even when anti-HBs testing occurs greater than 2 months after vaccination. This guidance can assist clinicians, occupational health and student health providers, infection-control specialists, hospital and health-care training program administrators, and others in selection of an approach for assessing HBV protection for vaccinated HCP. This report emphasizes the importance of administering HepB vaccination for all HCP, provides explicit guidance for evaluating hepatitis B protection among previously vaccinated HCP (particularly those who were vaccinated in infancy or adolescence), and clarifies recommendations for postexposure management of HCP exposed to blood or body fluids.	f	\N
24355565	The pancreas consists of two major divisions, the exocrine and the endocrine pancreas. Recent data from our laboratory have shown that the functions of the two divisions are under modulatory regulation by separate neurocircuits that originate in the dorsal motor nucleus of the vagus (DMV). Metabotropic glutamate receptors (mGluRs) are expressed throughout the central nervous system and have been implicated in the modulation of synaptic transmission. mGluRs consist of three groups of receptors, which can be distinguished based on their pharmacological properties and second messenger systems. Group I mGluRs predominantly increase, whereas group II and III mGluRs decrease synaptic transmission. Group II and group III mGluRs are present on excitatory and inhibitory synaptic terminals impinging on pancreas-projecting DMV neurons. We have shown that group II mGluRs regulate both exocrine pancreatic secretions and insulin release, whereas group III mGluRs only regulate insulin release. Several mGluR agonists and antagonists have been shown to have clinical uses for disorders accompanied by abnormal synaptic transmission, including anxiety and Parkinson's disease. Moreover, a negative allosteric modulator of Group I mGluRs is effective in alleviating symptoms of gastro-esophageal reflux disease (GERD). Since the role of the three mGluR groups in mediating different gastrointestinal (GI) functions appears to be highly specific, the use of agonists or antagonists directed at a single receptor group could potentially provide highly selective targets for the treatment of GI disorders including GERD, functional dyspepsia and acute pancreatitis.	f	\N
24361034	The integration of body, mind, and spirit has become a key dimension of health education and disease prevention and treatment; however, our health care system remains primarily disease centered. Finding simple steps to help each of us find our own balance can improve our lives, our work, and our relationships. On the basis of interviews with health care experts at the leading edge of the new model of medicine, this article identifies simple tools to improve the health of patients and caregivers.	f	\N
24362818	Follicular lymphoma is an incurable malignancy, with transformation to an aggressive subtype representing a critical event during disease progression. Here we performed whole-genome or whole-exome sequencing on 10 follicular lymphoma-transformed follicular lymphoma pairs followed by deep sequencing of 28 genes in an extension cohort, and we report the key events and evolutionary processes governing tumor initiation and transformation. Tumor evolution occurred through either a 'rich' or 'sparse' ancestral common progenitor clone (CPC). We identified recurrent mutations in linker histone, JAK-STAT signaling, NF-κB signaling and B cell developmental genes. Longitudinal analyses identified early driver mutations in chromatin regulator genes (CREBBP, EZH2 and KMT2D (MLL2)), whereas mutations in EBF1 and regulators of NF-κB signaling (MYD88 and TNFAIP3) were gained at transformation. Collectively, this study provides new insights into the genetic basis of follicular lymphoma and the clonal dynamics of transformation and suggests that personalizing therapies to target key genetic alterations in the CPC represents an attractive therapeutic strategy.	f	\N
24368549	Hugh Henry Bentall, the inventor of the surgical procedure that enabled concomitant replacement of the aortic valve and ascending aorta, died on September 2012 at the age of 92. He was the first Professor of Cardiothoracic Surgery in the United Kingdom, at the Hammersmith Hospital, and carried out the first open-heart operations with a heart-lung machine in London in 1953. Besides cardiac surgery, he paid particular attention to cardiac anatomy and embryology, which he enriched even following retirement. He leaves three sons and a daughter.	f	\N
24369205	Extracorporeal irradiation (ECI) is relatively a rare method used in the management of malignant bone tumors (MBT). It consists of en-bloc removal of the tumor bearing bone segment, removal of the tumor from the bone, irradiation, and re-implantation back in the body. We report our preliminary experience of using ECI for management of MBT. From year 2009 to 2010, 14 patients with primary MBT were enrolled into this study. The eligibility criteria included histopathological proof of malignancy, no evidence of distant metastases, and suitability for limb preservation therapy. Surgery was performed about 4 weeks after completion of neoadjuvant chemotherapy. The affected bone segment was resected, irradiated extracorporeally with a dose of 50 Gy and reimplanted. Local control, complications and short-term survival were studied. Functional outcome was assessed by Musculoskeletal Tumor Society (MSTS) scoring system. There were 10 males and four females with median age of 14 years. Histopthologically, nine patients had osteosarcoma (OS) and five had Ewing's sarcoma family of tumors (ESFT). Distribution of primary site was as follows: Femur eight patients, tibia five patients and humerus one patient. At a median follow-up was 22 months, three patients (two OS, one ESFT) had local recurrence. Two patients (14%) developed wound infection in the perioperative period. The 2 year local recurrence free survival was 73% and mean MSTS score was 88. Results of our study suggest that ECI is technically feasible in the management of MBT and provides decent local control and short-term survival rates.	f	\N
24377187	Optimal nutrition, immunological state and psychological condition play an important role in the process of chronic wound healing. Infections caused by pathogens resistant to commonly used antibiotics additionally complicate and disturb regeneration of wounds. As part of the treatment, modern wound dressings are used, for example designed on the basis of alginates, dextranomers, hydrogels, hydrofiber, polyurethanes foams, hydrocolloids and liquids for wound debridement such us 0.9% NaCl, the PWE liquid, Ringer's liquid, octenidine. Owing to their features, treatment in accordance with TIME concept could be realized, because they provide moisture wound bed, protection against contamination, gas exchange, protection of wound edges and infection control. Repairing process in chronic wounds is dependent on blood flow in tissues, which may be insufficient. The result is a permanent hypoxia. Natural occurring antioxidants are becoming more crucial in chronic wound treatment. They decrease oxygen radical concentration, increase angiogenesis, reduce inflammatory response, stimulate fibroblasts and keratinocytes proliferation, possess antibacterial properties against chemotherapeutic resistant strains. There are a lot of antioxidants in honey, papaya fruit (Carrica papaia L.), transgenic flax (Linum usitatissimum), and in orange oil (Citrus sinensis), stem of acanthus (Acanthus ebracteatus), leafs of tea (Camellia sinensis). Application of biologically active, natural derived compounds is nowadays a direction of intense in vitro and in vivo research focused on the chronic wound treatment. Results suggest beneficial influence of antioxidant on wound repairing process. Clinical research are needed to state effective influence of natural compound in the chronic wound treatment.	f	\N
24382893	Pathological inflammation and autoimmune disease frequently involve elevated neutrophil activity in the absence of infectious agents. Tumor necrosis factor-α (TNF-α) contributes to many of the problems associated with autoimmune diseases. We investigated the ability of serum α-1 antitrypsin (AAT) to control TNF-α biosynthesis and signaling in neutrophils and assessed whether AAT deficiency (AATD) is a TNF-α-related disease. In vitro studies demonstrate that serum AAT coordinates TNF-α intracellular signaling and neutrophil degranulation of tertiary and secondary granules via modulation of ligand-receptor interactions. AATD patients homozygous for the Z allele were characterized by increased activation of the TNF-α system, as demonstrated by increased membrane TNF-α levels and increased plasma concentrations of TNF receptor 1 and neutrophil-released secondary and tertiary granule proteins. The incidence of autoantibodies directed against degranulated lactoferrin and surface protein accessible to these antibodies was increased in ZZ-AATD, leading to an enhanced rate of neutrophil reactive oxygen species production. Treatment of ZZ-AATD individuals with AAT augmentation therapy resulted in decreased membrane TNF-α expression and plasma levels of granule antigenic proteins and immunoglobulin G class autoantibodies. These results provide a mechanism by which AAT augmentation therapy affects TNF-α signaling in the circulating neutrophil, indicating promising potential of this therapy for other TNF-α-related diseases.	f	\N
24390521	Patients with atrial fibrillation (AF) have an increased risk of congestive heart failure (CHF) as well as ischemic stroke. The aim of this study was to investigate the clinical predictors of CHF in patients with non-valvular AF (NVAF). Three hundred and forty-seven patients (derivation cohort) with NVAF were retrospectively evaluated between 2004 and 2005. The associations between potential risk factors and CHF were tested using a Cox proportional hazards analysis, and a risk score for predicting CHF was created. The model was then validated in 161 patients (validation cohort) enrolled between 2008 and 2010. During the follow-up period, 41 patients in the derivation cohort developed CHF requiring hospitalization due to New York Heart Association (NYHA) class III or IV disease. Four independent risk factors were identified, each of which was assigned a number of points as follows: Age ≥72 years (1 point), heart rate ≥80 bpm (1 point), hypertension (1 point), and a previous history of congestive heart failure (2 points). The patients were grouped into one of three risk categories according to the calculated risk score (ARC2H score): low risk (0 points), intermediate risk (1-3 points) and high risk (4-5 points). In the derivation cohort, the annual rates of CHF in these risk categories were 0%, 2.5% and 18% per year respectively. In the validation cohort, the corresponding rates were 0.8%, 8% and 35% per year respectively. A simple clinical risk score, the ARC2H score, was developed to predict CHF in patients with NVAF and validated in an independent cohort.	f	\N
24395633	Although Hodgkin's lymphoma (HL) was one of the first human cancers to be cured by chemotherapy, no new agents other than brentuximab vedotin (Adcetris®, CD 30 directed antibody drug conjugate) have received US Food and Drug Administration (FDA) approval for HL since 1977. Subsets of young adult patients with HL continue to relapse, even after stem cell transplantation, warranting new approaches. Against this background, we report a dramatic response in a young patient with advanced HL refractory to the standard treatment who responded to the combination of a pan-histone deacetylase inhibitor (vorinostat, suberoylanilide hydroxamic acid, SAHA) and mammalian target of rapamycin (mTOR) inhibitor therapy (sirolimus,rapamume). In-depth immunohistochemical and morphoproteomic analyses of this exceptional responder to targeted therapy have yielded potential insights into the biology of advanced HL. The PI3K/AKT/mTOR pathway is a commonly activated pathway in multiple tumor types including HL. The patient was treated using therapy based on mechanistic in vitro data demonstrating that combined histone deacetylase (HDAC) and mTOR inhibition act together on this pathway, resulting in inhibition of reciprocal feedback networks, leading to better anti-proliferative activity. The in vivo response signature from this patient's tissue sample sheds light on immune dysregulation in HL. We describe the response signature achieved from targeting immune dysregulation in addition to targeting the key oncogenic PI3K/AKT/mTOR pathway. We also expand on the role of rapamycin analogs in oncology. This study supports a role for an immune-type pathogenesis that is amenable to immune modulating targeted therapy in refractory HL. We report an exceptional responder to molecularly targeted and immune modulator therapy in advanced Hodgkin's lymphoma. The morphoproteomic/morphometric findings in this "unusual responder" patient's relapsed HL that correlate best, as a response signature with the subsequent clinical remission following rapamycin (sirolimus) and vorinostat (SAHA) therapies, center on an immune dysregulation involving an imbalance between effector and functional T regulatory cells in addition to targeting the mTOR pathway. This underscores the need for an approach illustrated in our study--namely of focusing on pathogenetic mechanisms and combinatorial therapies that target both the pathogenesis and adaptive responses to contemplated therapies.	f	\N
24395648	Information on the chimpanzee nasopharygeal colonization in captive sanctuaries and in the wild is rare. This study was undertaken to establish the nasopharygeal colonization and potential bacterial pathogens in sanctuary chimpanzees as a basis for improving chimpanzee and employee health. Nasopharygeal colonization of 39 healthy chimpanzees were analyzed by microbiological cultivation method and polymerase chain reaction (PCR) targeting the bacterial 16S rRNA gene. We report four major phyla dominated by Proteobacteria (50%), Fermicutes (35.7%), Bacteriodes (7.1%), and Cynobacteria (7.1%) in healthy semi-captive chimpanzees. Further classification based on 7-base oligomers revealed the following genera: Streptococcus, Veillonella, Neisseria, Prevotella, Kingella and unclassified Cynobacteria, Actinobacillus, Bacteriodes and Pasteurellaceae. On microbiological cultivation we were able to identify and characterize some of the bacteria to species level as Klebsiella pneumonie and Pseudomonas aeruginosa being dominant bacteria with 54.7% and 50% colonization, respectively. Of these, Streptococcus, Neisseria, Klebsiella, and Haemophillus have representatives known to potentially cause severe respiratory disease. Our data present important information on chimpanzee nasopharygeal colonization as a guide to understanding disease processes and pharmaceutical therapies required for improving the health of chimpanzees. The results from this study will guide the processes to improve procedures for routine management of sanctuary chimpanzees and use it as a basis for evaluation of future reintroduction possibilities.	f	\N
24418861	Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma and is mostly represented by the embryonal (ERMS) and alveolar (ARMS) histotypes. Whereas ERMS shows variable genetic alterations including TP53, RB1, and RAS mutations, ARMS carries a gene fusion between PAX3 or PAX7 and FOXO1. Epithelioid RMS is a morphologic variant of RMS recently described in adults. Five cases of epithelioid RMS were identified after histologic review of 85 cases of ARMS enrolled in Italian therapeutic protocols. Immunostaining analyses (muscle-specific actin, desmin, myogenin, AP-2β, EMA, cytokeratins, INI-1) and reverse transcription polymerase chain reaction assays to detect MyoD1, myogenin, and PAX3/7-FOXO1 transcripts were performed. In 4 cases DNA sequencing of TP53 was performed; and RB1 allelic imbalance and homozygous deletion were analyzed by quantitative real-time polymerase chain reaction. Histologically, epithelioid RMS displayed sheets of large cells without rhabdomyoblastic differentiation or anaplasia in 3 and prominent rhabdoid cells in 2; necrosis was evident in 4, often with a geographic pattern. Immunostainings for INI, desmin, myogenin (scattered cells in 4, diffuse in 1) were positive in all; EMA and MNF116 were positive in 2; AP-2β was negative. PAX3/7-FOXO1 transcripts were absent. In all cases RB1 was wild type, and a TP53 mutation at R273H codon was found in 1. All patients are in complete remission, with a median follow-up of 6 years. Epithelioid RMS may occur in children and is probably related to ERMS, as suggested by lack of fusion transcripts, weak staining for myogenin, negative AP-2β, evidence of TP53 mutation (although only in 1 case), and a favorable clinical course.	f	\N
24424075	Hyperphosphataemia, a common biochemical abnormality in chronic kidney disease, poses significant management challenges. This study aims to determine whether the reasons for this are multifactorial; including poor dietary knowledge, poor adherence to a low phosphate diet and phosphate-binding medications and the impact of age on these parameters. In order to compare serum phosphate and other associated parameters to the UK Renal Association Clinical Practice Guidelines 2010 an audit and service evaluation questionnaire was carried out in May 2011 on 130 haemodialysis outpatients attending the Plymouth Dialysis Unit. Fifty-three percent of patients had serum phosphate within the target range of 1.1-1.7 mmol/l, 77% and 85% had serum calcium and parathyroid hormone within target ranges, respectively. Younger patients (18-45 years) were significantly less likely to have serum phosphate within range χ(2) (2, n=124)=18.77, P<0.001. Despite better knowledge of their own phosphate levels (P=0.005), phosphorus-rich foods (P<0.001), symptoms of hyperphosphataemia (P<0.001) and increased use of Renal Patient View (P=0.002), <65 years old had significantly higher phosphate levels than those >65 years (P<0.001). No significant associations were found between phosphate control and the following factors: gender, timing of dialysis shift, years on dialysis or dialysis adequacy. In this population, despite better knowledge, younger patients have worse phosphate control than older patients. Using the same dietary education techniques may not be suitable for all ages, more innovative approaches supported by skilled health professionals are needed to motivate and engage with younger patients to promote self-management and adherence.	f	\N
24424629	To evaluate the long-term efficacy of pain reduction by two dose fractionation schedules used for low-dose radiotherapy of painful elbow syndrome. Between February 2006 and February 2010, 199 evaluable patients were recruited for this prospective trial. All patients received low-dose orthovoltage radiotherapy. One course consisted of 6 fractions in 3 weeks. In the case of insufficient pain remission after 6 weeks, a second course was administered. Patients were randomly assigned to one of two groups to receive single doses of either 0.5 or 1.0 Gy. Endpoint was pain reduction. Pain was measured before radiotherapy, as well as immediately after (early response), 6 weeks after (delayed response) and approximately 3 years after (long-term response) completion of radiotherapy using a questionnaire-based visual analogue scale (VAS) and a comprehensive pain score (CPS). Median follow-up was 35 months (range 9-57 months). The overall early, delayed and long-term response rates for all patients were 80, 90 and 94 %, respectively. The mean VAS scores before treatment and those for early, delayed and long-term response in the 0.5- and 1.0-Gy groups were 59.6 ± 20.2 and 55.7 ± 18.0 (p = 0.46); 32.1 ± 24.5 and 34.4 ± 22.5 (p = 0.26); 27.0 ± 27.7 and 23.5 ± 21.6 (p = 0.82) and 10.7 ± 15.0 and 21.5 ± 26.9 (p = 0.12), respectively. The mean CPS values before treatment and those for early, delayed and long-term response were 8.7 ± 2.9 and 8.1 ± 3.1 (p = 0.21); 4.5 ± 3.2 and 5.0 ± 3.4 (p = 0.51); 3.9 ± 3.6 and 2.8 ± 2.8 (p = 0.19) and 1.5 ± 2.3 and 2.4 ± 3.5 (p = 0.27), respectively. No significant differences in the quality of the long-term response were found between the 0.5- and 1.0-Gy arms (p = 0.28). Low-dose radiotherapy is an effective treatment for the management of benign painful elbow syndrome. For radiation protection reasons, the dose for a radiotherapy series should not exceed 3.0 Gy.	f	\N
24436152	L-Asparaginase is an integral component of standard chemotherapy regimens for the treatment of acute lymphoblastic leukemia (ALL). Clinical hypersensitivity, a common reason for treatment discontinuation, has been reported in 10-30% of patients receiving Escherichia coli-derived asparaginase. After hypersensitivity, E. coli-derived asparaginase should be discontinued and an alternative asparaginase preparation, such as asparaginase Erwinia chrysanthemi, may be initiated. We conducted a compassionate-use study to collect additional safety information on asparaginase Erwinia chrysanthemi and to support FDA approval of the product. Patients with ALL or lymphoblastic lymphoma (LBL; N = 1368) who developed a hypersensitivity reaction (grade ≥2) to an E. coli-derived asparaginase participated in this trial. The recommended asparaginase Erwinia chrysanthemi dose was 25,000 IU/m(2) three days per week (Monday/Wednesday/Friday) for two consecutive weeks for each missed pegylated E. coli-derived asparaginase dose and 25,000 IU/m(2) for each missed nonpegylated asparaginase dose for the completion of their planned asparaginase treatment. Adverse event reports and/or case report forms were completed for 940 patients. The most common adverse event (AE) was hypersensitivity (13.6%). Eighteen patients (1.9%) died during the study. Most patients (77.6%) completed their planned asparaginase treatment with asparaginase Erwinia chrysanthemi. There was no apparent difference in the incidence of the most commonly reported AEs with asparaginase treatment by age, administration, or disease state. This study further established the safety profile of asparaginase Erwinia chrysanthemi in patients with ALL or LBL who had a hypersensitivity reaction to an E. coli-derived asparaginase.	f	\N
24437400	The development of culture-independent techniques has revolutionized our understanding of how our human cells interact with the even greater number of microbial inhabitants of our bodies. As part of this revolution, data are increasingly challenging the old dogma that in health, the lung mucosa is sterile. To understand how the lung microbiome may play a role in human health, we identified five major questions for lung microbiome research: (1) Is the lung sterile? (2) Is there a unique core microbiome in the lung? (3) How dynamic are the microbial populations? (4) How do pulmonary immune responses affect microbiome composition? and (5) Are the lungs influenced by the intestinal immune responses to the gut microbiome? From birth, we are exposed to continuous microbial challenges that shape our microbiome. In our changing environment, perturbation of the gut microbiome affects both human health and disease. With widespread antibiotic use, the ancient microbes that formerly resided within us are being lost, for example, Helicobacter pylori in the stomach. Animal models show that antibiotic exposure in early life has developmental consequences. Considering the potential effects of this altered microbiome on pulmonary responses will be critical for future investigations.	f	\N
24446993	With an estimated 12.1% of children aged 2-5 years already obese, prevention efforts must target our youngest children. One of the best places to reach young children for such efforts is the early care and education setting (ECE). More than 11 million U.S. children spend an average of 30 hours per week in ECE facilities. Increased attention at the national, state, and community level on the ECE setting for early obesity prevention efforts has sparked a range of innovative efforts. To assist these efforts, CDC developed a technical assistance and training framework - the Spectrum of Opportunities for Obesity Prevention in the ECE setting - which also served as the organizing framework for the Weight of the Nation ECE track. Participants highlighted their efforts at national, state, and local levels pursuing opportunities on the Spectrum, the standards and best practices that had been the emphasis of their efforts, and common steps for developing, implementing, and evaluating initiatives. Strong leadership and collaboration among a broad group of stakeholders; systematic assessment of needs, opportunities and resources; funding sources; and training and professional development were reported to be integral for successful implementation of standards and best practices, and sustainability.	f	\N
24447640	Fungal endophthalmitis is a rare but serious infection. In March 2012, several cases of probable and laboratory-confirmed fungal endophthalmitis occurring after invasive ocular procedures were reported nationwide. We identified 47 cases in 9 states: 21 patients had been exposed to the intraocular dye Brilliant Blue G (BBG) during retinal surgery, and the other 26 had received an intravitreal injection containing triamcinolone acetonide. Both drugs were produced by Franck's Compounding Lab (Ocala, FL, USA). Fusarium incarnatum-equiseti species complex mold was identified in specimens from BBG-exposed case-patients and an unopened BBG vial. Bipolaris hawaiiensis mold was identified in specimens from triamcinolone-exposed case-patients. Exposure to either product was the only factor associated with case status. Of 40 case-patients for whom data were available, 39 (98%) lost vision. These concurrent outbreaks, associated with 1 compounding pharmacy, resulted in a product recall. Ensuring safety and integrity of compounded medications is critical for preventing further outbreaks associated with compounded products.	f	\N
24449063	Psychotic symptoms have previously been reported following right hemisphere brain injury. We sought to identify the specific neuroanatomical basis of delusions following stroke by studying a series of patients with post-stroke psychosis. Lesion overlap analysis was conducted on three individuals with delusions following right hemisphere stroke. These cases were compared with a control group of patients with similar anatomical damage. The main outcome measures were presence of delusions and presence of behavioural susceptibility. The right inferior frontal gyrus and underlying white matter, including the superior longitudinal fasciculus and anterior corona radiata, were involved in all three cases. All three had a preexisting untreated psychiatric disorder. In contrast, only one of nine control cases with equivalent lesions had evidence of previous psychiatric disorder (p = 0.0182, Fisher's exact test), and this was being treated at the time of stroke. We provide clinical evidence from patients with structural brain lesions implicating damage to the right inferior frontal lobe in the generation of persistent psychosis following stroke. We suggest that preexisting psychiatric disease provided a behavioural susceptibility to develop delusions in these individuals.	f	\N
24449064	The logopenic variant of primary progressive aphasia (lvPPA) strongly associates with Alzheimer's disease, but can also associate with frontotemporal lobar degeneration. We aimed to assess the frequency of lvPPA in patients with speech and language disorders without β-amyloid deposition, and to perform detailed neuroimaging and genetic testing in such lvPPA patients. Seventy-six patients with a neurodegenerative speech and language disorder and Pittsburgh compound B (PiB) PET imaging demonstrating no β-amyloid deposition were analyzed. Six lvPPA patients (8 %) were identified. All six underwent progranulin (GRN) gene testing. Structural abnormality index maps and Cortex ID analysis were utilized to assess individual patterns of grey matter atrophy on MRI and hypometabolism on 18-F fluorodeoxyglucose (FDG) PET. Statistical parametric mapping was used to perform MRI and FDG-PET group comparisons between those with (GRN-positive) and without (GRN-negative) progranulin mutations. All six lvPPA patients showed left temporoparietal atrophy and hypometabolism. Three patients (50 %) were GRN-positive. Speech, language, and neurological and neuropsychological profiles did not differ between GRN-positive and negative patients, although GRN-positive patients had family histories, were on average 8 years younger, and had lower PiB-PET ratios. All six patients showed similar patterns of atrophy and hypometabolism, although, as a group, GRN-positive patients had more severe abnormalities, particularly in anteromedial temporal lobes. Logopenic PPA accounts for a small minority of neurodegenerative speech and language disorders not associated with β-amyloid deposition. Identification of such patients, however, should prompt testing for GRN mutations, since GRN-positive patients do not have distinctive features, yet account for 50 % of this patient population.	f	\N
24449169	Low-frequency, bilateral stimulation of the subthalamic nucleus can improve axial symptoms of advanced Parkinson's disease (PD), but it is not particularly effective for segmental symptoms. The optimal contacts for low-frequency (60 Hz) and high-frequency (130 Hz) single monopolar stimulation were determined. Then, in a randomized, double-blind, prospective crossover manner, 60-Hz and 130-Hz stimulations via the respective optimal contacts were compared for immediate efficacy in improving the motor function of patients with PD. The optimal contacts for 60-Hz stimulation were situated more ventrally than those for 130-Hz stimulation (P = 0.038). Under the respective optimal, single monopolar stimulation, 60 Hz provided superior efficacy over 130 Hz in improving the total Unified Parkinson's Disease Rating Scale motor score (P < 0.001) and the akinesia (P = 0.011) and axial motor signs (P = 0.012) subscores without compromising the therapeutic effect on tremor and rigidity. Low-frequency stimulation via the optimal contacts is effective in improving overall motor function of patients with PD.	f	\N
24450996	Routine annual influenza vaccination is primarily recommended for all persons aged 60 and above and for people with underlying chronic conditions in Germany. Other countries have already adopted additional childhood influenza immunisation programmes. The objective of this study is to determine the potential epidemiological impact of implementing paediatric influenza vaccination using intranasally administered live-attenuated influenza vaccine (LAIV) in Germany. A deterministic age-structured model is used to simulate the population-level impact of different vaccination strategies on the transmission dynamics of seasonal influenza in Germany. In our base-case analysis, we estimate the effects of adding a LAIV-based immunisation programme targeting children 2 to 17 years of age to the existing influenza vaccination policy. The data used in the model is based on published evidence complemented by expert opinion. In our model, additional vaccination of children 2 to 17 years of age with LAIV leads to the prevention of 23.9 million influenza infections and nearly 16 million symptomatic influenza cases within 10 years. This reduction in burden of disease is not restricted to children. About one third of all adult cases can indirectly be prevented by LAIV immunisation of children. Our results demonstrate that vaccinating children 2-17 years of age is likely associated with a significant reduction in the burden of paediatric influenza. Furthermore, annual routine childhood vaccination against seasonal influenza is expected to decrease the incidence of influenza among adults and older people due to indirect effects of herd protection. In summary, our model provides data supporting the introduction of a paediatric influenza immunisation programme in Germany.	f	\N
24459296	Huntington disease (HD) is a debilitating neurodegenerative disease characterized by the loss of motor control and cognitive ability that ultimately leads to death. It is caused by the expansion of a polyglutamine tract in the huntingtin (HTT) protein, which leads to aggregation of the protein and eventually cellular death. Both the wild-type and mutant form of the protein are highly regulated by post-translational modifications including proteolysis, palmitoylation and phosphorylation. We now demonstrate the existence of a new post-translational modification of HTT: the addition of the 14 carbon fatty acid myristate to a glycine residue exposed on a caspase-3-cleaved fragment (post-translational myristoylation) and that myristoylation of this fragment is altered in a physiologically relevant model of mutant HTT. Myristoylated HTT553-585-EGFP, but not its non-myristoylated variant, initially localized to the ER, induced the formation of autophagosomes and accumulated in abnormally large autophagolysosomal/lysosomal structures in a variety of cell types, including neuronal cell lines under nutrient-rich conditions. Our results suggest that accumulation of myristoylated HTT553-586 in cells may alter the rate of production of autophagosomes and/or their clearance through the heterotypic autophagosomal/lysosomal fusion process. Overall, our novel observations establish a role for the post-translational myristoylation of a caspase-3-cleaved fragment of HTT, highly similar to the Barkor/ATG14L autophagosome-targeting sequence domain thought to sense, maintain and/or promote membrane curvature in the regulation of autophagy. Abnormal processing or production of this myristoylated HTT fragment might be involved in the pathophysiology of HD.	f	\N
24460750	In patients with essential thrombocythemia (ET), vascular complications contribute to both morbidity and mortality. To better predict the occurrence of thrombotic events, an International Prognostic Score of thrombosis for ET (IPSET-thrombosis) was recently developed. We hereby presented an external validation and analysis of this model in a large Cohort of Chinese Patients. We retrospectively evaluated the characteristics and risk factors for thrombosis in 970 Chinese patients with ET and estimated the clinical implications of the IPSET-thrombosis model. The median follow-up was 49 months (range, 0-360). Chinese ET patients had similar clinical characteristics as Caucasian patients. Similar to the IPSET-thrombosis study, our multivariate analysis revealed age >60 (HR = 1.949), previous thrombosis (HR = 2.484), JAK2V617F mutation (HR = 1.719), and cardiovascular risk factors (HR = 1.877) as independent risk factors for thrombosis. We confirmed that the above risk factors in IPSET-thrombosis, when compared with traditional risk factors (e.g., age ≥60 and previous thrombotic events), were more predictive of thrombotic events (C-index 0.714 vs. 0.647). Classification by IPSET-thrombosis risk groups revealed different cumulative thrombosis-free survival (P < 0.001). For treatment, patients in the intermediate- and high-risk group derived clinical benefit from cytoreductive agents (P < 0.05), but those in the low-risk group did not (P = 0.446). The lower risk of thrombosis on cytoreductive therapy was related to decrease in leukocyte count during the disease course. We validate the reproducibility of IPSET-thrombosis in Chinese ET patients and provide key clinical implications.	f	\N
24467498	alcohol use disorders are associated with a greater incidence of certain comorbidities in patients with celiac disease. Currently there is no available information about the impact that these disorders may have on length of hospital stays, overexpenditures during hospital stays, and excess mortality in these patients. a case-control study was conducted with a selection of patients 18 years and older hospitalized during 2008-2010 in 87 hospitals in Spain. Estimations of excess length of stays, costs, and attributable mortality were calculated using a multivariate analysis of covariance, which included age, gender, hospital group, alcohol use disorders, tobacco related disease and 30 other comorbidities. patients who had both celiac disease and alcohol use disorders had an increased length of hospital stay, an average of 3.1 days longer in women, and 1.7 days longer in men. Excess costs per stay ranged from 838.7 euros in female patients, to 389.1 euros in male patients. Excess attributable mortality was 15.1 % in women, 12.2 % in men. apart from a gluten-free diet and other medical measures, the prevention of alcohol abuse is indicated in these patients. Patients hospitalized who present these disorders should receive specialized attention after leaving the hospital. Early detection and treatment should be used to prevent the appearance of organic lesions and should not be solely focused on male patients.	f	\N
24469423	The molecular epidemiology of group B Streptococcus (GBS) in Ireland was investigated. Invasive (n = 132) and non-invasive (n = 45) isolates, collected in 2007-2011, were analysed by multilocus locus sequence typing, capsular polysaccharide (CPS) serotyping, profiling of surface proteins, pilus islands (PI), and antimicrobial susceptibility. Isolates grouped into 45 sequence types and five main clonal complexes (CC). CC1, CC17 and CC23 represented 67.2 % of isolates and the most prevalent serotypes Ia, III and V. Serotype and surface protein genes were largely predictive of CC. Accordingly, CPS V/alp3, CPS Ib/CPS II/bca + bac, and CPS Ia/eps predominated in CC1, CC12 and CC23, respectively, and CPS III/rib in CC17 and CC19. Supporting their vaccine potential, all isolates harboured at least one PI, of which the PI-1 + PI-2a combination was most prevalent. Macrolide resistance was found in 18.6 % of isolates. erm(B) and the globally disseminated CC1/CPS V were the most common resistance mechanism and CC/CPS type, respectively. CC17, significantly associated with neonatal disease, was also prevalent in pregnant adults, but was underrepresented among non-pregnant adults. Two of 46 CC17 isolates (typically CPS III) were CPS IV. Sequence analysis confirmed capsular switching and their relatedness to CC17/CPS IV strains recently characterized in France. CPS IV, detected only in invasive isolates (6.8 %), was most prevalent in adults (12 %) and showed an increase in prevalence to that reported (1.4 %) for invasive isolates in Ireland 1997-1999. Increases in serotype IV and evidence of capsular switching in CC17 highlights the importance of ongoing surveillance of GBS and may have implications for vaccine development strategies.	f	\N
24478094	Evidence from clinical trials of malaria vaccine candidates suggests that both cell-mediated and humoral immunity to pre-erythrocytic parasite stages can provide protection against infection. Novel pre-erythrocytic antibody (Ab) targets could be key to improving vaccine formulations, which are currently based on targeting antigens such as the circumsporozoite protein (CSP). However, methods to assess the effects of sporozoite-specific Abs on pre-erythrocytic infection in vivo remain underdeveloped. Here, we combined passive transfer of monoclonal Abs (MAbs) or immune serum with a luciferase-expressing Plasmodium yoelii sporozoite challenge to assess Ab-mediated inhibition of liver infection in mice. Passive transfer of a P. yoelii CSP MAb showed inhibition of liver infection when mice were challenged with sporozoites either intravenously or by infectious mosquito bite. However, inhibition was most potent for the mosquito bite challenge, leading to a more significant reduction of liver-stage burden and even a lack of progression to blood-stage parasitemia. This suggests that Abs provide effective protection against a natural infection. Inhibition of liver infection was also achieved by passive transfer of immune serum from whole-parasite-immunized mice. Furthermore, we demonstrated that passive transfer of a MAb against P. falciparum CSP inhibited liver-stage infection in a humanized mouse/P. falciparum challenge model. Together, these models constitute unique and sensitive in vivo methods to assess serum-transferable protection against Plasmodium sporozoite challenge.	f	\N
24501382	It has been established that bimanual coordination with augmented feedback (FB) versus no augmented feedback (NFB) is associated with activity in different brain regions. It is unclear however, whether this distinction remains after practice comprising both these conditions. Functional magnetic resonance imaging was used in humans to compare visual FB versus NFB conditions for a bimanual tracking task, and their differential evolution across learning. Scanning occurred before (Pre) and after 2 weeks (Post) of mixed FB and NFB training using an event-related design, allowing differentiation between the planning and execution phase of the task. Activations at the whole-brain level initially differed for FB versus NFB movements but this differentiation diminished with training for the movement execution phase. Specifically, in right dorsal premotor cortex and right dorsolateral prefrontal cortex activation increased for NFB and decreased for FB trials to converge toward the end of practice. This suggests that learning led to a decreased need to adjust the ongoing movement on the basis of FB, whereas online monitoring became more pronounced in NFB trials as discrepancies between the required and the produced motor output were detected more accurately after training, due to a generic internal reference of correctness supporting movement control under varying conditions.	f	\N
24505382	Public health surveillance systems provide valuable data for reliable predication of future epidemic events. This paper describes a study that used nine types of infectious disease data collected through a national public health surveillance system in mainland China to evaluate and compare the performances of four time series methods, namely, two decomposition methods (regression and exponential smoothing), autoregressive integrated moving average (ARIMA) and support vector machine (SVM). The data obtained from 2005 to 2011 and in 2012 were used as modeling and forecasting samples, respectively. The performances were evaluated based on three metrics: mean absolute error (MAE), mean absolute percentage error (MAPE), and mean square error (MSE). The accuracy of the statistical models in forecasting future epidemic disease proved their effectiveness in epidemiological surveillance. Although the comparisons found that no single method is completely superior to the others, the present study indeed highlighted that the SVMs outperforms the ARIMA model and decomposition methods in most cases.	f	\N
24507376	Human infections with different avian influenza viruses--eg, H5N1, H9N2, and H7N9--have raised concerns about pandemic potential worldwide. We report the first human infection with a novel reassortant avian influenza A H10N8 virus. We obtained and analysed clinical, epidemiological, and virological data from a patient from Nanchang City, China. Tracheal aspirate specimens were tested for influenza virus and other possible pathogens by RT-PCR, viral culture, and sequence analyses. A maximum likelihood phylogenetic tree was constructed. A woman aged 73 years presented with fever and was admitted to hospital on Nov 30, 2013. She developed multiple organ failure and died 9 days after illness onset. A novel reassortant avian influenza A H10N8 virus was isolated from the tracheal aspirate specimen obtained from the patient 7 days after onset of illness. Sequence analyses revealed that all the genes of the virus were of avian origin, with six internal genes from avian influenza A H9N2 viruses. The aminoacid motif GlnSerGly at residues 226-228 of the haemagglutinin protein indicated avian-like receptor binding preference. A mixture of glutamic acid and lysine at residue 627 in PB2 protein--which is associated with mammalian adaptation--was detected in the original tracheal aspirate samples. The virus was sensitive to neuraminidase inhibitors. Sputum and blood cultures and deep sequencing analysis indicated no co-infection with bacteria or fungi. Epidemiological investigation established that the patient had visited a live poultry market 4 days before illness onset. The novel reassortant H10N8 virus obtained is distinct from previously reported H10N8 viruses. The virus caused human infection and could have been associated with the death of a patient. Emergency Research Project on human infection with avian influenza H7N9 virus, the National Basic Research Program of China, and the National Mega-projects for Infectious Diseases.	f	\N
24508287	Ghrelin is an endogenous ligand of the growth hormone (GH) secretagogue receptor and is closely associated with chronic heart failure (CHF). We undertook this study to investigate the relevance of ghrelin in CHF prognosis. A total of 145 in-patients with CHF in NYHA class II, III or IV despite optimized therapy were prospectively included in the study, grouped according to NYHA class and compared with 55 healthy control subjects. Ghrelin and N-terminal pro-B-type natriuretic peptide (Nt pro-BNP) were measured in plasma by ELISA. Echocardiographic information was also measured, including left atrial dimension, left ventricular end-diastolic diameter, LV volume and left ventricular ejection fraction (LVEF). Patients were followed for 2 years or until major adverse cardiac events. Plasma ghrelin levels were significantly lower in patients with CHF than in control subjects (p = 0.014). In addition, plasma ghrelin levels differed significantly with the severity of CHF. Notably, survival analysis showed that high ghrelin levels were an indicator of a favorable prognosis for CHF. Our results also showed that ghrelin correlated inversely with plasma Nt pro-BNP levels (r = -0.562, p <0.001) and positively with LVEF (r = 0.620, p <0.001) in patients with CHF. Furthermore, multivariate analysis showed that ghrelin levels were independently associated with adverse cardiac events (hazard ratio: 0.72; 95% CI: 0.64-0.81, p = 0.03). Ghrelin is a new biomarker of CHF severity as well as a new prognostic predictor for patients with CHF. Future experimental and clinical studies are warranted to evaluate ghrelin as a novel prognostic tool and for its therapeutic potential in patients with CHF.	f	\N
24512284	To perform psychometric testing an owner self-administered questionnaire, the Canine Orthopedic Index (COI), designed to assess outcome in dogs with orthopedic disease. Original study. Owners (n = 20) of dogs with osteoarthritis (OA) for item (question) pretesting, and 80 owners of dogs with OA for reliability and validity testing. Standard methodology for the stepwise development and testing of instruments designed to assess subjective states was followed. Items generated in previous studies were pretested for readability, ambiguity, and inter-item correlations; poorly performing items were removed; and the reduced set of items subjected to factor analysis, reliability, and validity testing. Four factors were identified and named on the basis of the items contained in them: "Stiffness," "Gait," "Function," and "Quality of Life." Cronbach's α ranged from 0.76 to 0.86, suggesting the items in each factor could be assessed as a group to compute factor scores (i.e., stiffness, gait, function, and quality of life scores). The test-retest analysis revealed κ values from 0.68 to 0.80. Overall, the scores amongst the 4 factors correlated moderately well (r = 0.52-0.58), with a mild correlation (r = 0.35) between gait and function scores. The COI is a psychometrically sound owner completed instrument that can assess 4 domains in dogs with OA: Stiffness, Gait, Function, and Quality of Life.	f	\N
24513795	Blood sample and placenta were taken from a 37-week pregnant woman; serologic results indicated acute toxoplasmosis. Placenta was inoculated into mice. Seropositive mice were sacrificed and tissue cysts from brain were inoculated into new mice. Specific DNA was detected by PCR, and the isolate was characterized as Type II by nPCR-RFLP for nSAG2, SAG3, BTUB, GRA6, c29-2, c22-8, L358, PK1 and Apico markers. This is the first isolation and molecular characterization of Toxoplasma gondii from humans in Argentina.	f	\N
24517642	Salvage liver transplantation (SLT) is an attractive sequential strategy which combines liver resection (LR) for hepatocellular carcinoma (HCC), followed by liver transplant (LT) in the event of HCC recurrence or progressive liver deterioration. To compare the long-term results of SLT with primary liver transplant (PLT). Between 2000 and 2011, 125 patients (72 transplantable) underwent LR and 226 underwent LT in our unit. The outcome of SLT was analysed in a two-step fashion: firstly, SLT (n = 28) was compared with PLT (n = 198), secondly an intention-to-treat analysis was performed on all transplantable HCC patients who underwent LR (LRT group = 72) compared to PLT (n = 198). The five-year overall survival (OS) was 65.4% vs. 49.2% (P = 0.63), and disease-free survival (DFS) was 89.7% vs. 80.6% (P = 0.31) for PLT and SLT respectively. Predictive factors for DFS after LT included HCC total diameter [hazard ratio (HR) 1.29 P = 0.003], alpha-foetoprotein (HR 1.002 P < 0.001) and number of HCC nodules (HR 1.317 P = 0.035), whereas viral hepatitis C positivity (HR 1.911 P = 0.03) and outside Up-to-seven criteria (HR 2.652 P < 0.001) were negative independent prediction factors of OS. Intention-to-treat analysis showed that OS at 5 years was improved in PLT vs. LRT (LRT n = 72 including SLT plus LR group) and was 69.4% vs. 42.2% (P < 0.004), with an additional increase in DFS (89.2% vs. 54.5% respectively P < 0.001). Salvage liver transplantation is a safe treatment strategy, as it does not impair long-term survival. At intention-to-treat analysis, PLT showed improved survival compared with LRT.	f	\N
24519340	Mental health is a human right and fundamental to good personal health. Developing, planning, and implementing mental health programs is a key part of health policies worldwide. This paper uses the perspective of "mental health mainstreaming" to define mental health and explore its relationship with mental illness and psychiatric disease. Further, we apply this perspective to Taiwan's three-tiered community mental illness prevention strategy as a reference for mental health promotion and rehabilitation programs in hopes that all healthcare providers help facilitate holistic community health.	f	\N
24524071	Heat shock protein 72 (Hsp72) exhibits a protective role during times of increased risk of pathogenic challenge and/or tissue damage. The aim of the study was to ascertain Hsp72 protective effect differences between animal and human studies in sepsis using a hypothetical "comparative study" model. Forty-one in vivo (56.1%), in vitro (17.1%), or combined (26.8%) animal and 14 in vivo (2) or in vitro (12) human Hsp72 studies (P < 0.0001) were enrolled in the analysis. Of the 14 human studies, 50% showed a protective Hsp72 effect compared to 95.8% protection shown in septic animal studies (P < 0.0001). Only human studies reported Hsp72-associated mortality (21.4%) or infection (7.1%) or reported results (14.3%) to be nonprotective (P < 0.001). In animal models, any Hsp72 induction method tried increased intracellular Hsp72 (100%), compared to 57.1% of human studies (P < 0.02), reduced proinflammatory cytokines (28/29), and enhanced survival (18/18). Animal studies show a clear Hsp72 protective effect in sepsis. Human studies are inconclusive, showing either protection or a possible relation to mortality and infections. This might be due to the fact that using evermore purified target cell populations in animal models, a lot of clinical information regarding the net response that occurs in sepsis is missing.	f	\N
24529770	When tried in court, mothers accused of neonaticide may claim that the umbilical cord just broke during birth and the newborn child bled to death accordingly. To evaluate the possibility of a breakage of the umbilical cord is the goal of this work. Therefore 25 umbilical cords from neonates of both sexes born at term were stretched using an electrically operated material testing machine and the energy necessary to break them was measured. This experimental set-up equals a static strain, not a dynamic one. The maximum force endured (F max) ranged from 37.24 N to 150.04 N. The average force endured was 79.87 N with a standard deviation of 27.39. The elongation at break varied from 13.24% to a maximum of 119.93%. We found no relationship between the force endured and any of the following parameters: birth weight, pH of the venous umbilical blood, diameter of cord, free length under testing, duration of pregnancy or the mother's age. We performed a literature research and tried to define the circumstances in which a break is more likely to occur, these being malformations, entanglement or disease, e.g. inflammation.	f	\N
24550581	Levosimendan is a calcium sensitizer drug which has been used in cardiac surgery for the prevention of postoperative low cardiac output syndrome (LCOS) and in difficult weaning from cardiopulmonary bypass (CPB). This study aims to evaluate perioperative hemodynamic effects of levosimendan pretreatment in patients for off-pump coronary artery bypass graft (OPCABG) surgery with low left ventricular ejection fractions (LVEF < 30%). Fifty patients undergoing OPCABG surgery with low LVEF (<30%) were enrolled in the study. Patients were randomly divided in two groups: Levosimendan pretreatment (Group L) and placebo pretreatment (Group C) of 25 each. Group L, patients received levosimendan infusion 200 μg/kg over 24 h and in Group C Patients received placebo. The clinical parameters measured before and after the drug administration up to 48 h were heart rate (HR; for the hour after drug infusion), cardiac index (CI), and pulmonary capillary wedge pressure (PCWP). The requirement of inotropes, intraaortic balloon pump (IABP), CPB, intensive care unit (ICU) stay, and hospital stay were also measured. The patients in group L exhibited higher CI and PCWP during operative in early postoperative period as compared to control group C. Group L also had a less requirement for inotropes, CPB support and IABP with shorter ICU stay as well as hospital stay. Levosimendan pretreatment (24 h infusion) in patient for OPCABG with poor LVEF shows better outcomes and hemodynamics in terms of inotropes, CPB and IABP requirements. It also reduces ICU stay.	f	\N
24554437	The ER is the largest cellular compartment and a major storage site for lipids and ions. In recent years, much attention has focused on contacts between the ER and other organelles, and one particularly intimate relationship is that between the ER and the endosomal system. ER-endosome contacts intensify when endosomes mature, and the ER participates in endosomal processes, such as the termination of surface receptor signaling, multi-vesicular body formation, and transport and fusion events. Cholesterol and Ca(2+) are transferred between the ER and endosomes, possibly acting as messengers for ER-endosome crosstalk. Here, we summarize different types of ER-endosomal communication and discuss membrane contact sites that might facilitate this crosstalk. We review the protein pairs that interact at the ER-endosome interface and find that many of these have a role in cholesterol exchange. We also summarize Ca(2+) exchange between the ER and endosomes, and hypothesize that ER-endosome contacts integrate several cellular functions to guide endosomal maturation. We post the hypothesis that failure in ER-endosome contacts is an unrecognized but important contributor to diseases, such as Niemann-Pick type C disease, Alzheimer's disease and amyotrophic lateral sclerosis.	f	\N
24555602	This article will describe the elements of performing a thorough venous ultrasound evaluation of the lower extremity in patients with manifestations of chronic venous disorder. The emphasis will be on the evaluation of superficial venous reflux. Only the specific aspects of the evaluation of the deep system pertaining to chronic venous disease will be discussed. Duplex ultrasound requires the examiner to solve a puzzle to explain the patient's clinical manifestations. Patients who have been treated with surgery, thermal ablation, or ultrasound-guided sclerotherapy will require duplex ultrasound after treatment to identify complications, gauge the extent of treatment success, and evaluate the cause for any recurrence.	f	\N
24557586	The survival of patients with axial skeletal or pelvic osteosarcoma (OS) remains poor, and the management of these patients is challenging. The object of this study is a cohort of unselected patients aged < 19 years with primary high-grade pelvic/axial OS. Patients were treated with high-dose methotrexate, doxorubicin, cisplatin, ifosfamide followed or preceded by local treatment (surgery and/or radiotherapy). Twenty patients aged 3-19 years were treated. Eight patients had pelvic OS, 8 axial OS and 4 mandible/maxilla OS. All patients received chemotherapy, after which necrosis was evaluable in 9 patients (≥ 90% in 3). Sixteen patients underwent surgery. Radiotherapy was administered to 8 patients (total dose 34-60 Gy). The median follow-up was 35 months (8-276), and the 5-year disease-free survival and overall survival rates were 37 and 40%, respectively. Six patients were alive at the time of this report: 2 with pelvic OS (both responded well to chemotherapy, one underwent hemipelvectomy and the other had non-radical surgery plus radiotherapy); 1 with axial and multicentric OS (with a good histological response and radical surgery); 3 with mandible/maxilla OS. Two patients died of secondary tumors (one bone and one breast cancer). It is worth noting that 4 patients had a p53 mutation: 1 is alive, 2 died of their OS, 1 of breast cancer. Adequacy of local treatment and pathological response influenced the prognosis for axial OS, which remained dismal. A high incidence of p53 mutation emerged in our series of patients.	f	\N
24560191	In this issue of Immunity, Funabiki et al. (2014) have identified in mice a mutation of the IFIH1 gene, encoding the viral receptor MDA5 that causes constitutive IFN production and fatal autoimmune disease. The authors show that the autoimmune disease-associated variant of human MDA5 is permanently switched on.	f	\N
24566636	In the current open society and with the growth of human rights, people are more and more concerned about the privacy of their information and other important data. This study makes use of electrocardiography (ECG) data in order to protect individual information. An ECG signal can not only be used to analyze disease, but also to provide crucial biometric information for identification and authentication. In this study, we propose a new idea of integrating electrocardiogram watermarking and compression approach, which has never been researched before. ECG watermarking can ensure the confidentiality and reliability of a user's data while reducing the amount of data. In the evaluation, we apply the embedding capacity, bit error rate (BER), signal-to-noise ratio (SNR), compression ratio (CR), and compressed-signal to noise ratio (CNR) methods to assess the proposed algorithm. After comprehensive evaluation the final results show that our algorithm is robust and feasible.	f	\N
24568610	The generation of induced pluripotent stem cells (iPSCs) from somatic cells by expressing ectopic reprogramming transcriptional factors such as Oct3/4, Sox2, Klf4, c-Myc, and Nanog is one of the cutting-edge discoveries in stem cell and cancer research. This discovery has raised several safety issues regarding the use of iPSC technology for human disease research. Tumorigenesis is the major obstacle observed for iPSC-mediated transplantation therapy. Recently, a new method to generate human iPSCs either by a chemical method or by direct delivery of reprogramming factors has become a promising approach for future customized cell therapy of human disorders. These reprogramming transcriptional factors play critical roles in diverse cellular functions such as transactivation, cellular proliferation, differentiation, apoptosis, and tumorigenesis. Posttranslational modifications (PTMs) (phosphorylation, ubiquitination, acetylation, sumoylation, and so on) of these proteins act as a regulatory signal to control protein activity, expression, and stability in a wide variety of cellular processes. We attempt to summarize the accumulated evidence to address the role of PTMs of Oct3/4, Sox2, Klf4, c-Myc, and Nanog in regulating their biological functions. This review allows us to understand the importance of PTMs and their application in developing an efficient and safe reprogramming method without cancer development for cell therapy. Finally, we discuss the importance of PTMs of reprogramming factors in tumor pathogenesis.	f	\N
24574413	Interferons (IFNs) are cytokines produced by host cells in response to the infection with pathogens. By binding to the corresponding receptors, IFNs trigger different pathways to block intracellular replication and growth of pathogens and to impede the infection of surrounding cells. Due to their key role in host defense against viral infections, as well as for clinical therapies, the IFN responses and regulation mechanisms are well studied. However, studies of type I IFNs have mainly focused on alpha interferon (IFN-α) and IFN-β subtypes. Knowledge of IFN-κ and IFN-ω is limited. Moreover, most studies are performed in humans or mouse models but not in the original host of zoonotic pathogens. Bats are important reservoirs and transmitters of zoonotic viruses such as lyssaviruses. A few studies have shown an antiviral activity of IFNs in fruit bats. However, the function of type I IFNs against lyssaviruses in bats has not been studied yet. Here, IFN-κ and IFN-ω genes from the European serotine bat, Eptesicus serotinus, were cloned and functionally characterized. E. serotinus IFN-κ and IFN-ω genes are intronless and well conserved between microchiropteran species. The promoter regions of both genes contain essential regulatory elements for transcription factors. In vitro studies indicated a strong activation of IFN signaling by recombinant IFN-ω, whereas IFN-κ displayed weaker activation. Noticeably, both IFNs inhibit to different extents the replication of different lyssaviruses in susceptible bat cell lines. The present study provides functional data on the innate host defense against lyssaviruses in endangered European bats. We describe here for the first time the molecular and functional characterization of two type I interferons (IFN-κ and -ω) from European serotine bat (Eptesicus serotinus). The importance of this study is mainly based on the fact that very limited information about the early innate immune response against bat lyssaviruses in their natural host serotine bats is yet available. Generally, whereas the antiviral activity of other type I interferons is well studied, the functional involvement of IFN-κ and -ω has not yet been investigated.	f	\N
24579399	Patients with chronic kidney disease (CKD) who are treated with dialysis have impaired physical functioning that is associated with poor outcomes. Gait speed is an important measure of mobility that predicts adverse events and mortality in older people. Gait speed is low in patients with CKD, and those treated with hemodialysis average below cut-points known to indicate increased risk of reduced survival and adverse health events. Measurement of gait speed in patients with CKD may be valuable in identifying those at risk for adverse events, including disability and mortality.	f	\N
24583421	Magnetic resonance imaging has been shown to be a powerful tool for diagnosing multiple sclerosis (MS) and evaluating surrogate markers of the disease activity. However, biomarkers may provide more accurate information regarding ongoing immune responses leading to demyelination and treatment effects in MS patients. Although serum biomarkers are easily accessible, they do not provide clear-cut results, whereas cerebrospinal fluid (CSF) biomarkers provide unequivocal information, although samples cannot be repeatedly obtained. For diagnosis, the presence of oligoclonal IgG bands remains important. In addition, measuring the levels of adhesion molecules, matrix metalloproteinase-9 and complement regulator factor H in the serum and evaluating the proportion of Th1/Th2 cells in the blood may be clinically feasible for monitoring the disease activity. In CSF samples, increased IL-8, IL-12, IL-17, CCL3, CCL5 and CXCL10 levels indicate active disease, and the flow cytometry findings of CSF cells can be used to detect increases in Th1 and CD4(+)CD25(+) cells during relapse. Biomarkers closely linked to the disease activity may be informative of the pathogenesis of MS, while those associated with tissue damage or repair may be targets of new treatment strategies. Establishing the latter will be a primary point of research in the near future.	f	\N
24583589	A 76-year-old woman was admitted to our hospital because of convulsions that developed after a 1-month history of progressive right-leg palsy. MRI showed thickening of the meninges with gadolinium enhancement in the left parietal lobe and it revealed pia-subarachnoid space pattern. A lumbar puncture was performed, and cerebrospinal fluid analysis revealed no abnormality. Her serum adenosine deaminase level was elevated (28.7 IU/l). The results of serum cultures were normal. To differentially diagnose collagen disease, infection, malignancy, and inflammation of uncommon causes, we conducted brain and meningeal biopsies on the 15th hospital day. Histopathological examination of the brain tissue showed mainly necrosis and inflammation. There was severe pachymeningeal thickening without necrosis. Although it was difficult to reach a definitive diagnosis, a tissue sample taken from under the leptomeninges tested positive for mycobacterium on Ziehl-Neelsen staining. The results of polymerase chain reaction for mycobacterium were negative in the meningeal tissue. The patient received anti-tuberculous drugs, anti-nontuberculous mycobacteriosis drugs, and corticosteroids to treat Mycobacterium tuberculosis and nontuberculous mycobacterium. After starting treatment, the findings on magnetic resonance imaging improved dramatically, and no convulsions occurred during hospitalization. She was discharged on the 153rd hospital day without any neurological deficit. Because previous studies have reported that isolated mycobacterium meningitis is a diagnostically challenging condition, brain and meningeal biopsies should be considered in patients with gadolinium enhancement in the meninges.	f	\N
24585436	The development of fully automated and high-throughput systems for proteomics is now in demand because of the need to generate new protein-based disease biomarkers. Unfortunately, it is difficult to identify protein biomarkers that are low abundant when in the presence of highly abundant proteins, especially in complex biological samples such as serum, cell lysates, and other biological fluids. Membrane proteins, which are in many cases of low abundance compared to the cytosolic proteins, have various functions and can provide insight into the state of a disease and serve as targets for new drugs making them attractive biomarker candidates. Traditionally, proteins are identified through the use of gel electrophoretic techniques, which are not always suitable for particular protein samples such as membrane proteins. Microfluidics offers the potential as a fully automated platform for the efficient and high-throughput analysis of complex samples, such as membrane proteins, and do so with performance metrics that exceed their bench-top counterparts. In recent years, there have been various improvements to microfluidics and their use for proteomic analysis as reported in the literature. Consequently, this review presents an overview of the traditional proteomic-processing pipelines for membrane proteins and insights into new technological developments with a focus on the applicability of microfluidics for the analysis of membrane proteins. Sample preparation techniques will be discussed in detail and novel interfacing strategies as it relates to MS will be highlighted. Lastly, some general conclusions and future perspectives are presented.	f	\N
24588669	Tumour hypoxia is increasingly recognized as a major deleterious factor in cancer therapies, as it compromises treatment and drives malignant progression. This review seeks to clarify the oxygen levels that are pertinent to this issue. It is argued that normoxia (20% oxygen) is an extremely poor comparator for "physoxia", i.e. the much lower levels of oxygen universally found in normal tissues, which averages about 5% oxygen, and ranges from about 3% to 7.4%. Importantly, it should be recognized that the median oxygenation in untreated tumours is significantly much lower, falling between approximately 0.3% and 4.2% oxygen, with most tumours exhibiting median oxygen levels <2%. This is partially dependent on the tissue of origin, and it is notable that many prostate and pancreatic tumours are profoundly hypoxic. In addition, therapy can induce even further, often unrecognized, changes in tumour oxygenation that may vary longitudinally, increasing or decreasing during treatment in ways that are not always predictable. Studies that fail to take cognizance of the actual physiological levels of oxygen in tissues (approximately 5%) and tumours (approximately 1%) may fail to identify the real circumstances driving tumour response to treatment and/or malignant progression. This can be of particular importance in genetic studies in vitro when comparison to human tumours is required.	f	\N
24590608	Iron is an essential mineral in many proteins and enzymes in human physiology, with limited means of iron elimination to maintain iron balance. Iron accrual incurs various pathological mechanisms linked to cardiovascular disease. In atherosclerosis, iron catalyzes the creation of reactive oxygen free radicals that contribute to lipid modification, which is essential to atheroma formation. Inflammation further fuels iron-related pathologic processes associated with plaque progression. Given iron's role in atherosclerosis development, in vivo detection techniques sensitive iron are needed for translational studies targeting iron for earlier diagnosis and treatment. Magnetic resonance imaging is uniquely able to quantify iron in human tissues noninvasively and without ionizing radiation, offering appealing for longitudinal and interventional studies. Particularly intriguing is iron's complementary biology vs. calcium, which is readily detectable by computed tomography. This review summarizes the role of iron in atherosclerosis with considerable implications for novel diagnostic and therapeutic approaches.	f	\N
24603533	Telomere biology is frequently associated with disease evolution in human cancer and dysfunctional telomeres have been demonstrated to contribute to genetic instability. In BCR-ABL(+) chronic myeloid leukemia (CML), accelerated telomere shortening has been shown to correlate with leukemia progression, risk score and response to treatment. Here, we demonstrate that proliferation of murine CML-like bone marrow cells strongly depends on telomere maintenance. CML-like cells of telomerase knockout mice with critically short telomeres (CML-iG4) are growth retarded and proliferation is terminally stalled by a robust senescent cell cycle arrest. In sharp contrast, CML-like cells with pre-shortened, but not critically short telomere lengths (CML-G2) grew most rapidly and were found to express a specific 'telomere-associated secretory phenotype', comprising secretion of chemokines, interleukins and other growth factors, thereby potentiating oncogene-driven growth. Moreover, conditioned supernatant of CML-G2 cells markedly enhanced proliferation of CML-WT and pre-senescent CML-iG4 cells. Strikingly, a similar inflammatory mRNA expression pattern was found with disease progression from chronic phase to accelerated phase in CML patients. These findings demonstrate that telomere-induced senescence needs to be bypassed by leukemic cells in order to progress to blast crisis and provide a novel mechanism by which telomere shortening may contribute to disease evolution in CML.	f	\N
24610167	The aim of this study was to evaluate the diagnostic accuracy of postnatal multidetector computed tomography (MDCT) compared with prenatal ultrasound (US), surgical findings, and histology, in 33 patients with congenital cystic lung disease. Thirty-three patients, 17 males and 16 females, were evaluated by MDCT. Twenty-seven of these patients underwent prenatal US between week 18 and 22, and between week 32 and 35 of gestation. Lung lobectomy, segmentectomy, atypical resection, lesion resection were performed in 31 patients and surgical specimens were analysed. Prenatal US and MDCT correctly diagnosed 76.9 and 94 % of the lesions, respectively. Disagreement occurred in six lesions with prenatal US and in two lesions with MDCT. No statistically significant differences were observed between the two techniques (P = 0.122). As most surgeons consider the surgical resection of these lesions mandatory, our study underscores the essential role of imaging, in particular CT, in providing invaluable preoperative information on congenital cystic lung diseases recognised in uterus.	f	\N
24611185	To investigate factors associated with 30-day perioperative complications (POC) after aorto-iliac (AI) stenting, and to compare follow-up cardiovascular prognosis between patients with and without POC. This was a retrospective multicenter study. We used a multicenter database of 2012 consecutive patients who successfully underwent AI stenting for peripheral arterial disease in 18 centers in Japan from January 2005 to December 2009 to analyze independent predictors of POC and impact of POC on prognosis by logistic regression and a Cox proportional hazard regression model, respectively. Mean age was 71 ± 9 years (median: 72 years; range: 37-98 years), and 1,636 patients (81%) were men. POC occurred in 126 patients (6.3%). In multivariate logistic regression analysis, old age (≥80 years), critical limb ischemia (CLI), and Trans Atlantic Inter-Societal Consensus (TASC) II class C/D were independently associated with POC with adjusted odds ratios and 95% confidence intervals (CI) of 1.9 (1.3-2.9), 2.3 (1.5-3.4), and 2.4 (1.6-3.4), respectively. Out of 2012 patients, 1995 were followed up for more than 30 days (mean: 2.6 ± 1.5 years; range: 2-2,393 days). In a Cox hazard regression model adjusted for baseline clinical characteristics, POC was positively and independently associated with follow-up major adverse cardiac events (adjusted hazard ratio [HR]: 1.9; 95% CI: 1.3-2.8; p = .002), but not with major adverse limb events and target lesion revascularization (adjusted HR: 1.4; 95% CI: 0.7-2.7; p = .25; and adjusted HR: 1.2; 95% CI 0.6-2.6; p = .568), respectively. Age >80 years, CLI, and TASC C/D lesion were positively associated with POC after AI stenting. Occurrence of POC appears to adversely affect follow-up cardiovascular, but not limb and vessel prognosis.	f	\N
24614649	The microsatellite instability (MSI) pathway is one of the important mutational pathways that play a critical role in colorectal carcinogenesis. About 15% of colorectal cancers (CRCs) are characterized by MSI. MSI tumors usually arise because of a genetic defect in mismatch repair (MMR) genes, one of the main DNA-repairing systems. MMR is a highly conserved biological pathway that plays a key role in maintaining genomic stability by correcting the base-base mismatches and insertion/deletion mispairs generated during DNA replication and recombination. Escherichia coli MutS and MutL and their eukaryotic homologs, MutSα and MutLα, respectively, are key players in MMR-associated genome maintenance. Mutations in at least five pivotal genes of MMR, namely, in those encoding mutS homolog 2 (MSH2), mutL homolog 1 (MLH1), mutS homolog 6 (MSH6), postmeiotic segregation increased 1 (PMS1), and postmeiotic segregation, increased 2 (PMS2) have been found in CRC, highlighting the importance of understanding the basic structure and functions of the essential molecules that make up the MMR system. In this review, we have attempted to focus on this aspect, that is, the role that MMR molecules play in CRC carcinogenesis.	f	\N
24617559	Exaggerated postprandial lipemia has been reported after spinal cord injury (SCI). We examined metabolite and accompanying pro-inflammatory biomarker responses to repeat feeding of typical high-fat meals in individuals with chronic paraplegia. Descriptive trial. Metabolites (triglycerides, glucose, and insulin) and inflammatory biomarkers (interleukin-6 and high-sensitivity C-reactive protein (hsCRP)) were measured under fasting conditions in 11 recreationally active individuals with chronic (>1 year) paraplegia. Subjects received high-fat meals at time point 0 and again at minute 240. Antecubital venous blood was obtained at time points -30 (fasting), 0 (first meal), 30, 60, 90, 120, 240 (second meal), 360, and 480 minutes. Correlations were examined among the study variables. Exploratory subgroup analysis was performed for subjects with levels of postprandial glucose greater than >200 mg/dl. Triglycerides showed a significant rise 4 hours after eating. Basal inflammatory markers were elevated, and did not undergo additional change during the testing. Additionally, subjects with excessive postprandial glucose responses showed higher hsCRP levels than those having typical glucose responses both for fasting (11.8 ± 6.5 vs. 2.9 ± 2.7 mg/l, P = 0.064) and postprandial (11.1 ± 4.9 vs. 3.7 ± 3.8 mg/l, P = 0.018) values. Despite elevations in metabolic response markers, inflammatory markers did not change significantly after consumption of population-representative (i.e. hypercaloric) mixed-nutrient meals. Levels of fasting CRP in the high-risk range are consistent with other reports in persons with SCI and continue to pose concern for their cardiovascular disease risk. The possible association between postprandial metabolic responses and inflammatory states warrants further investigation to identify individual component risks for this secondary health hazard.	f	\N
24619118	The northward spread of leishmaniasis from Mediterranean to Continental Europe affects our area where it is typically associated with Leishmania infantum infection. In this study a 22-year survey was performed in patients (including both patients with and without history of travel through endemic areas other than Italy) attending the University Hospital of Parma, Northern Italy, in order to make a contribution to describe the cases of the visceral leishmaniasis (VL) and cutaneous leishmaniasis (CL) diagnosed in this area. One hundred fifty-six samples from 134 patients with clinical suspicion of leishmaniasis (96 suspected of having VL, 37 CL and one both VL and CL) were analyzed in our laboratory during 1992-2013 by microscopy, culture and, from 2005, also by real-time PCR. Leishmania spp. were detected in 23 samples of 15 patients (seven with VL and eight with CL), representing an infection rate of 11.2%. The figure of the cases of leishmaniasis herein reported, even if not comparable to that described for Italian areas other than Parma, underlines that suitable tools are mandatory for correct diagnosis. Moreover, the severity of this disease, particularly VL with its documented northward spread, requires physicians of continental Europe to increase their attention about the possibility of suspecting leishmaniasis in patients reporting related signs and symptoms and/or risk factors.	f	\N
24626438	Cardiovascular risk factors have different impact on different arterial territories. Diseases with elevated circulating parathyroid hormone (PTH) such as primary hyperparathyroidism and chronic renal failure have been shown to be associated with an increased risk of cardiovascular disease, predominantly heart or cerebrovascular diseases. However, data on the associations between circulating PTH and peripheral atherosclerosis are limited. Two prospective, community-based studies were used. In 306 men and women, who were 70 years old, from the Prospective investigation of the vasculature in Uppsala seniors (PIVUS) study, cross-sectional relations between PTH and atherosclerotic burden assessed by whole-body magnetic resonance angiography were investigated. In 998 men, who were 71 years old, from the Uppsala longitudinal study of adult men (ULSAM) study, the association between PTH concentration and risk of subsequent nonfatal atherosclerotic disease (excluding coronary or cerebrovascular disease) was investigated. Adjusting for established vascular risk factors, PTH was associated with burden of atherosclerosis (increase in total atherosclerotic score per SD PTH increase: 0.04, 0.003-0.08; P=0.03) in the PIVUS study. During follow-up in the ULSAM study (median 16.7 years), 89 men were diagnosed with nonfatal atherosclerotic disease. In Cox-regression analyses adjusting for established vascular risk factors and mineral metabolism, higher PTH was associated with an increased risk of nonfatal atherosclerotic disease (hazard ratio for 1 SD increase of PTH: 1.55, 1.33-1.88; P<0.0001). Results were similar when including fatal atherosclerotic disease in the outcome. In 2 independent community-based cohorts, PTH was associated to the degree of atherosclerosis and risk of clinically overt atherosclerotic disease, respectively. Our data confirm and extend previous studies supporting a role for PTH in the development of atherosclerotic disease.	f	\N
24628295	Imatinib (Glivec(®)/Gleevec(®)) has shown long-term efficacy and safety in randomized trials. No large-scale studies have prospectively assessed the benefit-risk profile of an imatinib copy drug. We prospectively evaluated the response of patients with chronic myeloid leukemia in chronic phase in one institution. Patients with a complete hematologic response (n = 126) switched from branded imatinib to an imatinib copy drug. Subsequently, all patients switched back to the branded imatinib. Many patients in this study had a loss of hematologic response and tolerability issues with the imatinib copy drug. Hematologic response and tolerability improved upon retreatment with branded Glivec.	f	\N
24628740	Pentraxin 3 (PTX3) is probably a specific marker of vascular inflammation. However, associations of PTX3 with cardiovascular disease (CVD) risk have not been well studied in healthy adults or multi-ethnic populations. We examined associations of PTX3 with CVD risk factors, measures of subclinical CVD, coronary artery calcification (CAC) and CVD events in the Multi-Ethnic Study of Atherosclerosis. Two thousand eight hundred and thirty-eight participants free of prevalent CVD with measurements of PTX3 were included in the present study. After adjustment for age, sex, and ethnicity, PTX3 was positively associated with age, obesity, insulin, systolic blood pressure, C-reactive protein (CRP), and carotid intima-media thickness (all P < 0.045). A one standard deviation increase in PTX3 level (1.62 ng mL(-1) ) was associated with the presence of CAC in fully adjusted models including multiple CVD risk factors (relative risk of 1.05; 95% confidence interval [CI] 1.01-1.08). In fully adjusted models, a standard deviation higher level of PTX3 was associated with an increased risk of myocardial infarction (hazard ratio [HR] 1.51; 95% [CI] 1.16-1.97), combined CVD events (HR 1.23; 95% [CI] 1.05-1.45), and combined CHD events (HR 1.33; 95% [CI] 1.10-1.60), but not stroke, CVD-related mortality, or all-cause death. In these apparently healthy adults, PTX3 was associated with CVD risk factors, subclinical CVD, CAC and incident coronary heart disease events independently of CRP and CVD risk factors. These results support the hypothesis that PTX3 reflects different aspects of inflammation than CRP, and may provide additional insights into the development and progression of atherosclerosis.	f	\N
24631511	The aim of this study was to report the frequency, patient and lesion-related characteristics, and outcomes of subclinical, nonculprit plaque ruptures in the PROSPECT (Providing Regional Observations to Study Predictors of Events in the Coronary Tree) study. Plaque rupture and subsequent thrombosis is the most common cause of acute coronary syndrome (ACS). Secondary, subclinical, nonculprit plaque ruptures have been seen in both stable patients and patients with ACS; however, reports of the natural history of these secondary plaque ruptures are limited. After successful stenting in 697 patients with ACS, 3-vessel grayscale and intravascular ultrasound virtual histology (IVUS-VH) was performed in the proximal-mid segments of all 3 coronary arteries as part of a prospective multicenter study. Among 660 patients with complete IVUS data, 128 plaque ruptures were identified in 105 nonculprit lesions in 100 arteries from 93 patients (14.1%). Although the minimum lumen area (MLA) was similar, the plaque burden was significantly greater in nonculprit lesions with a plaque rupture compared with nonculprit lesions without a plaque rupture (66.0% [95% confidence interval: 64.5% to 67.4%] vs. 56.0% [95% confidence interval: 55.6% to 56.4%]; p < 0.0001). IVUS-VH analysis revealed that a nonculprit lesion with a plaque rupture was more often classified as a fibroatheroma than a nonculprit lesion without a plaque rupture (77.1% vs. 51.4%; p < 0.0001). Independent predictors of a plaque rupture were lesion length (per 10 mm; odds ratio: 1.30; p < 0.0001), plaque burden at the MLA site (per 10%; odds ratio: 2.56; p < 0.0001), vessel area at the MLA site (per 1 mm(2); odds ratio: 1.13; p < 0.0001), and VH-thin-cap fibroatheroma (odds ratio: 1.80; p = 0.016). During 3 years of follow-up, the incidence of overall major adverse cardiac events did not differ significantly between the patients with and patients without subclinical, nonculprit plaque ruptures. Secondary, nonculprit plaque ruptures were seen in 14% of patients with ACS and were associated with a fibroatheroma phenotype with a residual necrotic core but not with adverse outcomes if patients were treated with optimal medical therapy as part of a multicenter study. (Providing Regional Observations to Study Predictors of Events in the Coronary Tree [PROSPECT]; NCT00180466).	f	\N
24634197	The redox-active transition metal copper is an essential trace element for growth and development and serves as a structural or catalytic cofactor for many enzymes in a range of physiological processes. Mammalian copper homeostasis is tightly regulated, and an imbalance in copper metabolism is implicated in various pathological disorders. Radioactive copper isotopes, in particular (64) Cu (t1/2  = 12.7 h) and (67) Cu (t1/2  = 62.01 h), have made important contributions to the understanding of copper metabolism in health and disease. This review gives a brief account of how radiolabelled copper(II) salts and bioreductive copper complexes have been used to trace copper uptake, transport and efflux in vitro and in vivo. Recently, positron emission tomography (PET) has emerged as a noninvasive tool to image copper metabolism in living subjects and (64) Cu-PET is investigated for the study of copper-related neurological disorders, genetic diseases and cancer.	f	\N
24642005	Every year about 2500 patients in Sweden undergo surgery due to heart valve disease. A mechanical heart valve prosthesis causes risk of thromboembolic stroke or thrombus formation in the valve while anticoagulant treatment increases the risk of bleeding. Treatment quality with warfarin is crucial for patients with mechanical valve prostheses. It has previously been shown that poorly controlled warfarin treatment increases mortality in this patient group. TTR (Time in Therapeutic Range) on warfarin has been shown to affect the risk of complications in atrial fibrillation, but has not been studied in patients with mechanical heart valves. Our aim is to evaluate the impact of TTR on the risk of complications in this patient group. A non-randomized, prospective study of 534 adults with mechanical heart valve prostheses from Malmö and Sundsvall registered in the Swedish National Quality Registry Auricula between 01.01.2008 and 31.12.2011. Quartiles regarding individual TTR levels were compared regarding risk of complications. The risk of complications was significantly higher at lower TTR levels for all complications (p=0.005), bleeding (p=0.01) and death (p=0.018) but not for thromboembolism. In multivariate analysis the risk was significantly increased at lower TTR levels for bleeding and all complications but not for death or thromboembolism. Patients with a lower warfarin treatment quality measured by TTR have a higher risk of complications such as severe bleeding or death. A TTR of 83% or higher at the individual level should be obtained for best outcome.	f	\N
24653575	There are various models of health care, such as the epidemiological, psychosocial, sociological, economic, systemic of Neuman, cognitive medicine or ecological, ayurvedic, supraparadigmatic among others. All of them are seeking to combine one or more elements to integrate a model of health care. The article presents a systemic approach to health care with complementary medicines such as rehabilitative acupuncture, homeopathy and chiropractic through the application of a method of holistic care and integrated approach. There was a participatory action research in January 2012 to January 2013, with a comprehensive approach in 64 patients using the clinical method. We included the environmental aspects, biological, emotional, and behavioral to identify, recognize and integrate the form of manifestation of the disease. Later, it was ordered in a coherent way the etiologic factors, precipitating factors and identified the vulnerability of the patients as well as the structural alterations, classifying them in immediate, mediate and late. Referred to the three disciplines: rehabilitative acupuncture, homeopathy and chiropractic to be seen doing references and against-references between them, evaluating the current state of health and each meeting by noting the clinical and behavioral changes submitted and thus the area of attention to which would be forwarded to continue their treatment. 64 patients rotated by the 3 areas taking an average of 30 meetings with rehabilitative acupuncture, 12 with homeopathy and 10 with chiropractic. The changes were submitted clinical attitudinal, behavioral, clinical and organic. The model of care was multifaceted and interdisciplinary with a therapeutic approach of individualization and a holistic view to carry out a comprehensive diagnosis and provide quality health care to the population.	f	\N
24654676	To identify the frequency of disc hyperfluorescence, and to use optical coherence tomography to look for vitreopapillary traction as a possible underlying cause. Eight patients with presumed Fuchs uveitis syndrome were included. A complete ocular examination, fundus fluorescein angiography, and spectral-domain optical coherence tomography for optic nerve head were performed. There were 4 males and 4 female patients, and the mean age at diagnosis was 41.7 years. The most common ocular symptom was floaters (5/9). The range of initial visual acuity was 6/5-6/12. The most frequent clinical sign was inflammatory cells in the anterior chamber (9/9). Fundus fluorescein angiography showed disc hyperfluorescence in all but 1 patient. Optical coherence tomography did not show evidence of vitreopapillary traction in all eyes but one eye. We think that the high frequency of disc hyperfluorescence on fundus fluorescein angiography is an indication of an inflammatory process rather than a mechanical one.	f	\N
24655021	Gliomas are highly vascular and rich in VEGF, which promotes angiogenesis. Bevacizumab is a monoclonal antibody against VEGF, inhibiting angiogenesis by preventing receptor activation. Early Phase II clinical trials using bevacizumab in both newly diagnosed and recurrent high-grade gliomas (HGG) showed promising results, but these have not been confirmed in recent Phase III trials. This review is an update including recently reported Phase II and III study results. This is a review of clinical trials investigating bevacizumab in newly diagnosed and recurrent HGG with a focus on outcome results. A future perspective about the expected future role of bevacizumab is given. Bevacizumab efficacy, safety and tolerability, the combination of radiation and bevacizumab, as well as the use of bevacizumab to treat pseudoprogression are discussed. Further criteria of response evaluation needed to be adjusted in the age of antiangiogenic therapy are also discussed. Bevacizumab has been shown to be safe and tolerable in HGG. In the recurrent disease setting, bevacizumab might offer clinical benefits and is currently approved as a single agent for this indication. Although clinical trials demonstrate a prolonged progression-free survival (PFS) in bevacizumab-treated HGG, a benefit on overall survival has not been demonstrated. Research so far shows that bevacizumab appears to prolong PFS in newly diagnosed glioblastoma. Available data do not demonstrate a survival benefit in newly diagnosed patients. In the recurrent setting, there is no adequately powered randomized clinical trial to address whether there is a PFS or survival benefit with bevacizumab. Bevacizumab has also been introduced into other settings in neuro-oncology, including concurrent administration with re-irradiation for recurrent HGG.	f	\N
24659875	Hepatitis C virus (HCV) is one of the main causes of liver disease worldwide, and alterations of glucose metabolism have reached pandemic proportions in western countries. However, the frequent coexistence between these two conditions is more than simply coincidental, since HCV can induce insulin resistance through several mechanisms. Indeed, the virus interferes with insulin signaling both directly and indirectly, inducing the production of pro-inflammatory cytokines. Furthermore, the entire viral life cycle has strict interconnections with lipid metabolism, and HCV is responsible for a "viral" steatosis which is frequently superimposed to a "metabolic" one. Several evidences suggest that HCV-induced metabolic disorders contribute both to the evolution of liver fibrosis and, likely, to the progression of the other disorders which are typically associated with altered metabolism, in particular atherosclerosis. In the present review, we will examine in depth the links between HCV infection and insulin resistance, liver steatosis and diabetes, and analyze the impact of these interactions on the progression of liver fibrosis and atherosclerosis. Special attention will be focused on the highly debated topic of the relationship between HCV infection and cardiovascular disease. The available clinical literature on this item will be broadly reviewed and all the mechanisms possibly implied will be discussed.	f	\N
24669569	Nasopharyngeal carcinoma (NPC) has the propensity to develop distant metastases at a high rate and with poor prognosis. The metastatic sites are usually multifocal and involve the bones, lungs, liver and distant lymph nodes. The management of metastatic disease is essenti- ally palliative and is based on radiochemotherapy. A 50-year old man with a huge hematoma in the liver derived from a diagnosed NPC was treated with intermittent drainage of the hepatic hematoma for abdominal decompression, and the cavity was packed with omentum. In addition, 2 suspected metastatic lesions were excised. Neoadjuvant radiochemotherapy followed by concurrent chemotherapy was administered. After surgical treatment of the huge hematoma, the suspect sites in the liver were diagnosed as metastatic carcinoma, similar to the primary tumor. Several months later, bone metastatic lesions in the vertebra and oss iliaca dextra were detected due to distant metastasis. Treatment of metastatic NPC is essentially palliative and survival is usually poor.	f	\N
24670466	To evaluate the feasibility of monitoring clopidogrel resistance with flow cytometric analysis of platelet vasodilator stimulated phosphoprotein (VASP) phosphorylation. Twenty patients with coronary heart disease (CHD) and 17 healthy volunteers were examined for platelet aggregation rate and phosphorylation of VASP (calculated as platelet reactivity index, PRI) using traditional optical nephelometry and flow cytometry before and after concurrent therapy of clopidogrel and aspirin. No significant differences were found in PRI between CHD group and healthy control group [(89.45∓5.22)% vs (86.58∓4.35)%] before treatment. The PRI in CHD group was significantly lowered after treatment to (67.66∓19.77)% (P<0.05). Clopidogrel resistance was found in 6 (30%) cases in CHD group by flow cytometric analysis, which showed a higher sensitivity than optical nephelometry (10%). Flow cytometric analysis of VASP phosphorylation is a more reliable test to specifically evaluate clopidogrel resistance.	f	\N
24670932	The second leading cause of cancer-related deaths (both genders combined) in the United States is colorectal cancer (CRC). This emphasizes the need to develop both effective therapies for CRC patients and pre-clinical models mimicking human disease that carry translational potential in drug-development. Notably, at present there are no in situ models of CRC metastasis to lung. In our azoxymethane-induced colon tumorigenesis study in A/J mice assessing grape seed extract (GSE) efficacy, during necropsy we also found multiple lung nodules suggestive of colon tumor metastasis to lung that were significantly inhibited in GSE fed group. Both histopathological and molecular studies were performed to characterize and establish the origin of these lesions in lung. Histologically these nodules were determined as adenocarcinoma of mucin origin. Molecular analyses by immunohistochemistry (IHC) and RT-PCR revealed strong protein and transcript levels of colon specific markers CDX2 and CK20 in these lung nodules compared to uninvolved control lung tissue. Vis-à-vis, these nodules also showed minimally expressed lung specific biomarkers, specifically surfactant D and TTF-1, in IHC analysis. Additionally, 0.25% GSE supplementation in diet (w/w) decreased the incidence of these lung nodules by 53% and their total number by 66%. Together, the characterization of this unique in situ mouse model of CRC metastasis to lung provides translational opportunities in developing effective therapies to clinically manage and treat CRC at the advanced stage. Moreover, GSE efficacy in inhibiting CRC metastasis to lung in this model further supports its translational potential in controlling CRC growth, progression and metastasis in patients.	f	\N
24671083	Determining the composition and function of subgingival dental plaque is crucial to understanding human periodontal health and disease, but it is challenging because of the complexity of the interactions between human microbiomes and human body. Here, we examined the phylogenetic and functional gene differences between periodontal and healthy individuals using MiSeq sequencing of 16S rRNA gene amplicons and a specific functional gene array (a combination of GeoChip 4.0 for biogeochemical processes and HuMiChip 1.0 for human microbiomes). Our analyses indicated that the phylogenetic and functional gene structure of the oral microbiomes were distinctly different between periodontal and healthy groups. Also, 16S rRNA gene sequencing analysis indicated that 39 genera were significantly different between healthy and periodontitis groups, and Fusobacterium, Porphyromonas, Treponema, Filifactor, Eubacterium, Tannerella, Hallella, Parvimonas, Peptostreptococcus and Catonella showed higher relative abundances in the periodontitis group. In addition, functional gene array data showed that a lower gene number but higher signal intensity of major genes existed in periodontitis, and a variety of genes involved in virulence factors, amino acid metabolism and glycosaminoglycan and pyrimidine degradation were enriched in periodontitis, suggesting their potential importance in periodontal pathogenesis. However, the genes involved in amino acid synthesis and pyrimidine synthesis exhibited a significantly lower relative abundance compared with healthy group. Overall, this study provides new insights into our understanding of phylogenetic and functional gene structure of subgingival microbial communities of periodontal patients and their importance in pathogenesis of periodontitis.	f	\N
24674299	Erdheim-Chester disease is a rare systemic disease. The diagnosis is difficult due to significant clinical and morphological polymorphism. Orbital involvement is rare, but constitutes a classic means of detection. We report the case of a 60-year-old man, who consulted for evaluation of bilateral retro-orbital tumors. These tumors had been discovered on head CT two years previously during work-up of proptosis. Two biopsies were performed. The first one revealed polymorphous inflammatory tissue. The second one revealed intense granulomatous reaction, rich in non-specific foamy histiocytes. Thoracic-abdominal-pelvic CT scan detected peri-aortic and retroperitoneal infiltration. The association of these signs pointed to a diagnosis of Erdheim-Chester disease, confirmed by the re-examination of the histological samples. Erdheim-Chester disease is a rare non-Langerhans histiocytosis with a specific tropism for perivascular and fatty connective tissue. The cause is not known. The diagnosis of this systemic disease is histological. In the case of bilateral intra-orbital tumors, the diagnosis of Erdheim-Chester disease must be considered.	f	\N
24674770	Excessive daytime sleepiness (EDS) is common in Parkinson's Disease (PD). Actigraphy uses periods of immobility as surrogate markers of nighttime sleep but there are no examples of its use in assessing EDS of PD. A commercial wrist worn system for measuring bradykinesia and dyskinesia also detects 2 min periods of immobility, which have a 85.2% concordance with the detection of sleep by ambulatory daytime polysomnography, (p < 0.0001 Chi Squared). High Epworth Sleepiness Scores (ESS) were associated with a proportion of time immobile (PTI) (p = 0.01 Mann-Whitney U). The median PTI between 0900 and 1800 h w in 30 age matched control subjects was 2%, representing 10 min and PTI at or above the 75th percentile (5% or 27 min) was taken as a high level. PD patients had higher PTI (median 4.8%) than controls (p < 0.0001, Mann-Whitney U). PD subjects with a high PTI had more bradykinesia, less dyskinesia and higher PDQ39 scores than those with low PTI. There was no relationship between PTI and dose or type of PD medications. However, in 53% of subjects, PTI increased in the 30-60 min after levodopa confirming that in some subjects levodopa results in increased sleepiness. In summary, immobility is a surrogate marker of daytime sleep in PD, confirmed by correlation with PSG and ESS. PD subjects measured this way are more likely to be sleepy and sleepy PD subjects are more likely to be bradykinetic and have a higher PDQ39. Levodopa leads to an increase in sleepiness in more than half of subjects post dosing.	f	\N
24677192	Donor factors influence hepatitis C virus (HCV) disease severity in liver transplant (LT) recipients. Living donors, because they are typically young and have short cold ischemic times, may be advantageous for HCV-infected patients. Among HCV-infected patients in the Adult-to-Adult Living Donor Liver Transplantation Cohort Study (A2ALL) surviving >90 days and followed for a median 4.7 years, advanced fibrosis (Ishak stage ≥3) and graft loss were determined. The 5-year cumulative risk of advanced fibrosis was 44% and 37% in living donor LT (LDLT) and deceased donor LT (DDLT) patients (P = 0.16), respectively. Aspartate aminotransferase (AST) activity at LT (hazard ratio [HR] = 1.38 for doubling of AST, P = 0.005) and biliary strictures (HR = 2.68, P = 0.0001) were associated with advanced fibrosis, but LDLT was not (HR = 1.11, 95% confidence interval [CI] 0.73-1.69, P = 0.63). The 5-year unadjusted patient and graft survival probabilities were 79% and 78% in LDLT, and 77% and 75% in DDLT (P = 0.43 and 0.32), with 27% and 20% of LDLT and DDLT graft losses due to HCV (P = 0.45). Biliary strictures (HR = 2.25, P = 0.0006), creatinine at LT (HR = 1.74 for doubling of creatinine, P = 0.0004), and AST at LT (HR = 1.36 for doubling of AST, P = 0.004) were associated with graft loss, but LDLT was not (HR = 0.76, 95% CI: 0.49-1.18, P = 0.23). Donor type does not affect the probability of advanced fibrosis or patient and graft survival in HCV-infected recipients. Thus, while LDLT offers the advantage of shorter wait times, there is no apparent benefit for HCV disease progression. Biliary strictures have a negative effect on HCV fibrosis severity and graft survival, and a high AST at LT may be an important predictor of fibrosis risk post-LT.	f	\N
24684672	Rheumatoid arthritis (RA) is an autoimmune disease of unknown cause and a chronic and progressive inflammatory disorder ensuing in genetically predisposed subjects, characterized by synovitis causing joint destruction, as well as inflammation in body organ systems, leading to anatomical alteration and functional disability. Immune competent cells, deregulated synoviocytes and cytokines play a key role in the pathophysiological mechanisms. The immune system function shows time-related variations related to the influence of the neuroendocrine system and driven by the circadian clock circuitry. Immune processes and symptom intensity in RA are characterized by oscillations during the day following a pattern of circadian rhythmicity. A cross-talk between inflammatory and circadian pathways is involved in RA pathogenesis and underlies the mutual actions of disruption of the circadian clock circuitry on immune system function as well as of inflammation on the function of the biological clock. Modulation of molecular processes and humoral factors mediating in RA the interplay between the biological clock and the immune response and underlying the rhythmic fluctuations of pathogenic processes and symptomatology could represent a promising therapeutic strategy in the future.	f	\N
24685603	The effects of thymidylate synthase (TS) polymorphisms on susceptibility to colorectal cancer (CRC) have been investigated in many studies, but the results remain conflicting rather than conclusive. To resolve these conflicts, we performed a quantitative synthesis of the evidence on the association between these two polymorphisms and CRC risk. All eligible case-control studies published up to September 2013 were identified by searching PubMed, Web of Science and CNKI. Effect sizes of odds ratio (OR) and 95% confidence interval (95% CI) were calculated by using a fixed- or random-effect model. A total of 11 case-control studies were included, including 10 studies (3324 cases and 4622 controls) for TSER polymorphism and 9 studies (3223 cases and 3886 controls) for TS1494del6 polymorphism. Overall, no significant association between the TS polymorphisms and CRC risk was found. In the subgroup analysis by ethnicity, a significantly association were found among Caucasian populations for TSER polymorphism; but for TS1494del6 polymorphism, no significantly association was observed in both Asian and Caucasian populations. When stratifying by source of controls, we found there was a statistically significant association between TSER polymorphism and risk of CRC in the population-based population; however, we detected no association in both population-based and hospital-based populations for TS1494del6 polymorphism. This meta-analysis suggests that the TSER polymorphism in TS gene but not TS1494del6 polymorphism might be a protective factor for CRC among Caucasian populations.	f	\N
24713244	To study the expression and clinicopathologic significance of cancer stem cell markers CD44v6 and CD24 in ovarian serous carcinoma tissues. One hundred and two cases of ovarian carcinoma diagnosed during the period from June, 2001 to December, 2010 were retrieved from archival files. The histology slides were reviewed and a two-tier system for grading of ovarian serous carcinoma was applied. The expression of CD44v6 and CD24 was detected by immunohistochemistry using EnVision method. The relationship between CD44v6/CD24 expression and various clinicopathologic parameters was analyzed. There were 46.1% (47/102) and 59.8% (61/102) cases expressing CD44v6 and CD24, respectively. Both CD44v6 and CD24 expression showed positive correlation with higher histopathologic grade (P = 0.003 and P < 0.05, respectively). CD24 expression also correlated with the presence of lymph node metastasis (P < 0.05). There was no statistically significant relationship between the expression of these two markers (χ(2) = 0.394, P = 0.530). The age of the patients, histopathologic grade, clinical stage and nodal status correlated with progression-free survival time (P < 0.05). CD44v6 expression and histopathologic grade correlated with the overall survival time (P < 0.05). Patient age was an independent poor prognostic factor by multivariate analysis. CD44v6 expression, age older than 50 years, high clinical stage and presence of lymph node metastasis are associated with poor prognosis in patients with ovarian serous carcinoma. The two-tier system for grading of ovarian serous carcinoma is useful in predicting survival; and high tumor grade represents an important poor prognostic indicator for ovarian serous carcinoma.	f	\N
24713591	High-density-lipoprotein cholesterol (HDL-C) has been identified in population studies as an independent inverse predictor of cardiovascular events. Although the causal nature of this association has been questioned, HDL and its major protein, apolipoprotein (apo)A1, have been shown to prevent and reverse atherosclerosis in animal models. In addition, HDL and apoA1 have several putatively atheroprotective functions, such as the ability to promote efflux of cholesterol from macrophages in the artery wall, inhibit vascular inflammation, and enhance endothelial function. Therefore, HDL-C and apoA1 have been investigated as therapeutic targets for coronary heart disease. However, recent clinical trials with drugs that raise HDL-C, such as niacin and inhibitors of cholesteryl ester transfer protein, have been disappointing. Here, we review the current state of the science regarding HDL as a therapeutic target.	f	\N
24715127	The objective of this study was to evaluate the 25-year outcome of patients with primary Sjögren's syndrome (pSS). One hundred and fifty-two patients diagnosed with pSS (American-European classification criteria) were retrospectively and descriptively analysed (1986-2011). Of all 152 patients, 55.9% were alive, 18.4% had died and 25.7% discontinued follow-up (mostly due to old age). Malignancy affected 28.3% and non-Hodgkin's lymphoma (NHL) affected 10.5%. The adjusted risk for development of NHL was an odds ratio (OR) of 10.5 (95% confidence interval [CI]: 3.05-36.42) in patients with vasculitis (p<0.001), and OR 3.4 (95% CI 1.05-11.2) in the presence of glandular complications (parotid swelling, lymphadenopathy) (p < 0.041). Seventy-five patients (49.3%) developed other autoimmune diseases (autoimmune thyroid disease [15.8%], pulmonary fibrosis [7.2%] and vasculitis [10.5%]). Although the course of pSS is relatively benign, over 25 years patients experience more clinical complications than previously described. In addition, vasculitis and glandular manifestations were significant predictors for NHL.	f	\N
24720286	There is currently no cure for metastatic castration-resistant prostate cancer (CRPC). Chemoresistance and metastatic disease remain the main causes of treatment failure and mortality in CaP patients. Although several advances have been made in the control of CRPC with some newly developed drugs, there is still an urgent need to investigate the mechanisms and pathways of prostate cancer (CaP) metastasis and chemoresistance, identify useful therapeutic targets, develop novel treatment approaches, improve current therapeutic modalities and increase patients' survival. Cancer stem cells (CSCs), a minority population of cancer cells characterised by self-renewal and tumor initiation, have gained intense attention as they not only play a crucial role in cancer recurrence but also contribute substantially to chemoresistance. As such, a number of mechanisms in chemoresistance have been identified to be associated with CSCs. Therefore, a thorough and integral understanding of these mechanisms can identify novel biomarkers and develop innovative therapeutic strategies for CaP treatment. Our recent data have demonstrated CSCs are associated with CaP chemosensitivity. In this review, we discuss the roles of putative CSC markers in CaP chemoresistance and elucidate several CSC-associated signaling pathways such as PI3K/Akt/mTOR, Wnt/β-catenin and Notch pathways in the regulation of CaP chemoresistance. Moreover, we will summarize emerging and innovative approaches for the treatment of CRPC and address the challenging CRPC that is driven by CSCs. Understanding the link between CSCs and metastatic CRPC will facilitate the development of novel therapeutic approaches to overcome chemoresistance and improve the clinical outcomes of CaP patients.	f	\N
24723322	The mitochondrial toxin 3-nitropropionic acid (3-NP) is an irreversible inhibitor of respiratory chain complex II. Chronic systemic administration of 3-NP to mice, rats, and non-human primates leads to preferential degeneration of the striatum, and produces motor and cognitive symptoms that are highly reminiscent of Huntington's disease (HD). HD is caused by a dominant inherited expansion of CAG repeats in the Huntington gene. Thus, many aspects of HD cannot be mimicked by 3-NP. However, recent research shows that mitochondrial defects and oxidative stress may play a key role in HD pathogenesis, further supporting the potential utility of the 3-NP model of striatal degeneration. First, a basic protocol to produce acute striatal lesions in rats using repeated intraperitoneal injection of 3-NP is described. Second, a more complex protocol that takes advantage of the use of osmotic minipumps to steadily release 3-NP leading to consistent lesions and motor symptoms in Lewis rats is presented. Curr. Protoc. Neurosci. 67:9.48.1-9.48.14. © 2014 by John Wiley & Sons, Inc.	f	\N
24725410	Maintenance of a constant cell volume in response to extracellular or intracellular osmotic changes is critical for cellular homeostasis. Activation of a ubiquitous volume-regulated anion channel (VRAC) plays a key role in this process; however, its molecular identity in vertebrates remains unknown. Here, we used a cell-based fluorescence assay and performed a genome-wide RNAi screen to find components of VRAC. We identified SWELL1 (LRRC8A), a member of a four-transmembrane protein family with unknown function, as essential for hypotonicity-induced iodide influx. SWELL1 is localized to the plasma membrane, and its knockdown dramatically reduces endogenous VRAC currents and regulatory cell volume decrease in various cell types. Furthermore, point mutations in SWELL1 cause a significant change in VRAC anion selectivity, demonstrating that SWELL1 is an essential VRAC component. These findings enable further molecular characterization of the VRAC channel complex and genetic studies for understanding the function of VRAC in normal physiology and disease.	f	\N
24726273	Central obesity represents the major factor responsible for NAFLD, but several immunological and endocrinological mechanisms are involved in fatty infiltration in the liver, inflammation and fibrosis. Gut microbiota and genetic factors were recently indicated as major players in liver injury. Loss of weight and physical activity represent till now the cornerstone of treatment, but they are very difficult to obtain and to maintain. Several pharamocotherapeutic approaches including insulin sensitizers, omega-3 fatty acids and vitamin E have been extensively studied in randomized trials, but final conclusions still could not be formulated. Therefore, new treatments based on pathogenetic mechanisms leading to NAFLD are under evaluation to establish the effective pharmacological therapy of this disorder.	f	\N
24734429	In 2013 the main efforts of the Medical Service were aimed at the following tasks: optimization of management system of military medical service, improvement of medical evacuation system, medical service security for military contingents, assigned according to territory principle to military-medical facilities of the Ministry of Defence of the Russian Federation, implementation of innovations at all stages of medical evacuation in peace- and wartime, security of combat and mobilization readiness of regulatory bodies of the Medical Service, medical military units and military medical facilities, medical service of troops battle training, improvement of material and technical resources, security of regular pharmacy and equipment supply, activation of research work in the Medical Service interests. Lines of military medicine development in 2014 are: transfer of treatment facilities that are not used by the Ministry of Defence into the Federal Biomedical Agency till the end of 2014, prevention of pneumonia and meningitis in military personnel, improvement of early diagnosis system, medical service for military contingents according to territory principle, improvement of diagnostic and treatment work in military-medical units and subunits and military-medical facilities by means of development of material and technical resources, monitor the implementation of innovative diagnostic and treatment technologies, completion of construction projects of central military hospitals and etc.	f	\N
24744504	Consumption of tomato fruits, like those of many other plant species that are part of the human diet, is considered to be associated with several positive effects on health. Indeed, tomato fruits are an important source of bioactive compounds with known beneficial effects including vitamins, antioxidants, and anticancer substances. In particular, antioxidant metabolites are a group of vitamins, carotenoids, phenolic compounds, and phenolic acid that can provide effective protection by neutralizing free radicals, which are unstable molecules linked to the development of a number of degenerative diseases and conditions. In this review, we will summarize the recent progress on tomatoes nutritional importance and mechanisms of action of different phytochemicals against inflammation processes and prevention of chronic noncommunicable diseases (e.g., obesity, diabetes, coronary heart disease, and hypertension). In addition, we will summarize the significant progress recently made to improve the nutritional quality of tomato fruits through metabolic engineering and/or breeding.	f	\N
24748016	Food allergy is a common condition that plays an important role in the pathogenicity and maintenance of atopic dermatitis (AD), however, must be carefully investigated before imposing a restrictive diet. The aim of this study was to evaluate the sensitivity to foods in patients with AD, correlating it with the severity of the disease and other possible associated factors. One hundred and eleven children (6-180 months of age) with AD were evaluated and later followed up at the Allergy and Clinical Immunology Division, Department of Pediatrics at FMABC. The serum concentrations of specific IgE to cow's milk (CM), egg, soy, wheat, corn, peanut and fish were measured using an enzymatic fluorescence method (ImmunoCAP™). In order to identify the clinical reactivity, the open oral provocation test was performed when specific IgE was positive to CM, egg and wheat and in all those who related symptoms after the intake of such foods regardless of the presence or absence of sensitization. In total, 40.5 % of the studied population was sensitized to at least one food allergen, especially those between 73 and 180 months of age. There was a higher prevalence of sensitization in children with more severe AD, and foods like CM, egg and wheat were the most involved, but with low clinical reactivity. We observed increased severity of AD in cases that initiated symptoms earlier and who had shorter duration of exclusive breastfeeding as well as a linear increase in sensitization in the most serious cases. Serum-specific immunoglobulin E was the only factor associated with the relationship that showed sensitization. The occurrence of sensitization to foods was frequent, mainly in the age group of 6-9 years and in patients with severe AD; however, the validation of the clinical reactivity was negative in most of the provocations performed, which agrees with the need to prove the same before the imposition of restrictive diets, often unnecessary and complex.	f	\N
24748137	This report describes the case of a 44-year-old Caucasian woman of Northern European descent with a medical history of pyoderma gangrenosum, chronic abdominal pain and erythema nodosum which required intermittent use of high-dose steroids that failed to improve her symptoms. The patient was initially diagnosed with Crohn's disease and most recently with sclerosing mesenteritis. She presented to the hospital with worsening abdominal pain. She was found to have recurrent painful aphthous oral, genital and perianal ulcers and a clinical diagnosis of Behçet's disease was made. Her hospitalisation was complicated by haemoptysis, and bronchoscopy revealed alveolar haemorrhage. Treatment was initiated with three days of pulse intravenous solumedrol 1 g/day and cyclophosphamide at 700 mg/m(2). The case had a favourable outcome despite the initial diagnostic challenges. This report emphasises that systemic diseases, including Behçet's disease, can have variable presentations and can be frequently misdiagnosed.	f	\N
24751894	Both the diagnosis and treatment of Mycoplasma pneumoniae infections in children are currently facing two main challenges: a relatively high carriage in asymptomatic children, and a worldwide increase in macrolide-resistant M. pneumoniae (MRMP). This review focuses on the scientific and clinical implications of these crucial issues. Recent studies have indicated that the prevalence of M. pneumoniae in the upper respiratory tract is similar among asymptomatic, healthy children and children with a symptomatic respiratory tract infection, and that current diagnostic procedures for M. pneumoniae are unable to differentiate between bacterial carriage and infection. It is therefore possible that the burden of M. pneumoniae-associated disease is overestimated. Another phenomenon that has an important impact on the treatment of M. pneumoniae infections is the rapid worldwide emergence of MRMP isolates. The current diagnostic procedures for M. pneumoniae cannot discern between bacterial carriage and infection in a clinically relevant time frame. It is therefore imperative that these procedures be modified such as to unambiguously detect symptomatic M. pneumoniae infections. Moreover, the emergence of MRMP necessitates the application of methods to detect macrolide resistance as well as the implementation of restrictive policies regarding the use of macrolides.	f	\N
24763465	Atrial fibrillation (AF) is the most common arrhythmia and is associated with increased morbidity. As the population ages and the prevalence of AF continues to rise, the socioeconomic consequences of AF will become increasingly burdensome. Although there are well-defined clinical risk factors for AF, a significant heritable component is also recognized. To identify the molecular basis for the heritability of AF, investigators have used a combination of classical Mendelian genetics, candidate gene screening, and genome-wide association studies. However, these avenues have, as yet, failed to define the majority of the heritability of AF. The goal of this review is to describe the results from both candidate gene and genome-wide studies, as well as to outline potential future avenues for creating a more complete understanding of AF genetics. Ultimately, a more comprehensive view of the genetic underpinnings for AF will lead to the identification of novel molecular pathways and improved risk prediction of this complex arrhythmia.	f	\N
24782446	We aimed to evaluate whether a recent knee injury was associated with accelerated knee osteoarthritis (OA) progression. In the Osteoarthritis Initiative, we studied participants free of knee OA on their baseline radiographs (Kellgren/Lawrence [K/L] <2). We compared 3 groups as follows: 1) individuals with accelerated progression of knee OA: defined as having at least 1 knee that progressed to end-stage knee OA (K/L grade 3 or 4) within 48 months, 2) common knee OA progression: at least 1 knee increased in radiographic scoring within 48 months (excluding those defined as accelerated knee OA), and 3) no knee OA: no change in K/L grade in either knee. At baseline, participants were asked if their knees had ever been injured, and at each annual visit they were asked about injuries during the prior 12 months. We used multinomial logistic regressions to determine whether a new knee injury was associated with the outcome of accelerated knee OA or common knee OA progression, after adjusting for age, sex, body mass index, static knee malalignment, and systolic blood pressure. A knee injury during the total observation period was associated with accelerated knee OA progression (n = 54; odds ratio [OR] 3.14) but not common knee OA progression (n = 187; OR 1.08). Furthermore, a more recent knee injury (within a year of the outcome) was associated with accelerated (OR 8.46) and common knee OA progression (OR 3.12). Recent knee injuries are associated with accelerated knee OA. Most concerning is that certain injuries may be associated with a rapid cascade toward joint failure in less than 1 year.	f	\N
24783461	Patients with established rheumatoid arthritis (RA) have a higher cardiovascular morbidity and mortality in comparison with the general population. It is considered to be an independent risk factor for cardiovascular disease. The purpose of this article is to describe the mechanisms responsible for accelerated atherogenesis in RA patients and to give an overview of the effects of different RA therapies (methotrexate, TNF antagonists and other biologicals).	f	\N
24800540	To analyze the clinical features and treatment of tuberculous otitis media and mastoiditis. Thirteen patients with tuberculous otitis media and mastoiditis were retrospectively analyzed and the related literatures were reviewed. One case was treated by surgery only, and anti-tuberculosis treatment was given to another one patient, and surgical removal of disease lesions in combination with anti-tuberculosis treatment were given to 12 patients. One patient received surgery only was found to recur after follow-up for seven months. The patient did not recur after seven months' follow-up after antituberculosis therapy,and other patients did not recur. Although the regular anti-tuberculosis chemotherapy treatment was the main treatment for tuberculous otitis and mastoiditis, surgical treatment was helpful to achieved more rapid healing of the ear.	f	\N
24804836	Non-melanoma skin cancers (NMSCs) are among the most common human malignancies. Current methods for their prevention include avoidance of natural and artificial sources of UV radiation and using photoprotective clothing and sunscreens. However, these methods have proven to be inadequate in stemming the rise in skin cancer incidence over the past several years. There is accumulating evidence that cyclooxygenase-2 (COX-2), an enzyme involved in prostaglandin synthesis, may be involved in the pathogenesis of NMSC. In preclinical studies, animals genetically deficient in the COX-2 enzyme or that have been treated with pharmacological inhibitors of COX-2 develop significantly fewer tumors when subjected to a UV-induced skin carcinogenesis protocol compared with control mice. Several epidemiological studies in humans support the concept that this enzyme is intimately involved in UV-induced skin cancer development, and UV radiation is known to augment COX-2 expression in human skin. Recent studies suggest that drugs that block COX-2 expression may prevent the development of NMSCs. Thus, pharmacologic agents that inhibit the enzyme COX-2 may be effective chemopreventive agents for NMSCs.	f	\N
24806099	The use of liver retransplantation (ReLT) for hepatitis C virus (HCV) recurrence is controversial because of subsequent viral recurrence after ReLT. Case-control analysis between patients undergoing ReLT for HCV reinfection between 1993 and 2012 (ReLT group: 26 patients) and patients undergoing liver transplantation (LT) for HCV infection immediately before and after each ReLT (LT group: 52 patients). ReLT group had worse hepatocellular function, higher preoperative viral load, higher transfusion requirements, and increased number of postoperative complications than LT group. ReLT patients showed a trend toward worse graft survival compared with LT (five-yr graft survival: 42.3% vs. 64.3%, p = 0.145), but the rate of severe HCV recurrence and infection-free survival (IFS) was similar. The use of donors older than 60 yr led to a lower IFS and graft survival in both groups. Early severe HCV infection rate was similar in both groups, but it affected prognosis in ReLT more markedly than in LT (three-yr graft survival: 0% vs. 66.7%, p = 0.003). ReLT for HCV reinfection has acceptable results when strict selection policies of donor and recipient are applied. However, early severe recurrence more markedly impairs prognosis in ReLT patients than in LT.	f	\N
24820120	Regardless of whether alone or in combination, cecal ligation and puncture (CLP) is the most commonly used model to emulate human polymicrobial sepsis. Numerous CLP studies have shown that female mice survive better than males. In adult mice, this effect may be partly due to the unequal cecum mass (larger in males), as cecum ligation is frequently not size standardized. Comparing two ligation approaches, we investigated whether cecum size influences gender-specific outcome differences. 15-month-old (middle-aged) female and male CD-1 mice underwent sublethal trauma/hemorrhage followed by CLP 48 h later. The evaluation of cecum size (in centimeters) and filling (score) was immediately followed by two ligation protocols: (1) ileocecal ligation (IC-L; n = 28/each gender) below the ileocecal valve, and (2) apex ligation (AP-L; n = 31 males, n = 24 females) 2 cm from the apex ceci - all followed by an identical double puncture and 10-day monitoring. Cecum length (3.4 cm in males vs. 2.65 cm in females) and filling (2.5 score points in males vs. 1.7 in females; both p < 0.05) were always greater in male than female mice (27 vs. 44%, respectively). Compared to AP-L, the 10-day CLP mortality was higher with IC-L (86% in males and 61% in females), and this exacerbation was similar in both genders (by 21% in male and 23% in female mice). Finally, the intergender comparison demonstrated that female mice displayed a significant and similar survival advantage regardless of the ligation approach: the difference reached 25% with IC-L and 24% with AP-L. Standardization by AP-L did not eliminate the gender-specific difference in mortality due to posttraumatic sepsis. The greater cecum length/filling in middle-aged male mice was not responsible for their inferior survival compared to females.	f	\N
24821164	Nephronophthisis is an autosomal recessive disease that leads to end-stage renal disease. These days, molecular genetic analysis is used pre-emptively for making a definitive diagnosis in patients who have clinical and radiological data suggestive of the disease. Herein, we are reporting a 12-year-old girl who was genetically diagnosed to have juvenile nephronophthisis, which explained the mystery of the chronic kidney disease in her four affected siblings.	f	\N
24821649	Hepatocellular carcinoma (HCC) is associated with a poor prognosis because of a lack of effective treatment options. The objective of this study was to examine a new strategy for HCC treatment, namely the use of poly (ADP-ribose) polymerase 1 (PARP-1) inhibitor (ABT-888) together with Temozolomide (TMZ) incorporated onto magnetic nanoparticles. Magnetic Fe3 O4 /Fe cores were encapsulated within a silica shell to facilitate the simultaneous incorporation of ABT-888 and TMZ. In vitro tests were performed with HepG2, Hep3B and PLC-PRF-5 liver tumoural cell lines and with WRL-68 liver non-tumoural cells. The magnetic nanocarriers were loaded simultaneously with ABT-888 and TMZ. High stability and extended release were achieved in culture medium. Confocal microscopy images showed that drug-loaded particles were uptaken and accumulated into the cytoplasm of liver tumoural cells, inducing the following effects: G2/M cell cycle arrest (P < 0.05), accumulation of DNA damage (P < 0.05), mitochondrial depolarization (P < 0.01), reduction in BCL-xL, FOS, JUND gene expression (P < 0.05), PARP-1 fragmentation, Caspase-3 activation and apoptotic cell death (P < 0.05). Interestingly, drugs loaded onto nanoparticles exhibited better efficiency than free drugs (cell death triggered by drug delivery nanosystem: 53.5% vs. 34.5% by free drugs, P = 0.01). These magnetic nanocompounds are able to incorporate both drugs simultaneously, enter the tumour cells and release them. ABT-888/TMZ/NPs decrease the transcription of key genes involved in tumour survival and induce apoptotic cell death in a more effective manner than is achieved by free drugs.	f	\N
24821915	Only a small fraction of individuals exposed to Mycobacterium tuberculosis develop clinical tuberculosis (TB). Over the past century, epidemiological studies have shown that human genetic factors contribute significantly to this interindividual variability, and molecular progress has been made over the past decade for at least two of the three key TB-related phenotypes: (i) a major locus controlling resistance to infection with M. tuberculosis has been identified, and (ii) proof of principle that severe TB of childhood can result from single-gene inborn errors of interferon-γ immunity has been provided; genetic association studies with pulmonary TB in adulthood have met with more limited success. Future genetic studies of these three phenotypes could consider subgroups of subjects defined on the basis of individual (e.g. age at TB onset) or environmental (e.g. pathogen strain) factors. Progress may also be facilitated by further methodological advances in human genetics. Identification of the human genetic variants controlling the various stages and forms of TB is critical for understanding TB pathogenesis. These findings should have major implications for TB control, in the definition of improved prevention strategies, the optimization of vaccines and clinical trials and the development of novel treatments aiming to restore deficient immune responses.	f	\N
24843888	The adaptive function of melanin located in the integument is well known. Although pigments are also deposited in various internal organs, their function is unclear. A review of the literature revealed that 'internal melanin' protects against parasites, pollutants, low temperature, oxidative stress, hypoxemia and UV light, and is involved in the development and function of organs. Importantly, several studies have shown that the amount of melanin deposited on the external body surface is correlated with the amount located inside the body. This finding raises the possibility that internal melanin plays more important physiological roles in dark than light-colored individuals. Internal melanin and coloration may therefore not evolve independently. This further emphasizes the major role played by indirect selection in evolutionary processes.	f	\N
24845215	Over 5100 colorectal cancers (CRCs) are diagnosed in the United Kingdom in 85 years and older age group per year but little is known of cancer progression in this group. We assessed clinical, pathological and molecular features of CRC with early and late mortality in such patients. Data were analysed in relation to early mortality and long-term survival in 90 consecutive patients with CRC aged 85 years or older in a single hospital. Patients not undergoing operation, those with an ASA score of III or greater and those with advanced tumour stage were more likely to die within 30 days. Regression analysis showed that 30 day mortality was independently related to failure to undergo resection (odds ratio (O.R.), 10.0; 95% confidence interval [C.I.], 1.7-58.2; p=0.01) and an ASA score of III or greater (O.R. 13.0; 95% C.I., 1.4-12.6; p=0.03). All cause three and five year survival were 47% and 23% respectively for patients who are alive 30 days after diagnosis. Three and five year relative survivals were 64% and 54%, respectively. Long-term outcome was independently related to tumour stage (relative risk [R.R.], 2; 95% C.I., 1.3-3.1; p=0.001), presence of co-morbid diseases (R.R., 2.8; 95% C.I., 1.3-6.0; p=0.007) and lipid peroxidation status (R.R., 2.9; 95% C.I., 1.1-7.5; p=0.025). An active multidisciplinary approach to the care of patients with CRC at the upper extreme of life is reasonable. It also seems sensible to individualise care based upon the extent of disease at diagnosis and the presence of co-morbid conditions. Further studies to examine the role of lipid peroxidation are warranted.	f	\N
24850149	Inflammasomes are specialized signaling platforms critical for the regulation of innate immune and inflammatory responses. Various NLR family members (i.e., NLRP1, NLRP3, and IPAF) as well as the PYHIN family member AIM2 can form inflammasome complexes. These multi-protein complexes activate inflammatory caspases (i.e., caspase-1) which in turn catalyze the maturation of select pro-inflammatory cytokines, including interleukin (IL)-1β and IL-18. Activation of the NLRP3 inflammasome typically requires two initiating signals. Toll-like receptor (TLR) and NOD-like receptor (NLR) agonists activate the transcription of pro-inflammatory cytokine genes through an NF-κB-dependent priming signal. Following exposure to extracellular ATP, stimulation of the P2X purinoreceptor-7 (P2X7R), which results in K(+) efflux, is required as a second signal for NLRP3 inflammasome formation. Alternative models for NLRP3 activation involve lysosomal destabilization and phagocytic NADPH oxidase and/or mitochondria-dependent reactive oxygen species (ROS) production. In this review we examine regulatory mechanisms that activate the NLRP3 inflammasome pathway. Furthermore, we discuss the potential roles of NLRP3 in metabolic and cognitive diseases, including obesity, type 2 diabetes mellitus, Alzheimer's disease, and major depressive disorder. Novel therapeutics involving inflammasome activation may result in possible clinical applications in the near future.	f	\N
24851665	Self-efficacy, a central construct in health interventions, has been measured in various contexts. The absence of any published meta-review of self-efficacy instrumentation led to the current meta-synthesis that reports and evaluates the instrumentation processes. A systematic search resulted in 39 self-efficacy instrumentation studies, which were evaluated for the aspects of conceptual bases, health contexts, operational definition, instrumentation procedures, reliability and scale length, and item content. Primarily based in Bandura's social cognitive theory, these studies reported self-efficacy instrumentation for developing new scales and modifying/validating measures for illness management, healthy behavior adoption/maintenance, disease/risk prevention, and aging management. Trait-like, specific-domain, and situation approaches were used for generating item content. Problems in some studies include non-efficacy items, a lack of systematic instrumentation procedures, item content too general for specific-domain self-efficacy, and measurement inefficiency. The piecemeal fashion of self-efficacy instrumentation has resulted in incomparable self-efficacy measures of similar domains of health functioning. A trans-domain framework, thus, is warranted. Suggestions are provided for solving other problems in self-efficacy instrumentation.	f	\N
24852869	The ABC-02 trial has defined the standard therapy for patients with advanced biliary tract cancer (ABC); however, outcome in an unselected patient population in the UK has not been described. We aimed to investigate the outcome of a series of patients with ABC from two large UK cancer networks. We retrospectively reviewed all cases of ABC presenting to two UK cancer networks over a nine-year period. Overall survival (OS) and factors influencing OS were assessed. Four hundred and two patients were available for analysis. The median OS was 6.2 months. On univariate analysis, age ≥70 years (P = 0.047), advanced disease stage (P <0.001), gall bladder primary (P = 0.033), poor performance status (P <0.001) and lack of chemotherapy (P <0.001) were associated with worse outcome. Survival was superior in the 36.4% of patients who received palliative chemotherapy (12.5 vs 4.3 months; P <0.001). On multivariate analysis of patients who had chemotherapy, those who did not receive fluoropyrimidine-based regimens (HR = 5.12; P = 0.022) or gemcitabine-based regimens (HR = 5.01; P = 0.021) had a higher mortality, whereas the effect of platinum-containing regimens was of borderline significance (HR = 2.23; P = 0.086). Sites, age, and multi-agent regimens were not significant. This is one of the largest retrospective studies reporting outcome of palliative chemotherapy for ABC. It confirms the benefit of palliative chemotherapy in an unselected group of patients. Fluoropyrimidine-based regimens appear to be as effective as gemcitabine-based treatments.	f	\N
24853219	Epidermal growth factor receptor (EGFR) inhibitors are widely used in the treatment of many cancers, and the cutaneous toxicity profile associated with these agents has become prominent. In fact, dermatologic side effects have also been reported with other targeted agents, including both BRAF and mTOR inhibitors. During her presentation at the NCCN 19th Annual Conference, Dr. Barbara Burtness reviewed the array of skin complications caused by many targeted therapies, focusing on the more common culprits, the role of prophylactic versus reactive management strategies, the need to be attentive to potential infections, the importance of mastering local measures to improve quality of life and cosmetic issues, the therapeutic mainstays (oral and topical antibiotics and topical steroids), and the preference of improving these cutaneous complications over suspending anticancer treatment.	f	\N
24861877	Vitamin D deficiency has been associated with hypertension, diabetes mellitus, and incident stroke. Little is known about the association between vitamin D and subclinical cerebrovascular disease. To examine the relationship of 25-hydroxyvitamin D (25[OH]D) levels with cerebrovascular abnormalities as assessed on brain magnetic resonance imaging (MRI) among participants of the Atherosclerosis Risk in Communities (ARIC) Brain MRI study. Participants were white and black adults aged 55 to 72 years with no history of clinical stroke who underwent a cerebral MRI at ARIC visit 3 (n = 1622) and a second cerebral MRI approximately 10 years later (n = 888). The 25(OH)D level was measured by mass spectrometry at visit 3, with levels adjusted for calendar month and categorized using race-specific quartiles. The cross-sectional and prospective associations of 25(OH)D levels with white matter hyperintensities (WMHs) and MRI-defined infarcts were investigated using multivariable regression models. The mean age of the participants was 62 years, 59.6% were women, and 48.6% were black. Lower 25(OH)D levels were not significantly associated with WMH score of severity, prevalent high-grade WMH score (≥3), or prevalent infarcts in cross-sectional, multivariable-adjusted models (all P > .05). Similarly, no significant prospective associations were found for lower 25(OH)D levels with change in WMH volume, incident high WMH score (≥3), or incident infarcts on the follow-up MRI, which occurred approximately 10 years later. A single measure of 25(OH)D was not cross-sectionally associated with WMH grade or prevalent subclinical infarcts and was not prospectively associated with WMH progression or subclinical brain infarcts seen on serial cerebral MRIs obtained approximately 10 years apart. These findings do not support optimizing vitamin D levels for brain health.	f	\N
24871260	A major symptom of hand-arm vibration syndrome is a secondary Raynaud's phenomenon-vibration white finger (VWF)-which results from a vasospasm of the digital arteries caused by work with vibration devices leading to occupational disease. Pharmacotherapy of VWF is often ineffective or has adverse effects. The aim of this work was to verify the influence of inhalation of partially ionized oxygen (O2•-) on peripheral blood vessels in the hands of patients with VWF. Ninety one (91)patients with VWF underwent four-finger adsorption plethysmography, and the pulse wave amplitude was recorded expressed in numeric parameters-called the native record. Next, a cold water test was conducted following with second plethysmography. The patients were divided in to the three groups. First and second inhaled 20-min of ionized oxygen O2•- or oxygen O2 respectively. Thirth group was control without treatment. All three groups a follow-up third plethysmography-the post-therapy record. Changes in the pulse wave amplitudes were evaluated. Inpatients group inhaling O2•- a modest increase of pulse wave amplitude was observed compared to the native record; patients inhaling medical oxygen O2 and the control showed a undesirable decline of pulse wave amplitude in VWF fingers. Strong vasodilatation were more frequent in the group inhaling O2•- compare to O2 (p < 0.05). Peripheral vasodilatation achieved by inhalation of O2•- could be used for VWF treatment without undesirable side effect in hospital as well as at home environment.	f	\N
24872268	Excessive postoperative hemorrhage in cardiac surgery is a serious complication associated with adverse postoperative events. Also, its associated risk of re-exploration, places a high demand on hospital resources in terms of transfusion needs, ventilatory support requirements, intensive care support, and manpower requirements. To determine predictors of 24-hour drain volume (pleural and mediastinal) after coronary artery bypass graft (CABG), in order to focus on preventive measures for patients with identified risk factors. Fifty-four consecutive adult patients who had CABG at the Madras Medical Mission, Chennai, India in July 2008 were retrospectively studied. In order to determine risk factors for excessive post-operative bleeding, 11 pre-operative, and 13 operative and 2 post-operative variables were analyzed using univariate analysis and multiple linear regression. Cardiopulmonary bypass was used for all the patients and anti-fibrinolytic in 13 (22.8%). No mortality was recorded. Mean 24-hour post-operative drain volume was 458 ± 270 ml (range 90-1230). Re-exploration for bleeding was required in 2 (3.5%) patients. Predictors of 24-hour drain volume were heparin therapy before commencement of CPB (p=0.024), intra-operative transfusion of fresh frozen plasma (p=0.010), and pre-operative serum ALT value (p=0.047). The strongest predictor was intra-operative transfusion of platelets (p=0.005). To guard against excessive post-operative haemorrhage after CABG, pre-operative stabilisation and correction of coagulation should be achieved. Also the administration of heparin intra-operatively should be individualized and not only based on dose per body weight.	f	\N
24875660	Peritoneal dialysis (PD) continues to be underutilized in the United States, even though it is less expensive, provides better quality of life and has better outcomes compared with hemodialysis. The reasons for low utilization of PD are influenced by complex psychosocial and economic factors, lack of physician training, physician bias and inadequate pre-end-stage renal disease care and education to the patients. Providing quality pre-end-stage renal disease education to patients and families and improving education and training of physician in PD, so that they become comfortable with the therapy, are of paramount importance to increase PD growth. Minimizing episodes of PD-related infections and noninfectious complications, preserving peritoneal membrane using more biocompatible solutions and drugs, such as angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, and careful management of volume status can reduce the loss of PD patients to hemodialysis. Timely surgical interventions can prevent the malfunction and loss of PD catheters. Consolidating smaller PD facilities in a given geographical area into a single large PD center can further improve PD outcomes and PD growth. Finally, with the introduction of bundled payment for dialysis services, PD may emerge as a cost-effective therapy and rekindle interest in the dialysis community to consider PD as a better renal replacement therapy option.	f	\N
24877851	This was a systematic review of the literature to determine which compression method is superior in promoting ulcer healing and reducing recurrence in patients with lower extremity venous ulcer disease. We conducted a comprehensive search of multiple databases for randomized and nonrandomized comparative studies from 1990 to December 2013. We identified 36 studies and two Cochrane systematic reviews. Many studies had moderate risk of bias. We found no overall difference between compression stockings vs compression bandages with respect to ulcer healing, time to ulcer healing, or ulcer recurrence outcomes. When we compared stockings vs short stretch bandages, stockings were superior with respect to ulcer healing. However, stockings compared with four-layer systems showed no difference in ulcer healing outcomes. When four-layer systems were compared with compression with less than four layers, there was also no significant difference in ulcer healing outcomes. Similarly, short stretch bandages were not superior to long stretch bandages with respect to ulcer healing, time to ulcer healing, or ulcer recurrence. One Cochrane review presented many additional comparisons and reported increased wound healing with compression compared with no compression, with multicomponent systems over single component systems, and compression systems with an elastic component over no elastic component. Another Cochrane review demonstrated a reduction in recurrence with compression in patients with healed ulcers. At least moderate-quality evidence supports compression over no compression, multicomponent systems over single component systems, and systems with an elastic component over those without. We did not find significant differences with respect to ulcer healing outcomes for other comparisons. Low-quality evidence supports the effect of compression on ulcer recurrence.	f	\N
24878150	To explore barriers and facilitators to implementing and sustaining Healthy Choices, a 3-year multicomponent obesity prevention intervention implemented in middle schools in Massachusetts. Using purposive sampling, 56 in-depth interviews were conducted with middle school employees representing different positions (administrators, teachers, food service personnel, and employees serving as intervention coordinators). Interviews were recorded and transcribed. Emergent themes were identified using thematic analyses. State-mandated testing, budget limitations, and time constraints were viewed as implementation barriers, whereas staff buy-in, external support, and technical assistance were seen as facilitating implementation. Respondents thought that intervention sustainability depended on external funding and expert assistance. Results confirm the importance of gaining faculty and staff support. Schools implementing large-scale interventions should consider developing sustainable partnerships with organizations that can provide resources and ongoing training. Sustainability of complex interventions may depend on state-level strategies that provide resources for implementation and technical assistance.	f	\N
24882305	Loeys-Dietz syndrome (LDS) is a recently recognized connective tissue disorder caused by mutations of the transforming growth factor (TGF)-β receptors. It is an autosomal dominant syndrome characterized by the triad of arterial tortuosity and aneurysms, hypertelorism, and bifid uvula or cleft palate. We treated an 18-year-old woman with a 100-mm-diameter aortic root aneurysm and severe aortic valve regurgitation. She underwent urgent aortic root replacement and bioprosthetic valve implantation. LDS was diagnosed by postoperative genetic screening results. Histopathologic examination of the aortic wall showed diffuse degeneration and elastin fragmentation in the media.	f	\N
24895051	Haploidentical stem cell transplantation (haploSCT) offers an alternative treatment option for advanced leukemia patients lacking a HLA-compatible donor. Transfer of NK cells represents a promising therapeutic option in combination with SCT, as NK cells can promote graft versus leukemia with low risk of GVH disease. In this study, we show results from a phase I/II trial in which 24 acute myeloid leukemia patients underwent haploSCT in combination with early transfer of unmodified NK cells and observed a promising 2-year overall survival rate of 37%. By performing immunomonitoring and subsequent principal component analysis, we tracked donor NK-cell dynamics in the patients and distinguished between NK cells reconstituting from CD34(+) precursors, giving rise over time to a continuum of multiple differentiation stages, and adoptively transferred NK cells. Transferred NK cells displayed a mature phenotype and proliferated in vivo during the early days after haploSCT even in the absence of exogenous IL-2 administration. Moreover, we identified the NK-cell phenotype associated with in vivo expansion. Thus, our study indicates a promising path for adoptive transfer of unmodified NK cells in the treatment of high-risk acute myeloid leukemia.	f	\N
24896322	The design of antioxidant pharmaceuticals is a major challenge for the treatment of many clinical conditions and in aging. Free radical damage (FRD) is primarily catalysed by iron catalytic centers. Most of the natural and synthetic antioxidants are ineffective in inhibiting FRD because of the achievement of low concentrations at the affected tissues. Despite that many chelators inhibit FRD in vitro and in vivo, only Deferiprone (L1) has been shown to be effective and safe in the reversal of oxidative stress related tissue damage in iron overload and other conditions such as cardiomyopathy, acute kidney disease, Friedreich ataxia etc. Deferiprone, other chelators and their combinations could be used as main, adjuvant and alternative therapies in untreated conditions eg forms of cancer, Alzheimer's and Parkinson's diseases. Therapeutic targeting in each case requires specific chelator selection based on structure/activity correlation and consideration of other parameters eg ADMET. The ability of L1 to reach extracellular and intracellular compartments of almost all tissues including the brain is a major advantage for further development and use in many clinical conditions.	f	\N
24896980	Abnormally aggregated tau is the hallmark pathology of tauopathy neurodegenerative disorders and is a target for development of both diagnostic tools and therapeutic strategies across the tauopathy disease spectrum. Development of carbon-11- or fluorine-18-labeled radiotracers with appropriate affinity and specificity for tau would allow noninvasive quantification of tau burden using positron emission tomography (PET) imaging. We have synthesized [(18)F]lansoprazole, [(11)C]N-methyl lansoprazole, and [(18)F]N-methyl lansoprazole and identified them as high affinity radiotracers for tau with low to subnanomolar binding affinities. Herein, we report radiosyntheses and extensive preclinical evaluation with the aim of selecting a lead radiotracer for translation into human PET imaging trials. We demonstrate that [(18)F]N-methyl lansoprazole, on account of the favorable half-life of fluorine-18 and its rapid brain entry in nonhuman primates, favorable kinetics, low white matter binding, and selectivity for binding to tau over amyloid, is the lead compound for progression into clinical trials.	f	\N
24902046	Infection, graft-versus-host disease (GVHD), and to a lesser extent sinusoidal obstructive syndrome (SOS) represent the major causes of morbidity and mortality in patients undergoing allogeneic hematopoietic stem cell transplantation (AHSCT). During the last decade, progress in prevention and treatment of these complications led to improvement in the outcome of these patients. Despite the fact that nonmyeloablative regimens have been increasingly used in elderly patients and in patients with co-morbidities, the nonrelapse related mortality remains a challenge and long-term follow-up is required. The objective of this manuscript is to provide an updated concise review of the complications of AHSCT and of the available treatment interventions.	f	\N
24910429	Acute myeloid leukemia (AML) therapy involves compounds that are cytotoxic to both normal and cancer cells, and relapsed AML is resistant to subsequent chemotherapy. Thus, agents are needed that selectively kill AML cells with minimal toxicity. Here, we report that AML is dependent on DDX5 and that inhibiting DDX5 expression slows AML cell proliferation in vitro and AML progression in vivo but is not toxic to cells from normal bone marrow. Inhibition of DDX5 expression in AML cells induces apoptosis via induction of reactive oxygen species (ROS). This apoptotic response can be blocked either by BCL2 overexpression or treatment with the ROS scavenger N-acetyl-L-cysteine. Combining DDX5 knockdown with a BCL2 family inhibitor cooperates to induce cell death in AML cells. By inhibiting DDX5 expression in vivo, we show that DDX5 is dispensable for normal hematopoiesis and tissue homeostasis. These results validate DDX5 as a potential target for blocking AML.	f	\N
24924164	Drug resistance mutations (DRMs) can serve as distinct, nonpolymorphic markers for evaluating diversity of expressed HIV-1. We screened for DRMs during early-acute viremia and examined the diversity in reverse transcriptase (RT) relative to envelope (env) in cases of transmitted drug resistance. We evaluated 111 longitudinal plasma samples collected every 2-7 days from 15 individuals who seroconverted for HIV-1 infection in 1994-2000. The samples were screened with sensitive polymerase chain reaction assays for the commonly transmitted M41L and K70R mutations and for K65R, which was undetected by bulk sequencing. Mutation-positive samples were further characterized by clonal sequencing of RT and env V1-V3. Drug resistance mutations were detected in 4 of 15 seroconverters at 5-50 days of viral nucleic acid expression; most mutations disappeared about the time of seroconversion. Clonal sequencing verified low-level K65R at frequencies of 0.4%-4.9%. In each case, K65R coexisted unlinked with variants carrying 2-5 thymidine analog mutations at frequencies of 1.6%-23.0%. In one seroconverter, variants with M184V and nonnucleoside RT inhibitor mutations were also identified at first RNA expression. Each seroconverter displayed a homogeneous V1-V3 env population. Reverse-transcriptase DRMs demonstrate that the breadth of variants in transmission may be greater than what is reflected in envelope sequences.	f	\N
24935472	In the context of cancer, transforming growth factor β (TGF-β) is a cell growth suppressor; however, it is also a critical inducer of invasion and metastasis. SMAD is the important mediator of TGF-β signaling pathway, which includes receptor-regulated SMADs (R-SMADs), common-mediator SMADs (co-SMADs), and inhibitory SMADs (I-SMADs). I-SMADs block the activation of R-SMADs and co-SMADs and thus play important roles especially in the SMAD-dependent signaling. SMAD7 belongs to the I-SMADs. As an inhibitor of TGF-β signaling, SMAD7 is overexpressed in numerous cancer types and its abundance is positively correlated to the malignancy. Emerging evidence has revealed the switch-in-role of SMAD7 in cancer, from a TGF-β inhibiting protein at the early stages that facilitates proliferation to an enhancer of invasion at the late stages. This role change may be accompanied or elicited by the tumor microenvironment and/or somatic mutation. Hence, current knowledge suggests a tumor-favorable timer nature of SMAD7 in cancer progression. In this review, we summarized the advances and recent findings of SMAD7 and TGF-β signaling in cancer, followed by specific discussion on the possible factors that account for the functional changes of SMAD7.	f	\N
24940479	Although the pathophysiology of facioscapulohumeral dystrophy (FSHD) has been controversial over the last decades, progress in recent years has led to a model that incorporates these decades of findings and is gaining general acceptance in the FSHD research community. Here we review how the contributions from many labs over many years led to an understanding of a fundamentally new mechanism of human disease. FSHD is caused by inefficient repeat-mediated epigenetic repression of the D4Z4 macrosatellite repeat array on chromosome 4, resulting in the variegated expression of the DUX4 retrogene, encoding a double-homeobox transcription factor, in skeletal muscle. Normally expressed in the testis and epigenetically repressed in somatic tissues, DUX4 expression in skeletal muscle induces expression of many germline, stem cell, and other genes that might account for the pathophysiology of FSHD. Although some disagreements regarding the details of mechanisms remain in the field, the coalescing agreement on a central model of pathophysiology represents a pivot-point in FSHD research, transitioning the field from discovery-oriented studies to translational studies aimed at developing therapies based on a sound model of disease pathophysiology.	f	\N
24944260	To determine whether droxidopa, an oral norepinephrine precursor, improves symptomatic neurogenic orthostatic hypotension (nOH). Patients with symptomatic nOH due to Parkinson disease, multiple system atrophy, pure autonomic failure, or nondiabetic autonomic neuropathy underwent open-label droxidopa dose optimization (100-600 mg 3 times daily), followed, in responders, by 7-day washout and then a 7-day double-blind trial of droxidopa vs placebo. Outcome measures included patient self-ratings on the Orthostatic Hypotension Questionnaire (OHQ), a validated, nOH-specific tool that assesses symptom severity and symptom impact on daily activities. From randomization to endpoint (n = 162), improvement in mean OHQ composite score favored droxidopa over placebo by 0.90 units (p = 0.003). Improvement in OHQ symptom subscore favored droxidopa by 0.73 units (p = 0.010), with maximum change in "dizziness/lightheadedness." Improvement in symptom-impact subscore favored droxidopa by 1.06 units (p = 0.003), with maximum change for "standing a long time." Mean standing systolic blood pressure (BP) increased by 11.2 vs 3.9 mm Hg (p < 0.001), and mean supine systolic BP by 7.6 vs 0.8 mm Hg (p < 0.001). At endpoint, supine systolic BP >180 mm Hg was observed in 4.9% of droxidopa and 2.5% of placebo recipients. Adverse events reported in ≥ 3% of double-blind droxidopa recipients were headache (7.4%) and dizziness (3.7%). No patients discontinued double-blind treatment because of adverse events. In patients with symptomatic nOH, droxidopa improved symptoms and symptom impact on daily activities, with an associated increase in standing systolic BP, and was generally well tolerated. This study provides Class I evidence that in patients with symptomatic nOH who respond to open-label droxidopa, droxidopa improves subjective and objective manifestation of nOH at 7 days.	f	\N
24948193	Acute inflammation is the result of a complex signal transduction pathway that protects and heals our body and is necessary for our good health and normal wellbeing. Whereas, chronic inflammation can be correlated well with the onset of a plethora of autoimmune disorders; rheumatoid arthritis, systemic lupus and polymyalgia, rheumatic and other diseases like asthma, inflammatory bowel diseases, cardiovascular disorders, ulcerative colitis and Crohn's disease. Also, it has been reported to be associated with the onset of various cancers. An effective anti-inflammatory drug should be able to inhibit the development of chronic inflammation without interfering in normal homeostasis. A number of herbal drugs have been identified in the past that can target inflammatory cytokines. Among these, Ganoderma lucidum: a powerful medicinal mushroom has been found to possess immune-modulating and immune-potentiating capabilities and has been characterized as a wonder herb. This review mainly focuses on the molecular mechanism of anti-inflammatory and antiallergic action of this mushroom and also sheds light on various patent studies related to its pharmacological action.	f	\N
24952923	Extraosseous Gaucher cell deposits are a rare complication of Gaucher disease that can mimic malignancy. We describe a case of Gaucher cell deposition in the subcutaneous soft tissues overlying the lower thoracic spine in an 18-year-old woman with known type III Gaucher disease. This case is unique in the literature because this subcutaneous Gaucher mass was not associated with extension from underlying bone involvement or clear lymph node origin. It demonstrated no discernible continuity with the adjacent thoracic spinous processes, the cortices of which appeared intact. Although patients with Gaucher disease are at increased risk of malignancy, Gaucher cell deposition should remain a differential consideration for soft tissue masses with or without adjacent bone involvement in patients with known Gaucher disease.	f	\N
24953225	The association between the C3435T polymorphism in the MDR1 gene and refractory epilepsy remains controversial. The association appears to be influenced by ethnicity and region. We have performed a systematic review and meta-analysis to assess the link between the MDR1 C3435T polymorphism and refractory epilepsy in the Chinese population. We searched the Cochrane Library, MIDLINE, EMBASE, CBM disc, CNKI, VIP, and WANFANG databases for literature published through August 2013 for case-control studies that evaluated the association between the MDR1 C3435T polymorphism and refractory epilepsy. Twenty-one case-control studies involving 4269 patients (1863 cases in the group with drug-resistant epilepsy and 2406 in the group with drug-responsive epilepsy) were included in the systematic review and meta-analysis. The analysis showed that there were significantly more cases with the MDR1 3435 CC genotype in the group with drug-resistant epilepsy than in the group with drug-responsive epilepsy [odds ratio (OR)=1.50, 95% confidence interval (CI)=1.09-2.06, P=0.01]. In a subanalysis of patients from the southern regions of China, the correlation was not significant [odds ratio (OR)=1.2, 95% confidence interval (CI)=0.89-1.64, P=0.24]. The relationship established in a subset of the Chinese population between the MDR1 C3435T polymorphism and refractory epilepsy will guide epilepsy treatment and development of new AEDs.	f	\N
24955837	Pulmonary arterial hypertension (PAH) is a life-threatening disorder that is associated with elevated pulmonary pressures and right heart failure resulting from progressive loss and thickening of small pulmonary arteries. Despite their ability to improve symptoms, current therapies fail to prevent disease progression, leaving lung transplantation as the only therapy in end-stage PAH. To overcome the limitations of current therapies, there is an active search for disease-modifying agents capable of altering the natural history of, and improving clinical outcomes in, PAH. The Wnt signaling pathways have emerged as attractive treatment targets in PAH given their role in the preservation of pulmonary vascular homeostasis and the recent development of Wnt-specific compounds and biological therapies capable of modulating pathway activity. In this review, we summarize the literature describing the role of Wnt signaling in the pulmonary circulation and discuss promising advances in the field of Wnt therapeutics that could lead to novel clinical therapies capable of preventing and/or reversing pulmonary vascular pathology in patients with this devastating disease.	f	\N
24962034	The HIV Modes of Transmission (MOT) model estimates the annual fraction of new HIV infections (FNI) acquired by different risk groups. It was designed to guide country-specific HIV prevention policies. To determine if the MOT produced context-specific recommendations, we analyzed MOT results by region and epidemic type, and explored the factors (e.g. data used to estimate parameter inputs, adherence to guidelines) influencing the differences. We systematically searched MEDLINE, EMBASE and UNAIDS reports, and contacted UNAIDS country directors for published MOT results from MOT inception (2003) to 25 September 2012. We retrieved four journal articles and 20 UNAIDS reports covering 29 countries. In 13 countries, the largest FNI (range 26 to 63%) was acquired by the low-risk group and increased with low-risk population size. The FNI among female sex workers (FSWs) remained low (median 1.3%, range 0.04 to 14.4%), with little variability by region and epidemic type despite variability in sexual behaviour. In India and Thailand, where FSWs play an important role in transmission, the FNI among FSWs was 2 and 4%, respectively. In contrast, the FNI among men who have sex with men (MSM) varied across regions (range 0.1 to 89%) and increased with MSM population size. The FNI among people who inject drugs (PWID, range 0 to 82%) was largest in early-phase epidemics with low overall HIV prevalence. Most MOT studies were conducted and reported as per guidelines but data quality remains an issue. Although countries are generally performing the MOT as per guidelines, there is little variation in the FNI (except among MSM and PWID) by region and epidemic type. Homogeneity in MOT FNI for FSWs, clients and low-risk groups may limit the utility of MOT for guiding country-specific interventions in heterosexual HIV epidemics.	f	\N
24965397	Several studies indicated that the expression level of MLL3 gene in gastric cancer tissue was associated with prognosis, and previous studies also suggested that genetic polymorphisms of MLL3 were related to the risk for gastric cancer. The present study aimed to investigate the association of a missense mutation (S3660L) in the MLL3 gene with gastric cancer risk in a Chinese population. In the present study, we identified a novel missense mutation in MLL3 gene (S3660L) by directly sequencing method in 48 gastric cancer patients. To further explore the relation between gastric cancer and this mutation, we selected 354 gastric cancer patients and 377 healthy control subjects and designed a case-control study. We found that the AG genotype (14.9 vs 6.40%, odds ratio/OR=2.58, 95% CI: 1.33-4.54, p<0.001) and A allele (7.5 vs 3.2%, OR=2.46, 95% CI: 1.55~5.34, p<0.001) were common in the gastric cancer patients than in the control subjects. We concluded that this novel missense (S3660L) mutation in MLL3 gene is likely to increase the gastric cancer risk.	f	\N
24970372	During the 2009 A(H1N1) influenza pandemic, a suite of studies conducted in Canada showed an unexpected finding, that patients with medically attended laboratory-confirmed pandemic influenza were more likely to have received seasonal influenza vaccination than test-negative control patients. Different bodies, including scientific journals and government scientific advisory committees, reviewed the evidence simultaneously to determine its scientific validity and implications. Decision-making was complicated when the findings made their way into the media. The normal trajectory of non-urgent research includes peer-review publication after which decision-makers can process the information taking into account other evidence and logistic considerations. In the situation that arose, however, the congruence of an unexpected finding and the simultaneous review of the evidence both within and outside the traditional peer-review sphere raised several interesting issues about how to deal with emerging evidence during a public health emergency. These events are used in this article to aid discussion of the complex interrelationship between researchers, public health decision-makers and scientific journals, the trade-offs between sharing information early and maintaining the peer-review quality assurance process, and to emphasise the need for critical reflection on the practical and ethical norms that govern the way in which research is evaluated, published and communicated in public health emergencies.	f	\N
24973485	This study explored the care challenges experienced by older patients with multimorbidity, their informal caregivers and family physicians. Semi-structured interviews were conducted with 27 patients, their informal caregivers and family physicians. Qualitative description was used to identify key themes in the interview transcripts. Participants experienced many common challenges when managing multimorbidity, including a lack of decision-making support, poor communication and uncoordinated health services. Within these themes, unique perspectives specific to the role of being a patient, caregiver or family physician emerged. The study adds to a limited evidence base on the experience of patients with multimorbidity. By including the perspectives of their family caregivers and physicians, we provide important insight into the management of multimorbidity and recommend the uptake of specific strategies to address them.	f	\N
24986275	Cyclical outbreaks of mumps have been noticed across Chandigarh city during winter months. Chandigarh does not provide measles, mumps and rubella (MMR) vaccination in the State immunization schedule. Epidemiological shift in age at diagnosis of mumps was noticed with higher incidence in older children and adults. Increased occurrence of complications can be predicted with this age shift. Silent burden of rubella with serious outcomes in newborns further strengthen the case for MMR vaccine inclusion in routine immunization program of Chandigarh.	f	\N
24988612	Autophagy, the process of degradation of unwanted or damaged cell elements, is extremely important for a variety of human diseases, especially cancers. This process influences various stages of initiation and progression of cancer, which is caused by overlapping signaling pathways of autophagy and carcinogenesis. However, due to the complexity of cancer as a systemic disease, the fate of tumor cells is not determined by one signal pathway. Chronic autophagy inhibition leads to tumor promotion, due to instability of the genome, defective cell growth, also as a result of cellular stress. However, increased induction of autophagy may be a mechanism for tumor cell survival in the state of hypoxia, acidosis, as well as under the influence of chemotherapy. Therefore, in the context of cancer development, the process of autophagy should be considered in two directions. Determination of the molecular mechanisms underlying the process of autophagy and its role in the carcinogenesis is a key element of the anticancer strategy. The main objective of modern oncology, which should eventually lead to personalized therapy, is the possibility to predict the response of a particular type of cancer to the used drug. Results of in vitro and in vivo studies show the magnitude of the relationship between changes in the genome, and response to the therapy. This information indicates the mechanism and thereby the target point of the drugs. In this review we focus on the mechanism of autophagy and its role in cancer therapy, which can help to understand the autophagy-cancer relationship and indicate the direction for the design of new drugs with anticancer activity.	f	\N
24989056	Flow volume loops (FVLs) are considered part of the workup of patients with thyroid enlargement presenting to the endocrinology clinic. They are used to detect upper airway obstruction (UAO) secondary to tracheal compression (TC) from a goitre. Surgical assessment in contrast tends to focus on clinical evaluation supplemented when required by imaging. The aim of this study was to investigate whether FVLs influence the decision to operate in patients with a goitre. We identified patients with a goitre referred by the department of endocrinology for FVLs between 2006 and 2011. The results of the FVL were collated, and their impact on patient management was assessed. Ninety-six patients were referred for FVL. In 38 patients, the indication was specifically to evaluate the effects of a goitre. Of these, 33 were reported as normal. Five FVLs were reported as abnormal (3 suggesting lung pathology and 2 TC). Both patients with TC on FVL presented no CT evidence of TC and underwent surgery due to abnormal cytology. Of the 33 normal FVLs, 7 underwent surgery: 2 for local compression, 4 for abnormal cytology and 1 for Graves' disease. None of the FVLs influenced the decision to operate. FVLs may detect subradiological TC, but rarely influence management in patients with a goitre. In view of this and the cost of £235 per investigation, FVL should be reserved for goitre patients with suspected primary lung pathology, where the distinction between large and small airway compression is likely to influence management.	f	\N
24994677	Uveal melanoma (UM) is the most common primary tumor of the eye in adults. There is no standard adjuvant treatment to prevent metastasis and no effective therapy in the metastatic setting. We have established a unique panel of 7 UM cell lines from either patient's tumors or patient-derived tumor xenografts (PDXs). This panel recapitulates the molecular landscape of the disease in terms of genetic alterations and mutations. All the cell lines display GNAQ or GNA11 activating mutations, and importantly four of them display BAP1 (BRCA1 associated protein-1) deficiency, a hallmark of aggressive disease. The mTOR pathway was shown to be activated in most of the cell lines independent of AKT signaling. mTOR inhibitor Everolimus reduced the viability of UM cell lines and significantly delayed tumor growth in 4 PDXs. Our data suggest that mTOR inhibition with Everolimus, possibly in combination with other agents, may be considered as a therapeutic option for the management of uveal melanoma.	f	\N
25003989	Understanding how the immune system facilitates or controls HIV-1 disease progression has important implications for the design of effective interventions. We report that although B-cell dysregulations associated with HIV-1 disease progression are accompanied by an overall decrease in the percentage of total blood B-cells, we observe an increase in relative frequencies of cells presenting characteristics of both transitional immature and first-line marginal zone (MZ) B-cell populations, we designated as precursor MZ-like B-cells. B-cells with similar attributes have been associated with IL-10 expression and "regulatory" potential. As such, the relative frequencies of precursor MZ-like B-cells expressing IL-10 are increased in the blood of viremic HIV-1-infected individuals when compared to HIV-negative subjects. Importantly, in aviremic HIV-1 Elite-Controllers (EC), we found unaltered relative percentages of precursor MZ-like B-cells which presented normal IL-10 expression patterns. Furthermore, EC had increased relative frequencies of blood MZ-like B-cells expressing LT-α. Thus in contrast to viremic HIV-1-infected individuals, EC present MZ-like B-cell populations which IL-10 and LT-α expression profiles may favour homeostasis of immune responses and lymphoid microenvironments.	f	\N
25011952	We recently demonstrated a beneficial effect of metformin compared with glipizide in type 2 diabetic patients regarding cardiovascular outcomes for 3-year treatment in the SPREAD-DIMCAD study. However, the potential mechanism for the clinical effects remains unclear. Here, we performed a comprehensive lipidomics study to evaluate the different lipid metabolites in serum samples obtained from participants in this study. Liquid chromatography-quadrupole time of flight-mass spectrometry was used to evaluate the different lipid metabolites in serum samples obtained from the participants (21 patients in glipizide group and 23 patients in metformin group) before and after each year of treatment (at 0 [baseline], 1, 2, and 3 years of study drug administration). A total of 118 serum lipid molecular species was identified and quantified. During treatment, metformin induced a substantially greater change in serum lipid species compared with glipizide, especially at the 2- and 3-year time points (with 2, 11, and 12 lipid species being significantly different between the groups after each year of treatment [1, 2, or 3 years], P < 0.05). Among the significantly changed lipid species, three lipid metabolites were linked to long-term composite cardiovascular events (adjusted P < 0.05). After treatment, triacylglycerols (TAGs) of a relatively higher carbon number showed a clearly increased trend in metformin group compared with the glipizide group, whereas the changes in TAGs with different double bonds were minimal. Our findings revealed the differential therapeutic effects of metformin and glipizide on comprehensive lipidomics, which were comparable with their different long-term effects on cardiovascular outcomes.	f	\N
25014130	To conduct the first population size estimation and biological and behavioral surveillance survey among men who have sex with men (MSM) in Angola. Population size estimation with multiplier method and a cross-sectional study using respondent-driven sampling. Luanda Province, Angola. Study was conducted in a large hospital. Seven hundred ninety-two self-identified MSM accepted a unique object for population size estimation. Three hundred fifty-one MSM were recruited with respondent-driven sampling for biological and behavioral surveillance survey. Interviews and testing for HIV and syphilis were conducted on-site. Analysis used Respondent-Driven Sampling Analysis Tool and STATA 11.0. Univariate, bivariate, and multivariate analyses examined factors associated with HIV and unprotected sex. Six imputation strategies were used for missing data for those refusing to test for HIV. A population size of 6236 MSM was estimated. Twenty-seven of 351 individuals were tested positive. Adjusted HIV prevalence was 3.7% (8.7% crude). With imputation, HIV seroprevalence was estimated between 3.8% [95% confidence interval (CI): 1.6 to 6.5] and 10.5% (95% CI: 5.6 to 15.3). Being older than 25 (odds ratio = 10.8, 95% CI: 3.5 to 32.8) and having suffered episodes of homophobia (odds ratio = 12.7, 95% CI: 3.2 to 49.6) significantly increased the chance of HIV seropositivity. Risk behaviors are widely reported, but HIV seroprevalence is lower than expected. The difference between crude and adjusted values was mostly due to treatment of missing values in Respondent-Driven Sampling Analysis Tool. Solutions are proposed in this article. Although concerns were raised about feasibility and adverse outcomes for MSM, the study was successfully and rapidly completed with no adverse effects.	f	\N
25015744	Endoscopic ultrasound (EUS)-guided drainage is an effective treatment for many abscesses in the abdomen. We review our experience with EUS-guided drainage of pelvic abscesses. Thirty consecutive patients who underwent EUS-guided pelvic abscess drainage were evaluated after excluding three patients with distance to transducer >2 cm or organized abscess. Thirty patients (25 male) aged 60 ± 4.5 years (mean ± SD) had 4 prostatic abscesses, 7 perisigmoid abscesses, and 19 perirectal abscesses with mean ± SD sizes of 2.5 ± 0.3, 4.7 ± 0.6, and 5.4 ± 0.4 cm, respectively. Surgery was the most common predisposing factor (n = 14, 46.6 %) followed by diverticulitis (n = 5, 16.6 %). Interventions included aspiration only (2 prostatic and 3 perisigmoid), aspiration and dilatation (2 patients in each group), and dilatation and stenting (2 perisigmoid and 17 perirectal). Five (16.6 %) patients needed re-intervention, and two (6.6 %) needed surgery. There were no recurrences. Technical success of EUS-guided pelvic abscess drainage overall was 90.9 % (30/33) and was 93.3 % (27/30) in patients in whom EUS-guided drainage was attempted, with 16.5 % (n = 5) re-intervention rate. EUS-guided drainage has an excellent success rate in drainage of pelvic abscesses.	f	\N
25022060	The measurement of antinuclear antibodies (ANA) is used for screening of connective tissue diseases (CTD) in the laboratory. ANA detection is performed by indirect immunofluorescence (IF) assay on HEp-2 cells from human larynx carcinoma. However, it lacks specificity for the identification of specific diseases and antigen reactivity. The aim of the present study was to evaluate the EliA CTD Screen (EliA), a new enzyme fluoroimmunoassay (Phadia AB, Uppsala, Sweden) for detection of ANA in human serum. The study involved a total of 732 serum samples, 200 from healthy donors, 297 from patients with CTD and 235 from patients with rheumatoid arthritis, vasculitis syndrome and relative disease of CTD. For all sera, ANA was measured by IF, commercial assay (MESACUP) and EliA. The sensitivity and specificity of EliA were 73.7% and 78.7%, respectively, whereas those of MESACUP were 80.8% and 64.7%, respectively. Area under the receiver operating curves for EliA, MESACUP and IF were 0.821, 0.786 and 0.730, respectively. The concordance rate between EliA and MESACUP was 84.2%. These discrepancies between those 2 assays were found in 84 sera. Further investigation were done by each ANA antigen tests for the discrepant results of EliA in 83 sera. The discrepancies might be occurred by antigen difference or non-specific response. AUC results showed that the diagnostic performance of EliA was superior to MESACUP and IF. EliA had a good performance as method for screening of CTD.	f	\N
25027632	This longitudinal, exploratory study was designed to better understand the lived experience of spousal caregivers age 60 and older providing care to partners with Alzheimer's disease and related dementias resident in a care facility. Twenty eight spousal caregivers were interviewed up to three times over a period of 2 years, and long-term care facility staff from four locations across British Columbia (BC), Canada participated in four focus groups. Thematic analysis of interview and focus group transcripts revealed a central, unifying theme 'together but apart'. The results identify key targets for policy makers and service providers to support positive health and well-being outcomes for spousal caregivers providing care to their partners diagnosed with Alzheimer's disease and related dementia and living in care facilities.	f	\N
25034390	Patients with multiple myeloma (MM) manifesting acute kidney injury (AKI) and who later recover renal function and independence from renal replacement therapy (RRT) are considered to have a better outcome. The aim of this work was to study the factors associated with renal function recovery (independence of hemodialysis) and longer survival in these patients. A retrospective single center study including patients with a diagnosis of MM and severe AKI, defined as stage 3 of the Kidney Disease: Improving Global Outcomes (KDIGO) criteria: 3.0 times baseline increase in serum creatinine (sCr) or increase in sCr to ≥4.0mg/dL or initiation of RRT, was conducted. Data was registry-based and collected between January 2000 and December 2011. We examined demographic and laboratorial data, presenting clinical features, precipitating factors, need for RRT and chemotherapy. Death was considered the primary endpoint. Lower serum β2-microglobulin was the only independent factor associated with recovery of renal function and independence of RRT (OR 0.95, 95% CI: 0.91-0.99, P=0.02). The median survival after AKI was 10.7±12.1months. The factors associated with longer survival were independence of RRT (HR 2.21; 95% CI: 1.08-4.49; P=0.02), lower CRP (HR 1.07; 95% CI: 1.03-1.12; P=0.001) and younger age (HR 1.03; 95% CI: 1.01-1.06; P=0.005). Our study suggests that MM patients with lower serum β2-microglobulin have a higher likelihood of recovering renal function after severe AKI. Independence of RRT, lower CRP and younger age are associated with longer survival.	f	\N
25038555	The rapidly increasing availability of electronic health records (EHRs) from multiple heterogeneous sources has spearheaded the adoption of data-driven approaches for improved clinical research, decision making, prognosis, and patient management. Unfortunately, EHR data do not always directly and reliably map to medical concepts that clinical researchers need or use. Some recent studies have focused on EHR-derived phenotyping, which aims at mapping the EHR data to specific medical concepts; however, most of these approaches require labor intensive supervision from experienced clinical professionals. Furthermore, existing approaches are often disease-centric and specialized to the idiosyncrasies of the information technology and/or business practices of a single healthcare organization. In this paper, we propose Limestone, a nonnegative tensor factorization method to derive phenotype candidates with virtually no human supervision. Limestone represents the data source interactions naturally using tensors (a generalization of matrices). In particular, we investigate the interaction of diagnoses and medications among patients. The resulting tensor factors are reported as phenotype candidates that automatically reveal patient clusters on specific diagnoses and medications. Using the proposed method, multiple phenotypes can be identified simultaneously from data. We demonstrate the capability of Limestone on a cohort of 31,815 patient records from the Geisinger Health System. The dataset spans 7years of longitudinal patient records and was initially constructed for a heart failure onset prediction study. Our experiments demonstrate the robustness, stability, and the conciseness of Limestone-derived phenotypes. Our results show that using only 40 phenotypes, we can outperform the original 640 features (169 diagnosis categories and 471 medication types) to achieve an area under the receiver operator characteristic curve (AUC) of 0.720 (95% CI 0.715 to 0.725). Moreover, in consultation with a medical expert, we confirmed 82% of the top 50 candidates automatically extracted by Limestone are clinically meaningful.	f	\N
25044634	The potential benefit of vitamin K as a therapeutic in osteoporosis is controversial and the vitamin K regimen being used clinically (45 mg/day) employs doses that are many times higher than required to ensure maximal gamma-carboxylation of the vitamin K-dependent bone proteins. We therefore tested the hypothesis that vitamin K catabolites, 5-carbon (CAN5C) and 7-carbon carboxylic acid (CAN7C) aliphatic side-chain derivatives of the naphthoquinone moiety exert an osteotrophic role consistent with the treatment of osteoporosis. Osteoblast-like MG63 cell cultures were challenged with lipopolysaccharide and the levels of interleukin-6, an osteoclastogenic cytokine, measured with and without catabolites; low concentrations of CAN7C significantly inhibited interleukin-6 release, but CAN5C did not. In models of bone loss induced by ovariectomy or sciatic neurectomy in C57BL/6 mice, we found that the rarer CAN7C catabolite markedly restricted ovariectomy-induced bone loss and possibly limited sciatic neurectomy-induced bone loss. CAN7C activity depends on a free carboxylic acid and its particular side-chain structure. These in vivo data indicate for the first time that the clinical utility of vitamin K for osteoporosis may reside in an unusual catabolite.	f	\N
25046696	Cystic and alveolar hydatid disease of humans caused by infection with Echinococcus granulosus or Echinococcus multilocularis are significant zoonoses in developing countries. For human infections, the main definitive host is the dog, and reduction in the population of unwanted dogs, together with anthelmintic treatment of wanted dogs, are recommended control procedures for these zoonoses. Both owned and unowned dogs have been shown to be a major source of Echinococcus spp. infection in developing countries. Unowned dogs are the most challenging category in dog population management for the control of major zoonotic diseases. Unowned dogs are those dogs that do not have an owner, and those dogs whose owner cannot readily be identified. Control of numbers of unowned dogs can be done in various ways if funds are available. Fertility control and humane euthanasia are likely to be the most effective procedures in developing countries. Fertility control requires significant funding, and where resources are scarce humane euthanasia may be the most effective option. Both procedures are ongoing events, with no predictable end point. This paper examines the sociology and technology for the population management of owned and unowned dogs, specifically for the reduction of human hydatid disease. Examples are given for developing and developed countries. Although a "One Health" approach is desirable, the technology for hydatid control is different from that for rabies, and FAO Animal Welfare recommendations for dog population management should be adjusted accordingly.	f	\N
25051669	The paper presents data on the frequency of polymorphisms of candidate genes involved in the formation of endothelial dysfunction--endothelin-1 (EDN1 Lys198Asn) and endothelial nitric oxide synthase (NOS3 T786C) together with the concentrations of their active products (nitric oxide, endothelin-1) in individuals with chronic mercury intoxication. The concentration change of nitric oxide and endothelin-1 indicates the presence of endothelial dysfunction in the individuals examined. The studied polymorphisms appeared to play a minor role in the pathogenesis of endothelial dysfunction in patients with chronic mercury intoxication.	f	\N
25055486	Postoperative intracranial infectious complications are one of the most topical problems of neurosurgical intensive care due to theirs significant capability to impair outcomes of the main disease. To define the risk factors of postoperative meningitis in patients with chiasm-sellar tumors. 1. to define the effect of somatic and intracranial risk factors on occurrence of postoperative meningitis in patients after transsphenoidal and transcranial approaches to the tumor. 2. To define the effect of postoperative meningitis on outcomes of treatment in patients after transsphenoidal and transcranial approaches to the tumor. Somatic and intracranial risk factors of occurrence of postoperative meningitis (pneumonia, urinary tract infection, sepsis, intra-abdominal hypertension, the presence of external ventricular and lumbar drainage, monitoring of intracranial pressure, cerebrospinal fluid, and reoperation) were fixed every day. The study was conducted in the ICU of the Burdenko from October, 2010 to July, 2012. The 34 patients (19 males, 15 females) were included in the study (average age 47.5 years). The patients were divided into two groups; 17 patients each group. The group-1 included patients after transcranial approach to the tumor and the group-2 included patients after transsphenoidal approach. In the group-1 a meningitis occurred in 3 patients (17.6% +/- 9.2%, DI [-0.4 - 35.6]). In the group-2 a meningitis occurred in 7 patients (41.2% +/- 11.9) DI 95% [17.8 - 64.4]. Accumulation of cerebrospinal fluid under the skin flap authentically increased a risk of a meningitis occurrence in patients after transcranial approach to the tumor (p = 0.031). There was no defined statistical significance of other risk factors. But there was defined a trend of the increasing of meningitis occurrence in patients after transsphenoidal approach in case of lumbar drainage or reoperation. Duration of mechanical ventilation and ICU stay in patients with meningitis was authentically longer than in patients without meningitis in both groups. In the group-2 the duration of mechanical ventilation and ICU stay was significantly shorter than in the group-1. Meningitis is not a typical complication of postoperative period in patients with transcranial approach to the tumor. After transsphenoidal approach a meningitis occurrence is likely in case of postoperative liquorrhea, lumbar drainage or reoperation. Subcutaneous accumulation of cerebrospinal fluid is a single defined statistically significant risk factor of meningitis. Postoperative meningitis impairs a condition of patients with chiasm-sellar tumors, increases the duration of mechanical ventilation and impairs treatment outcomes.	f	\N
25056937	Cancer is responsible for many deaths and is a major source of healthcare expenditures. The identification of new, non-invasive biomarkers might allow improvement of the direct diagnostic or prognostic ability of already available tools. Here, we took the innovative approach of interrogating the activity of exopeptidases in the serum of cancer patients with the aim of establishing a distinction based on enzymatic function, instead of simple protein levels, as a means to biomarker discovery. We first analyzed two well-characterized mouse models of prostate cancer, each with a distinct genetic lesion, and established that broad exopeptidase and targeted aminopeptidase activity tests reveal proteolytic changes associated with tumor development. We also describe new peptide-based freeze-frame reagents uniquely suited to probe the altered balance of selected aminopeptidases, as opposed to the full array of exopeptidases, and/or their modulators in patient serum or plasma. One particular proteolytic activity was impaired in animals with aggressive disease relative to cancer-free littermates. We identified the protease in question as dipeptidyl peptidase 4 (DPP4) by analyzing selected knockout mice and evaluating the effect of specific inhibitors. DPP4 activity was also reduced in the sera of patients with metastatic prostate cancer relative to patients with localized disease or healthy controls. However, no significant differences in DPP4 serum levels were observed, which established the loss of activity as the result of impaired enzymatic function. Biochemical analysis indicated that reduced activity was the result not of post-translational modifications or allosteric changes, but instead of a low-molecular-weight inhibitor. After we adjusted for age and total prostate-specific antigen, reduced DPP4 activity remained a significant predictor of cancer status. The results of this proof-of-principle study suggest that DPP4 activity might be a potential blood-based indicator of the presence of metastatic cancer of prostatic origin, either by itself or, more likely, as a means to improve the sensitivity and specificity of existing markers.	f	\N
25063009	When microinvasion cannot be ruled out on core needle biopsy (CNB) in the setting of ductal carcinoma in situ (DCIS), the surgeon must decide whether to perform a sentinel lymph node biopsy (SLNB) at the time of surgery. Up to 10 % of patients with T1mi have nodal disease, but the utility of SLNB in DCIS suspicious for microinvasion (Smic) is unclear. The University of Chicago pathology database was queried for a diagnosis of Smic or definite microinvasion (Mic) on CNB from 2000 to 2014. We analyzed histology, imaging, core needle size, and the use of myoepithelial immunohistochemistry (IHC) markers. We identified 103 women, 72 with Smic and 31 with Mic on CNB. After surgery, 32 % of Smic patients had infiltrating ductal carcinoma (IDC). Seventy-two percent of Smic patients underwent SLNB, with 67 % performed at the initial surgery. SLNB was positive in 6 % and 10 % of Smic and Mic patients, respectively (p = 0.66). Excluding N1mic, the incidence of macrometastatic nodal disease was 1.9 % for Smic patients and 3.3 % for Mic patients (p = 1.00). For Smic patients, IDC was associated with a larger lesion size and smaller CNB needle. In the setting of Smic, grade, necrosis, or presence of a mass did not increase the risk of IDC. In patients with Smic on CNB, the incidence of macrometastatic nodal disease after SLNB is rare. Surgeons may consider omitting SLNB until IDC is definitively confirmed, especially in patients with Smic apart from other high-risk features.	f	\N
25065742	Mitochondrial DNA (mtDNA) is a genome possessed by mitochondria. Since reactive oxygen species (ROS) are generated during aerobic respiration in mitochondria, mtDNA is commonly exposed to the risk of DNA damage. Mitochondrial disease is caused by mitochondrial dysfunction, and mutations or deletions on mitochondrial tRNA (mt tRNA) genes are often observed in mtDNA of patients with the disease. Hence, the correlation between mt tRNA activity and mitochondrial dysfunction has been assessed. Then, cybrid cells, which are constructed by the fusion of an enucleated cell harboring altered mtDNA with a ρ(0) cell, have long been used for the analysis due to difficulty in mtDNA manipulation. Here, we propose a new method that involves mt tRNA cleavage by a bacterial tRNA-specific ribonuclease. The ribonuclease tagged with a mitochondrial-targeting sequence (MTS) was successfully translocated to the mitochondrial matrix. Additionally, mt tRNA cleavage, which resulted in the decrease of cytochrome c oxidase (COX) activity, was observed.	f	\N
25076776	Schizophrenia and bipolar disorder are severe neuropsychiatric disorders, affecting about 1% of the population. Identifying endophenotypes in the brains of neuropsychiatric patients is now considered the way to understand the underlying mechanisms and to improve therapeutic outcomes. However, the endophenotypes and brain mechanisms of the disorders remain unknown. We have previously reported that alpha-CaMKII heterozygous knockout mice show abnormal behaviors related to neuropsychiatric disorders. In these mutant mice, almost all neurons in the hippocampal dentate gyrus stay at a pseudo-immature state, which we refer to as "immature dentate gyrus (iDG)." So far, the iDG phenotype and similar behavioral abnormalities have been found in Schnurri-2 knockout, SNAP-25 mutant, and forebrain-specific calcineurin knockout mice. In addition, we found that both chronic fluoxetine treatment and pilocarpine-induced seizures can reverse the maturation state of the mature neurons, resulting in the iDG phenotype in wild-type mice. Such an iDG-like phenomenon was observed in the post-mortem brains from patients with schizophrenia/bipolar disorder. Recent studies suggest that cortex and amygdala of schizophrenia patients are also at a pseudo-immature state. Based on the findings, we proposed that immaturity of certain types of cells in the brain is a potential endophenotype of neuropsychiatric disorders.	f	\N
25081727	To retrospectively review the safety and clinical efficacy of bevacizumab concomitant with chemotherapy in Chinese patients with advanced non-squamous non-small cell lung cancer (NSNSCLC). Clinical data for 79 patients with NSNSCLC who received bevacizumab concomitant with chemotherapy in Chinese PLA General Hospital from April 28th 2009 to May 5th 2013 were retrospectively reviewed to analyze the clinical efficacy including disease control rate (DCR), overall response rate (ORR), progression-free survival (PFS), overall survival (OS), the Eastern Cooperative Oncology Group (ECOG) score and the safety. The Eastern Cooperative Oncology Group (ECOG) score was 0-2. By the final cutoff date (June 9, 2013), 54 (68.4%) patients had disease progression and 37 (46.8%) died. The ORR was 32.9% and the DCR was 83.5%. The ORR of the first-, second-, and third- or later-line treatments were 51.4%, 25.0% and 12.5%, while the DCR were 94.3%, 80.0% and 70.8%, respectively. The median OS (mOS) and PFS (mPFS) were 13.5 and 5.83 months, respectively. The mOS of patients with the first-, second-, and third- or later-line treatments were 16.2, 10.9 and 8.30 months, while the mPFS were 7.27, 5.90 and 5.17 months, respectively. Chemotherapy-related adverse events included myelosuppression, vomiting, hepatic dysfunction and renal dysfunction, while the common serious bevacizumab-related adverse events were thromboembolic problems, gastrointestinal perforation and reversible posterior leukoencephalopathy syndrome, which could be well managed. Bevacizumab concomitant with chemotherapy is effective and the related toxicity can be well tolerated in Chinese patients with NSNSCLC.	f	\N
25083284	Diagnosing coeliac disease (CD) can be challenging, despite highly specific autoantibodies and typical mucosal changes in the small intestine. The T-cell response to gluten is a hallmark of the disease that has been hitherto unexploited in clinical work-up. We aimed to develop a new method that directly visualizes and characterizes gluten-reactive CD4+ T cells in blood, independently of gluten challenge, and to explore its diagnostic potential. We performed bead-enrichment of DQ2.5-glia-α1a and DQ2.5-glia-α2 tetramer+ cells in the blood of control individuals, treated (TCD) and untreated patients (UCD). We visualized these cells by flow cytometry, sorted them and cloned them. We assessed their specificity by antigen stimulation and re-staining with tetramers. We detected significantly more gliadin-tetramer+ CD4+ effector memory T cells (TEM) in UCD and TCD patients, compared to controls. Significantly more gliadin-tetramer+ TEM in the CD patients than in controls expressed the gut-homing marker integrin-β7. Quantification of gut-homing, gluten-specific TEM in peripheral blood, visualized with human leukocyte antigen (HLA) -tetramers, may be used to distinguish CD patients from healthy individuals. Easy access to gluten-reactive blood T cells from diseased and healthy individuals may lead to new insights on the disease-driving CD4+ T cells in CD.	f	\N
25095816	Falls in people with Parkinson's disease (PD) are frequent and recurrent events with devastating and widespread consequences. Despite this, understanding of the predictive and explanatory value of fall risk factors, as well as the development and testing of interventions aimed at reducing falls, are in their infancy. This review focuses on fall prediction and risk factors that are potentially remediable with physical interventions. We show that falls can be predicted with high accuracy using a simple three-step clinical tool. Evidence from recently published randomized controlled trials supports the implementation of balance-challenging exercises in reducing falls. Larger scale trials utilizing technologically advanced monitoring methods will further elucidate those interventions most likely to be cost effective according to individual risk factor profiles.	f	\N
25097994	Results of surgical treatment of 1220 patients, suffering inguinal hernia, were analyzed. Among the patients there were 810 ageing more than 60 yrs old (main group), from 40 to 59 yrs--410 (control group). There was established, that in patients older than 60 yrs, due to presence of age-related atrophic-dystrophic changes in the inguinal channel muscles, the disease recurrence rate is more than in younger patients. That is why in the inguinal channel hernioplasty the priority must be on the side of alloplastic methods with application of miniinvasive and endoscopic procedures. There was not trustworthy difference between the groups of patients for the rate of intraoperative and early postoperative complications.	f	\N
25115192	Good prognostic tools for predicting disease progression in early stage prostate cancer (PCa) are still missing. Detection of molecular subtypes, for instance by using microarray gene technology, can give new prognostic information which can assist personalized treatment planning. The detection of new subtypes with validation across additional and larger patient cohorts is important for bringing a potential prognostic tool into the clinic. We used fresh frozen prostatectomy tissue of high molecular quality to further explore four molecular subtype signatures of PCa based on Gene Set Enrichment Analysis (GSEA) of 15 selected gene sets published in a previous study. For this analysis we used a statistical test of dependent correlations to compare reference signatures to signatures in new normal and PCa samples, and also explore signatures within and between sample subgroups in the new samples. An important finding was the consistent signatures observed for samples from the same patient independent of Gleason score. This proves that the signatures are robust and can surpass a normally high tumor heterogeneity within each patient. Our data did not distinguish between four different subtypes of PCa as previously published, but rather highlighted two groups of samples which could be related to good and poor prognosis based on survival data from the previous study.The poor prognosis group highlighted a set of samples characterized by enrichment of ESC, ERG-fusion and MYC + rich signatures in patients diagnosed with low Gleason score,. The other group consisted of PCa samples showing good prognosis as well as normal samples. Accounting for sample composition (the amount of benign structures such as stroma and epithelial cells in addition to the cancer component) was important to improve subtype assignments and should also be considered in future studies. Our study validates a previous molecular subtyping of PCa in a new patient cohort, and identifies a subgroup of PCa samples highly interesting for detecting high risk PCa at an early stage. The importance of taking sample tissue composition into account when assigning subtype is emphasized.	f	\N
25120773	Hirschsprung's disease (HSCR) is characterized by the absence of enteric ganglion cells along variable regions of the colon. Established theory demonstrates that HSCR is the consequence caused by the abnormal arrest of the migration and differentiation of neural crest-derived stem cells (NCSCs). And retinoid signaling was considered to be involved. We speculated that, HA117, a retinoid-related transcript of a long noncoding RNA (LncRNA), may be involved in the genesis of HSCR. In current research, colon specimens were collected from 25 HSCR patients and grouped into 3 segments: proximal anastomosis, dilated segment and stenotic segment. Real-Time PCR was used to analyze the expression profiles of HA117 and its neighboring gene DPF3 in different colon segments. Fluorescence in situ hybridization (FISH) was employed to detect the distribution of HA117 in the gut wall. Immunohistochemistry was performed to analyze the protein expression of DPF3 in different colon segments. HA117 expression in stenotic segment was higher compared to proximal anastomosis and dilated segment (p < 0.05). Whereas DPF3b mRNA was lower in stenotic segment than that in two other segments (p < 0.05). FISH detected HA117 was distributed in mucosa and muscle layer, mainly present in stenotic segment. Immunohistochemical staining showed that intensive DPF3 staining occurred in proximal anastomosis and the positive staining was hardly observed in stenotic segment. The results suggested that HA117 may be a factor exerting an anti-differentiation or or anti-maturation role in the genesis of HSCR. This gave us a novel cue for better understanding the etiology of HSCR.	f	\N
25132753	More than 50% of the world population is infected with Helicobacter pylori (H. pylori). The bacterium highly links to peptic ulcer diseases and duodenal ulcer, which was classified as a group I carcinogen in 1994 by the WHO. The pathogenesis of H. pylori is contributed by its virulence factors including urease, flagella, vacuolating cytotoxin A (VacA), cytotoxin-associated gene antigen (Cag A), and others. Of those virulence factors, VacA and CagA play the key roles. Infection with H. pylori vacA-positive strains can lead to vacuolation and apoptosis, whereas infection with cagA-positive strains might result in severe gastric inflammation and gastric cancer. Numerous medicinal plants have been reported for their anti-H. pylori activity, and the relevant active compounds including polyphenols, flavonoids, quinones, coumarins, terpenoids, and alkaloids have been studied. The anti-H. pylori action mechanisms, including inhibition of enzymatic (urease, DNA gyrase, dihydrofolate reductase, N-acetyltransferase, and myeloperoxidase) and adhesive activities, high redox potential, and hydrophilic/hydrophobic natures of compounds, have also been discussed in detail. H. pylori-induced gastric inflammation may progress to superficial gastritis, atrophic gastritis, and finally gastric cancer. Many natural products have anti-H. pylori-induced inflammation activity and the relevant mechanisms include suppression of nuclear factor-κB and mitogen-activated protein kinase pathway activation and inhibition of oxidative stress. Anti-H. pylori induced gastric inflammatory effects of plant products, including quercetin, apigenin, carotenoids-rich algae, tea product, garlic extract, apple peel polyphenol, and finger-root extract, have been documented. In conclusion, many medicinal plant products possess anti-H. pylori activity as well as an anti-H. pylori-induced gastric inflammatory effect. Those plant products have showed great potential as pharmaceutical candidates for H. pylori eradication and H. pylori induced related gastric disease prevention.	f	\N
25142630	To describe metastatic pattern of uterine leiomyosarcomas (ULMS) and correlate it with clinical and histopathologic parameters. We included 113 women (mean age, 53 years; range, 29 to 72 years) with histopathology-confirmed ULMS from 2000 to 2012. Distribution of metastases was noted from imaging by two radiologists in consensus. Predictors of development of metastases were analyzed with univariate and multivariate analysis. Impact of various clinical and histopathologic parameters on survival was compared using Log-rank test and Cox proportional hazard regression model. Distant metastases were seen in 81.4% (92/113) of the patients after median interval of 7 months (interquartile range, 1 to 21). Lung was most common site of metastases (74%) followed by peritoneum (41%), bones (33%), and liver (27%). Local tumor recurrence was noted in 57 patients (50%), 51 of whom had distant metastases. Statistically significant correlation was noted between local recurrence and peritoneal metastases (p<0.001) and between lung and other common sites of hematogeneous metastases (p<0.05). Age, serosal involvement, local recurrence, and the International Federation of Gynecology and Obstetrics (FIGO) stage were predictive factors for metastases. At the time of reporting, 65% (74/113) of the patients have died; median survival was 45 months. Stage, local recurrence, and age were poor prognostic factors. ULMS metastasizes most frequently to lung, peritoneum, bone, and liver. Local recurrence was associated with peritoneal spread and lung metastases with other sites of hematogeneous metastases. Age, FIGO stage and local recurrence predicted metastatic disease and advanced stage, older age and local recurrence predicted poor outcome.	f	\N
25148165	The purpose of this study is to compare CT urography (CTU) with unenhanced CT in the evaluation of upper urinary tracts in adults younger than 50 years with asymptomatic microscopic hematuria. In this study, 1516 CTU examinations were reviewed in adults younger than 50 years. Inclusion criteria were no significant prior urologic disease and asymptomatic microscopic hematuria with at least one urinalysis with greater than or equal to 3 RBCs/high-power field and less than or equal to 50 RBCs/high-power field. Upper urinary tract findings on CTU were classified as malignancy-related or non-malignancy-related hematuria and incidental non-hematuria-related findings. A blinded radiologist reviewed the unenhanced images, recording upper urinary tract findings and recommendations for further contrast-enhanced imaging. The modified Wald equation at a 95% CI, the "Rule of Threes" equation, and binomial distribution were used for malignancy-related findings. Four hundred forty-five examinations in 442 patients met inclusion criteria. CTU reports showed zero malignancy-related hematuria findings, 64 non-malignancy-related hematuria findings (62 renal calculi and two others), and 138 incidental non-hematuria-related findings. Unenhanced CT interpretation had a sensitivity of 100% (64/64) and a specificity of 89.2% (337/378). The theoretic risk of an upper urinary tract malignancy is 0-1.1%. CTU added no additional diagnostic benefit versus unenhanced CT in evaluating the upper urinary tracts of adults younger than 50 years with asymptomatic microscopic hematuria. Using only unenhanced CT can reduce radiation and minimize contrast agent-associated risk, with a less than 1.0% risk of missing upper urinary tract hematuria-related malignancy.	f	\N
25151899	To assess the effects of neoadjuvant chemoradiotherapy on survival outcomes of low rectal cancer after sphincter-preserving or removing surgery. A total of 135 patients with rectal cancer within 10 cm from anal verge after neoadjuvant chemoradiotherapy were enrolled into this retrospective study from 2005 to 2012 at a single institute. There were 79 males and 56 females with a mean age of (58 ± 12) years and an average distance of (5.2 ± 2.1) cm from anal verge. The effects of gender, age, distance of tumor from anal verge, surgical procedure, T-stage downstaging, lateral resection margin and post-treatment lymphatic node status on 3-year disease-free survival (DFS) were examined. The overall 3-year DFS was 85.2% (115/135). Among 95 sphincter-preserving operations, there were anterior resection (n = 79), anterior perineal plane for ultra low anterior resection (APPEAR) technique (n = 12), Hartmann procedure (n = 3) and Parks procedure (n = 1). Among 40 sphincter-removing operations, there were abdominoperineal resection (APR) procedure (n = 39) and intersphincteric resection(ISR) (n = 1). The survival of patients undergoing sphincter-preserving or removing procedures did not differ in 3-year DFS (85.3% (81/95) vs 85.0% (34/40) , χ(2) = 0.000, P = 0.985) . Lateral resection margin and post-treatment lymphatic node status significantly affected DFS. The differential level from anal verge showed a trend of close relationship to 3-year DFS (81.5% (22/27) for 2-3 cm, 82.5% (47/57) for 4-5 cm vs 95.1% (39/41) for 6-7 cm), but without statistic significance (χ(2) = 3.111, 3.522; P = 0.078, 0.061). The survival rate for patients with sphincter-preserving at 6-7 cm from anal verge was significantly higher than that at 4-5 cm (95.0% (38/40) vs 79.5% (31/39) ,χ(2) = 4.227, P = 0.039) , but showed no differences to that with sphincter-removing at 2-3 cm from anal verge (81.0% (17/21),χ(2) = 2.864, P = 0.091) . The multivariate analysis showed that post-treatment lymphatic node status was the only prognostic factor to 3-year DFS (Wald = 4.454, P = 0.035) . Lateral resection margin and post-treatment lymphatic node status play an important role on DFS for patients with low rectal cancer after neoadjuvant chemoradiotherapy. The distance from anal verge is correlated with 3-year disease-free survival. Patients with tumor at 4-5 cm from annal verge can not benefit for survival when they get sphincter-preserving operations.	f	\N
25155018	Frontotemporal dementia (FTD) is the most common cause of dementia in people under 60 yr of age and is pathologically associated with mislocalization of TAR DNA/RNA binding protein 43 (TDP-43) in approximately half of cases (FLTD-TDP). Mutations in the gene encoding progranulin (GRN), which lead to reduced progranulin levels, are a significant cause of familial FTLD-TDP. Grn-KO mice were developed as an FTLD model, but lack cortical TDP-43 mislocalization and neurodegeneration. Here, we report retinal thinning as an early disease phenotype in humans with GRN mutations that precedes dementia onset and an age-dependent retinal neurodegenerative phenotype in Grn-KO mice. Retinal neuron loss in Grn-KO mice is preceded by nuclear depletion of TDP-43 and accompanied by reduced expression of the small GTPase Ran, which is a master regulator of nuclear import required for nuclear localization of TDP-43. In addition, TDP-43 regulates Ran expression, likely via binding to its 3'-UTR. Augmented expression of Ran in progranulin-deficient neurons restores nuclear TDP-43 levels and improves their survival. Our findings establish retinal neurodegeneration as a new phenotype in progranulin-deficient FTLD, and suggest a pathological loop involving reciprocal loss of Ran and nuclear TDP-43 as an underlying mechanism.	f	\N
25159901	Previous studies have suggested that long-chain n-3 fatty acids derived from seafood are associated with a lower risk of mortality, CHD and stroke. Whether α-linolenic acid (ALA, 18 : 3n-3), a plant-derived long-chain essential n-3 fatty acid, is associated with a lower risk of these outcomes is unclear. The aim of the present study was to examine the associations of plasma phospholipid and dietary ALA with the risk of mortality, CHD and stroke among older adults who participated in the Cardiovascular Health Study, a cohort study of adults aged ≥ 65 years. A total of 2709 participants were included in the plasma phospholipid ALA analysis and 2583 participants were included in the dietary ALA analysis. Cox regression was used to assess the associations of plasma phospholipid and dietary ALA with the risk of mortality, incident CHD and stroke. In minimally and multivariable-adjusted models, plasma phospholipid ALA was found to be not associated with the risk of mortality, incident CHD or stroke. After adjustment for age, sex, race, enrolment site, education, smoking status, diabetes, BMI, alcohol consumption, treated hypertension and total energy intake, higher dietary ALA intake was found to be associated with a lower risk of total and non-cardiovascular mortality; on comparing the highest quintiles of dietary ALA with the lowest quintiles, the HR for total mortality and non-cardiovascular mortality were found to be 0·73 (95 % CI 0·61, 0·88) and 0·64 (95 % CI 0·52, 0·80), respectively. Dietary ALA was found to be not associated with the risk of cardiovascular mortality, incident CHD or stroke. In conclusion, the results of the present suggest study that dietary ALA, but not plasma phospholipid ALA, is associated with a lower risk of total and non-cardiovascular mortality in older adults.	f	\N
25176287	Oxygen-enhanced MRI (OE-MRI) biomarkers have potential value in assessment of COPD, but need further evaluation before treatment-induced changes can be interpreted. The objective was to evaluate how OE-MRI parameters of regional ventilation and oxygen uptake respond to standard pharmacological interventions in COPD, and how the response compares to that of gold standard pulmonary function tests. COPD patients (n=40), mean FEV1 58% predicted normal, received single-dose inhaled formoterol 9μg, or placebo, followed by 8 weeks treatment bid with a combination of budesonide and formoterol Turbuhaler(®) 320/9μg or formoterol Turbuhaler(®). OE-MRI biomarkers were obtained, as well as X-ray computed tomography (CT) biomarkers and pulmonary function tests, in a two-center study. An ANCOVA statistical model was used to assess effect size of intervention measurable in OE-MRI parameters of lung function. OE-MRI data were successfully acquired at both study sites. 8-week treatment with budesonide/formoterol significantly decreased lung wash-out time by 31% (p<0.01), decreased the change in lung oxygen level upon breathing pure oxygen by 13% (p<0.05) and increased oxygen extraction from the lung by 58% (p<0.01). Single-dose formoterol increased both lung wash-out time (+47%, p<0.05) and lung oxygenation time (+47%, p<0.05). FEV1 was improved by single-dose formoterol (+12%, p<0.001) and 8 weeks of budesonide/formoterol (+ 18%, p<0.001), consistent with published studies. In COPD, OE-MRI parameters showed response to both single-dose bronchodilatory effects of a β2-agonist, formoterol, and 8-week treatment with an inhaled corticosteroid, budesonide, and the measurements are feasible in a small-scale multi-center trial setting.	f	\N
25178342	In the last decade, the clinical picture of primary hyperparathyroidism has changed, with the majority of patients being diagnosed while asymptomatic and the "classical" clinical pattern characterized by bone disease, recurrent nephrolithiasis, peptic ulcer disease, neurological or psychiatric disorders being rarely encountered. In this context, most patients have minimal hypercalcemia and small parathyroid adenomas. Not surprisingly, giant parathyroid adenomas have seldom been described in the literature. We herein report three cases of giant parathyroid adenomas weighing more than 30 g and discuss their clinicopathological and therapeutic particularities. We also review the relevant literature, with the principal aim of outlining the rarity of these giant parathyroid adenomas and the issues concerning their diagnosis and treatment.	f	\N
25179307	To explore if inhibition of vitronectin can be used for the treatment of hepatocellular carcinoma. RNAi technology was used to silence the expression of VTN in HepG2 and SMMC 7721 cells. Change of growth characteristics in these cells was evaluated. VTN silencing does not affect growth characteristics of cancer cells in monolayer cell culture, but could suppress the colonized growth of cells in soft agar. VTN-siRNA suppresses colony formation more than 80% compared with that of control in SMMC7721cells and leads to the inhibition of colony formation of over 70% in HepG2 cells. In addition, VTN silencing decreases the size of tumor xenografts in nude mice, particularly in male mice, with an inhibition rate of 46.6%. VTN plays a significant role in the malignant growth of tumor. Inhibition of VTN could potentially be applied for the treatment of hepatocellular carcinoma.	f	\N
25182131	The difficulties arising from association analysis with rare variants underline the importance of suitable reference population cohorts, which integrate detailed spatial information. We analyzed a sample of 1684 individuals from Western France, who were genotyped at genome-wide level, from two cohorts D.E.S.I.R and CavsGen. We found that fine-scale population structure occurs at the scale of Western France, with distinct admixture proportions for individuals originating from the Brittany Region and the Vendée Department. Genetic differentiation increases with distance at a high rate in these two parts of Northwestern France and linkage disequilibrium is higher in Brittany suggesting a lower effective population size. When looking for genomic regions informative about Breton origin, we found two prominent associated regions that include the lactase region and the HLA complex. For both the lactase and the HLA regions, there is a low differentiation between Bretons and Irish, and this is also found at the genome-wide level. At a more refined scale, and within the Pays de la Loire Region, we also found evidence of fine-scale population structure, although principal component analysis showed that individuals from different departments cannot be confidently discriminated. Because of the evidence for fine-scale genetic structure in Western France, we anticipate that rare and geographically localized variants will be identified in future full-sequence analyses.	f	\N
25185440	To estimate the prevalence and risk factors of dry eye disease (DED) in a female cohort in the UK. Population-based cross-sectional association study of 3824 women from the TwinsUK cohort aged 20-87 years. A questionnaire was used to evaluate DED and several risk factors. Binary logistic regression, corrected for age, was used to examine the association between DED and risk factors. 9.6% of women had a DED diagnosis and concomitant use of artificial tears, and 20.8% experienced DED symptoms in the past 3 months. Risk factors that were significantly associated with DED were age, asthma, eczema, the presence of any allergy, cataract surgery, rheumatoid arthritis, osteoarthritis, migraine and stroke. The highest effect sizes were found with depression, pelvic pain, irritable bowel syndrome and chronic widespread pain syndrome (all p<0.0005). Subjects with DED symptoms scored significantly lower on self-perceived health, compared with controls (p=0.001). DED is common and increases with age within this cohort of female twins. We confirmed established risk factors for the first time in a British population, and found important risk factors that might relate to an underlying aetiology involving chronic pain predisposition or somatisation.	f	\N
25187623	The phenomenon that adverse environmental exposures in early life are associated with increased susceptibilities for many adult, particularly metabolic diseases, is now referred to as 'developmental origins of health and disease (DOHAD)' or 'Barker' hypothesis. Fetal overnutrition and undernutrition have similar long-lasting effects on the setting of the neuroendocrine control systems, energy homeostasis, and metabolism, leading to life-long increased morbidity. There are sensitive time windows during early development, where environmental cues can program persistent epigenetic modifications which are generally assumed to mediate these gene-environment interactions. Most of our current knowledge on fetal programing comes from animal models and epidemiological studies in humans, in particular the Dutch famine birth cohort. In industrialized countries, there is more concern about adverse long-term consequences of fetal overnutrition, i.e. by exposure to gestational diabetes mellitus and/or maternal obesity which affect 10-20% of pregnancies. Epigenetic changes due to maternal diabetes/obesity may predispose the offspring to develop metabolic disease later in life and, thus, transmit the adverse environmental exposure to the next generation. This vicious cycle could contribute significantly to the worldwide metabolic disease epidemics. In this review article, we focus on the epigenetics of an adverse intrauterine environment, in particular gestational diabetes, and its implications for the prevention of complex disease.	f	\N
25197402	After 3 months of combination treatment using interferon α-2a and Ribavirin, a case of 59-year-old female patient with chronic viral hepatitis C demonstrated symptoms such as headache, dizziness accompanied by nausea, vomiting, dry cough, breathing difficulty, and shortness of breath. Dynamic electrocardiogram showed occasional atrial premature beats, paroxysmal tachycardia, and abnormal ST-T (T wave inversion and prolongation of the QT interval). Ambulatory blood pressure indicated that mean blood pressure was elevated than before. Myocardial radionuclide scan showed focal myocardial ischemia in left ventricular inferior wall. Pulmonary function tests showed that pulmonary diffusion function was decreased, indicating the possibility of interstitial pneumonia. The patient had no history of coronary heart disease or chest X-ray abnormalities before medication, but had hypertensive medical history for 8 years with good blood pressure control. After withdrawal of antiviral drugs, symptoms such as dry cough, breathing difficulty and T wave inversion were gradually relieved. This case indicated that myocardial ischemia and pulmonary lesions were associated with the application of pegylated interferon α-2a.	f	\N
25204216	Acquired immunodeficiency syndrome (AIDS) is a major health problem worldwide. The number of infected people is increasing daily. Knowledge and awareness toward prevention and control of the disease is necessary among both educated and illiterate people. This study is aimed at assessing the knowledge and awareness about human immunodeficiency virus (HIV)/AIDS among undergraduate students studying in a technical institute in Gorakhpur, Uttar Pradesh, India. A community-based cross-sectional study was conducted among youths aged 15-30 years studying in a technical institution in Gorakhpur. Data were collected using a semistructured questionnaire developed with the help of existing literature, from 250 participants (students). The main source of information was the television; knowledge about the difference between HIV/AIDS was satisfactory. The findings showed that the knowledge about modes of prevention (blood checkup, needle/syringe sterilization) was satisfactory. There were several misconceptions about the modes of transmission of the disease, such as through mosquito bites, eating/drinking, and kissing. The knowledge of the study population was satisfactory, and there is a need for innovation and comprehensive education to impart better knowledge and understanding about HIV/AIDS.	f	\N
25204587	Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disorder involving both upper and lower motor neurons in the cerebral cortex, brainstem and spinal cord. Vascular endothelial growth factor (VEGF) was originally described as a factor with a regulatory role in vascular growth and development, and now it also functions as a neurotrophic factor protecting motoneurons from insults such as oxidative stress, hypoxia and glutamate-excitotoxicity, but the role of VEGF in ALS is still unclear. The aim of this study is to measure cerebrospinal fluid (CSF) and serum VEGF levels in patients with ALS, and to investigate whether there are correlations between CSF and serum VEGF levels and clinical parameters of the disease and whether VEGF has a prognostic and evaluating potential for ALS. Results showed that VEGF levels were found to increase significantly in CSF and serum in ALS patients studied; they were positively and significantly correlated with the disease duration in ALS patients and inversely and significantly correlated with disease progression rate (DPR) of ALS patients. Moreover, CSF and serum from ALS patients with long duration and slow disease progression rate revealed higher VEGF levels as compared to ALS patients with short duration and rapid disease progression rate. In conclusion, VEGF upregulation may indicate an activation of compensatory responses in ALS which may reflect or in fact account for increased duration and slow disease progression rate. We propose that VEGF may be a useful biomarker having the prognostic and evaluating potential for ALS.	f	\N
25216396	Whether carotid artery stenosis predicts stroke after noncardiac surgery remains unknown. We therefore tested the primary hypothesis that degree of carotid artery stenosis is associated with in-hospital stroke or 30-day all-cause mortality after noncardiac surgery. As carotid artery stenosis is also a marker for cardiovascular disease, our secondary hypothesis was that degree of carotid artery stenosis is associated with postoperative myocardial injury. We included adults who had noncardiac, noncarotid surgery at Cleveland Clinic from 2007 to 2011 and had carotid duplex ultrasound performed either within 6 months before or 1 month after surgery. Internal carotid artery peak systolic velocity (ICA PSV) was used as a measure of carotid artery stenosis severity. A multivariate (i.e., multiple outcomes per patient) generalized estimating equation model was used to assess the association between highest ICA PSV and the composite of stroke and 30-day mortality after adjusting for predefined potentially confounding variables. Of 2,110 patients included, 112 (5.3%) died within 30 days and 54 (2.6%) suffered postoperative in-hospital stroke. ICA PSV was not associated with this composite outcome (odds ratio of 1.0 [95% confidence interval: 0.99, 1.02] for a 10-unit increase, P = 0.55). ICA PSV was also not associated with postoperative myocardial injury (odds ratio 1.00 [0.99, 1.02], P = 0.49). This cohort represents a high-risk population, as carotid duplex examinations were likely prompted by neurological symptoms. There was nonetheless no association between carotid artery stenosis and perioperative stroke or 30-day mortality after noncardiac surgery.	f	\N
25222481	Thrombocytopenia (defined as a platelet count <150×10(9)) is a well-known complication in patients with liver cirrhosis and has been observed in 76% to 85% of patients. Significant thrombocytopenia (platelet count <50×10(9) to 75×10(9)) occurs in approximately 13% of patients with cirrhosis. Thrombocytopenia can negatively impact the care of patients with severe liver disease by potentially interfering with diagnostic and therapeutic procedures. Multiple factors can contribute to the development of thrombocytopenia including splenic platelet sequestration, immunological processes, bone marrow suppression by chronic viral infection, and reduced levels or activity of the hematopoietic growth factor thrombopoietin. The present review focuses on the etiologies and management options for severe thrombocytopenia in the setting of advanced liver disease.	f	\N
25225437	Cabozantinib (XL184), an oral inhibitor of multiple receptor tyrosine kinases such as MET and VEGFR2, was evaluated in a phase II nonrandomized expansion study in castration-resistant prostate cancer (CRPC). Patients received open-label cabozantinib at daily starting doses of 100 mg or 40 mg until disease progression or unacceptable toxicity. The primary end point was bone scan response, defined as ≥ 30% reduction in bone scan lesion area. Other efficacy end points included overall survival, pain, analgesic use, and biomarkers. One hundred forty-four patients sequentially enrolled in either a 100-mg (n = 93) or 40-mg (n = 51) study cohort. Ninety-one patients (63%) had a bone scan response, often by week 6. Treatment resulted in clinically meaningful pain relief (57% of patients) and reduction or discontinuation of narcotic analgesics (55% of patients), as well as improvements in measurable soft tissue disease, circulating tumor cells, and bone biomarkers. Improvements in each of these outcomes were observed in both cohorts: bone scan response in 73% and 45%, respectively; reductions in measurable soft tissue disease in 80% and 79%, respectively. Median overall survival was 10.8 months for the entire population. Most common grade 3 or 4 adverse events were fatigue (22%) and hypertension (14%). Fewer dose reductions because of toxicity were required in the 40-mg group. The evidence suggests that cabozantinib has clinically meaningful activity in CRPC. Cabozantinib resulted in improvements in bone scans, pain, analgesic use, measurable soft tissue disease, circulating tumor cells, and bone biomarkers. Taken together, these phase II observations warrant further development of cabozantinib in prostate cancer.	f	\N
25230241	Chagas disease (CD) has been associated with an elevated risk of stroke, but current data are conflicting and prospective controlled studies are lacking. We performed a systematic review and meta-analysis examining the association between stroke and CD. Pubmed, Embase, Cochrane Central, Latin American database, and unpublished data were searched with the use of the following terms: ("Chagas" OR "American trypanosomiasis") AND ("dilated" OR "ischemic" OR "idiopathic" OR "nonChagasic" OR "stroke" OR "cerebrovascular"). We included studies that reported prevalence or incidence of stroke in a CD group compared with a non-CD control group. Odds ratios (ORs) and their 95% confidence intervals (CIs) were computed with the use of a random-effects model. A total of 8 studies and 4,158 patients were included, of whom 1,528 (36.7%) had CD. Risk of stroke was elevated in the group of patients with CD (OR 2.10, 95% CI 1.17-3.78). Similar results were observed in a subanalysis of cardiomyopathy patients (OR 1.74, 95% CI 1.02-3.00) and in sensitivity analysis with removal of each individual study. Furthermore, exclusion of studies at higher risk for bias also yielded consistent results (OR 1.70, 95% CI 1.06-2.71). Subanalysis restricted to studies that included patients with the indeterminate form found no significant difference in the stroke prevalence between CD and non-CD patients (OR 3.10, 95% CI 0.89-10.77). CD is significantly associated with cerebrovascular events, particularly among patients with cardiomyopathy. These findings underline the need for prospective controlled studies in patients with Chagas cardiomyopathy to ascertain the prognostic significance of cerebrovascular events and to evaluate the role of therapeutic anticoagulation in primary prevention.	f	\N
25231249	Drug-induced liver injury (DILI) is a major safety concern during drug development and remains one of the main reasons for withdrawal of drugs from the market. Although it is crucial to develop methods that will detect potential hepatotoxicity of drug candidates as early and as quickly as possible, there is still a lack of sensitive and specific biomarkers for DILI that consequently leads to a scarcity of reliable hepatotoxic data. Hence, in this study, we assessed characteristic molecular signatures in rat liver treated with drugs (pyrazinamide, ranitidine, enalapril, carbamazepine and chlorpromazine) that are known to cause DILI in humans. Unsupervised hierarchical clustering analysis of transcriptome changes induced by DILI-causing drugs resulted in three different subclusters on dendrogram, i.e., hepatocellular, cholestatic and mixed type of DILI at early time points (2 days), and multiclassification analysis suggested 31 genes as discernible markers for each DILI pattern. Further analysis for characteristic molecular signature of each DILI pattern provided a molecular basis for different modes of DILI action. A proteomics study of the same rat livers was used to confirm the results, and the two sets of data showed 60 matching classifiers. In conclusion, the data of different DILI-causing drug treatments from genomic analysis in a rat model suggest that DILI-specific molecular signatures can discriminate different patterns of DILI at an early exposure time point, and that they provide useful information for mechanistic studies that may lead to a better understanding of the molecular basis of DILI.	f	\N
25297522	Ebola viruses and Marburg viruses include some of the most virulent and fatal pathogens known to humans. These viruses cause severe haemorrhagic fevers, with case fatality rates in the range 25-90%. The diagnosis of filovirus using formalin-fixed tissues from fatal cases poses a significant challenge. The most characteristic histopathological findings are seen in the liver; however, the findings overlap with many other viral and non-viral haemorrhagic diseases. The need to distinguish filovirus infections from other haemorrhagic fevers, particularly in areas with multiple endemic viral haemorrhagic agents, is of paramount importance. In this review we discuss the current state of knowledge of filovirus infections and their pathogenesis, including histopathological findings, epidemiology, modes of transmission and filovirus entry and spread within host organisms. The pathogenesis of filovirus infections is complex and involves activation of the mononuclear phagocytic system, with release of pro-inflammatory cytokines, chemokines and growth factors, endothelial dysfunction, alterations of the innate and adaptive immune systems, direct organ and endothelial damage from unrestricted viral replication late in infection, and coagulopathy. Although our understanding of the pathogenesis of filovirus infections has rapidly increased in the past few years, many questions remain unanswered.	f	\N
25302175	Cervical cancer is a worldwide disease that constitutes a significant public health problem, especially in developing countries, not only due to its high incidence but also because the most affected population comprises women who belong to marginalized socio-economic classes. Clinical and molecular research has identified immunological impairment in squamous intraepithelial cervical lesions and cervical cancer patients. Human Papillomavirus (HPV) has several mechanisms for avoiding the immune system: it down-regulates the expression of interferon and upregulates interleukin (IL)-10 and transforming growth factor (TGF)-β1 to produce a local immunosuppressive environment, which, along with altered tumor surface antigens, forms an immunosuppressive network that inhibits the antitumor immune response. In this review we analyzed the available data on several deregulated cellular immune functions in patients with NIC I, NIC II and NIC III and cervical cancer. The effects of immunosuppressive cytokines on innate immune response, T-cell activation and cellular factors that promote tumor cell proliferation in cervical cancer patients are summarized. We discuss the functional consequences of HPV E2, E6, and E7 protein interactions with IL-10 and TGF-β1 promoters in the induction of these cytokines and postulate its effect on the cellular immune response in squamous intraepithelial cervical lesions and cervical cancer patients. This review provides a comprehensive picture of the immunological functions of IL-10 and TGF-β1 in response to HPV in humans.	f	\N
25305425	Vascular blowout syndrome is a well-known, life-threatening condition complicating advanced-stage head and neck malignancies but has rarely been reported in the gynecologic oncology realm in association with the femoral circulation. A 50-year-old woman with metastatic vulvar squamous cell carcinoma presented with left threatened femoral arterial blowout, secondary to an exophytic neoplastic mass originating from the left inguinal lymph nodes. Bland embolization of the tumor as well as 3 vessel covered stent revascularization was successfully performed with excellent tumor devascularization and reinstitution of arterial integrity. Successful devascularization of the tumor, with no non-target embolization was achieved, with excellent apposition and deployment of 3 covered stents in the femoral artery bifurcation. We present a unique case of threatened femoral artery blowout syndrome in the setting of metastatic vulvar carcinoma requiring various endovascular techniques for palliation. These endovascular techniques can be invaluable in minimally invasive palliation of advanced stage neoplasms abutting the iliofemoral circulation.	f	\N
25312087	Despite the pressing need for novel cancer treatments, our improved understanding of tumor biology is not being successfully translated into better therapies. Here we present a lentiviral vector that enables in vivo validation of cancer therapeutic targets when combined with existing cancer animal models that faithfully reproduce the natural history of human disease. Unlike the conventional genetic approaches with targeted alleles, the outlined experimental strategy could be used to assess the preclinical efficacy of a growing number of putative therapeutic hits in a rapid and cost-effective manner.	f	\N
25313751	There is a rising trend in the incidence of (colorectal carcinoma) colorectal cancer (CRC) in India. Nuclear factor kappa B (NFkB) is a transcription factor which belongs to the Rel family. It has an impact on phenomena such as apoptosis, tumor progression and differentiation. (1) To evaluate the grade and stage in 50 cases of colorectal carcinoma. (2) To evaluate the NFkB translocation into the nucleus of the cells. (3) To compare the benign and malignant areas with the degree of NFkB translocation and compare the translocation with the grade and pathological stage. The grade and stage of the tumors was evaluated. NFkB staining was performed on the tissues. The results of the immunostaining were analyzed semi quantitatively as a percentage of positive cells. Statistical Package for Social Sciences 13.0 statistical package program (SPSS, Lead Technologies Inc, USA) for windows was used. Correlation was carried out using the Pearson's correlation co-efficient and the Chi-square test. There were 29 males (58%) and 21 females (42%). Most of the cases were well-differentiated adenocarcinomas (58%). There was a significant difference between NFkB translocation in the epithelial cells and lymphocytes in the benign and malignant areas (P - 0.04 and P - 0.001 respectively). There was a significant correlation between the grade of NFkB staining in the malignant epithelial cells with the tumor and nodal status (P - 0.001 and P - 0.001). It is likely that NFkB is an important factor in the pathogenesis of CRC. Further studies including therapeutic intervention using strategies which prevent activation of NFkB in colorectal carcinoma patients will tell if we could alter the course of the disease favorably.	f	\N
25320726	Methimazole and propylthiouracil have been used in the management of hyperthyroidism for more than half a century. However, hepatotoxicity is one of the most deleterious side effects associated with these medications. The mechanism(s) of hepatic injury induced by antithyroid agents is not fully recognized yet. Furthermore, there are no specific tools for predicting the occurrence of hepatotoxicity induced by these drugs. The purpose of this article is to give an overview on possible susceptibility factors in liver injury induced by antithyroid agents. Age, gender, metabolism characteristics, alcohol consumption, underlying diseases, immunologic mechanisms, and drug interactions are involved in enhancing antithyroid drugs-induced hepatic damage. An outline on the clinically used treatments for antithyroid drugs-induced hepatotoxicity and the potential therapeutic strategies found to be effective against this complication are also discussed.	f	\N
25323223	Pneumococcal conjugated vaccines (PCVs) have shown protection against invasive pneumococcal disease by vaccine serotypes, but an increase in non-vaccine serotype disease has been observed. Type-specific effects on clinical manifestation need to be explored. Clinical data from 2096 adults and 192 children with invasive pneumococcal disease were correlated to pneumococcal molecular serotypes. Invasive disease potential for pneumococcal serotypes were calculated using 165 invasive and 550 carriage isolates from children. The invasive disease potential was lower for non-PCV13 compared to vaccine-type strains. Patients infected with non-PCV13 strains had more underlying diseases, were less likely to have pneumonia and, in adults, tended to have a higher mortality. Furthermore, patients infected with pneumococci belonging to clonal serotypes only expressing non-PCV13 capsules had a higher risk for septicaemia and mortality. PCV vaccination will probably lead to a decrease in invasive pneumococcal disease but an alteration in the clinical manifestation of invasive pneumococcal disease. Genetic lineages causing invasive pneumococcal disease in adults often express non-vaccine serotypes, which can expand after vaccination with an increased risk of infection in patients with underlying diseases.	f	\N
25326379	Ubiquitin C-terminal hydrolase L1 (UCH-L1) is a deubiquitinating enzyme that is highly expressed in neurons. A possible role for UCH-L1 in neurodegeneration has been highlighted because of its presence in Lewy bodies associated with Parkinson disease and neurofibrillary tangles observed in Alzheimer disease. UCH-L1 exists in two forms in neurons, a soluble cytoplasmic form (UCH-L1(C)) and a membrane-associated form (UCH-L1(M)). Alzheimer brains show reduced levels of soluble UCH-L1(C) correlating with the formation of UCH-L1-immunoreactive tau tangles, whereas UCH-L1(M) has been implicated in α-synuclein dysfunction. Given these reports of divergent roles, we investigated the properties of UCH-L1 membrane association. Surprisingly, our results indicate that UCH-L1 does not partition to the membrane in the cultured cell lines we tested. Furthermore, in primary cultured neurons, a proportion of UCH-L1(M) does partition to the membrane, but, contrary to a previous report, this does not require farnesylation. Deletion of the four C-terminal residues caused the loss of protein solubility, abrogation of substrate binding, increased cell death, and an abnormal intracellular distribution, consistent with protein dysfunction and aggregation. These data indicate that UCH-L1 is differently processed in neurons compared with clonal cell lines and that farnesylation does not account for the membrane association in neurons.	f	\N
25332150	We conducted this pilot randomized clinical trial to determine the feasibility of a large clinical trial aimed at testing whether early use of catheter ablation of ventricular tachycardia (VT) is superior to antiarrhythmic medications at reducing mortality. Patients were enrolled at 4 sites if they had ischemic heart disease, an implantable cardioverter defibrillator (ICD), and received ≥1 ICD shock or ≥3 antitachycardia pacing therapies for VT. Patients were randomized to 2 arms: (1) antiarrhythmic medication (n = 14) and (2) catheter ablation (n = 13); patients were followed at 3 and 6 months. Endpoints included recurrent VT, time to first ICD therapy for VT, and death. Of 243 screened patients, 27 were enrolled. Main reasons for screen failures were: (1) patient was already on an antiarrhythmic medication (88 [41%]), (2) VT due to a reversible cause (23 [11%]), and (3) incessant VT (20 [9%]). Fourteen patients had recurrent VT, 8 (62%) in the ablation arm and 6 (43%) in the antiarrhythmic medication arm. Median time to recurrent VT was 75 days (25th, 75th: 51, 89) in the ablation arm and 57 days (30, 145) in the antiarrhythmic arm. Four patients died, 2 in each arm. This clinical trial shows that most patients in clinical practice have already failed antiarrhythmic drug therapy before catheter ablation is considered, and the VT recurrence rates and death in these patients are high. For a large clinical trial to be feasible, factors limiting early consideration of catheter ablation need to be identified and addressed.	f	\N
25336691	To evaluate the relevance between lumican expression patterns and the clinical course of patients with pancreatic ductal adenocarcinoma (PDAC), and to investigate the role of lumican in PDAC progression. One hundred thirty-one patient tumors were chosen for tissue microarray staining, and Cox regression analysis was used to test the associations between lumican expression and clinical, pathologic, and oncologic outcomes in all patients. Primary PDAC cells and recombinant human lumican protein were used to establish a working model to mimic the in vivo interactions between stromal lumican and PDAC cells. Using this model, we tested the effects of lumican on EGFR signaling via Akt and hypoxia-inducible factor-1α (HIF1α) and its subsequent influence on glucose consumption, lactate production, intracellular ATP, and apoptotic cell death. Lumican was present in the stroma surrounding PDAC cells in roughly one-half of primary tumors and the direct xenografts. Patients with stromal lumican were associated with a profound reduction in metastatic recurrence after surgery and 3-fold longer survival than patients without stromal lumican. In PDAC cells, extracellular lumican reduced EGFR expression and phosphorylation through enhanced dimerization and internalization of EGFR and the resultant inhibition of Akt kinase activity. Lumican also reduced HIF1α expression and activity via Akt. PDAC cells with enhanced HIF1α activity were resistant to lumican-induced inhibition of glucose consumption, lactate production, intracellular ATP, and apoptosis. There is a positive association between stromal lumican in primary PDAC tumors and prolonged survival after tumor resection. Lumican plays a restrictive role in EGFR-expressing pancreatic cancer progression.	f	\N
25348595	Bioorthogonal cleavable linkers are attractive building blocks for compounds that can be manipulated to study biological and cellular processes. Sodium dithionite sensitive azobenzene-containing (Abc) peptides were applied for the temporary stabilization of recombinant MHC complexes, which can then be employed to generate libraries of MHC tetramers after exchange with a novel epitope. This technology represents an important tool for high-throughput studies of disease-specific T cell responses.	f	\N
25348708	Papillary squamous cell carcinoma (PSCC) of the uterine cervix is difficult to diagnose due to its rarity and limited data regarding its clinical behavior. We attempted to assess the degree of stromal invasion using magnetic resonance imaging (MRI) and evaluate possible treatments for this lesion in view of its clinical behavior. We analyzed 28 cases of PSCC diagnosed on the colposcopic selective biopsies. We studied the rate of accuracy of diagnoses of the colposcopic selective biopsies compared with the final diagnoses, and compared the rate of stromal invasion between the MRI and pathological findings while focusing on surgical methods and the clinical prognosis. Of the 28 patients, only 12 exhibited true PSCC. The other 16 patients were ultimately diagnosed with SCC or adenosquamous carcinoma based on the finding of the surgical specimens and exhibited relatively poor prognoses. Among the 12 true PSCC cases, the rate of diagnostic accuracy of stromal invasion (with or without) was only 58% (7/12) on the colposcopic selective biopsies. However, we were able to predict the presence of stromal invasion (microscopic borderline: approximately 3 mm) before surgery using MRI. None of the 10 patients treated with radical surgery displayed lymph node metastases. In addition, all 12 study patients exhibited no recurrence (mean: 49 months) and survived. MRI can be used to detect preinvasive and microinvasive disease before surgery. It is possible to select a less invasive surgical method than radical surgery in cases of preinvasive and microinvasive PSCC in view of the indolent clinical behavior of this disease.	f	\N
25348855	This perspective discusses the report by Pinsky and colleagues, which addresses whether noncalcified pulmonary nodules identified on CT screening carry short- and long-term risk for lung cancer. We are facing challenges related to distinguishing a large majority of benign nodules from malignant ones and among those a majority of aggressive from indolent cancers. Key questions in determining individual probabilities of disease, given their history, findings on CT, and upcoming biomarkers of risk, remain most challenging. Reducing the false positives associated with current low-dose computed tomography practices and identification of individuals who need therapy and at what time during tumor surveillance could reduce costs and morbidities associated with unnecessary interventions.	f	\N
25359996	To determine whether the prescription of co-trimoxazole with an angiotensin converting enzyme inhibitor or angiotensin receptor blocker is associated with sudden death. Population based nested case-control study. Ontario, Canada, from 1 April 1994 to 1 January 2012. Ontario residents aged 66 years or older treated with an angiotensin converting enzyme inhibitor or angiotensin receptor blocker. Cases were those who died suddenly shortly after receiving an outpatient prescription for one of co-trimoxazole, amoxicillin, ciprofloxacin, norfloxacin, or nitrofurantoin. Each case was matched with up to four controls on age, sex, chronic kidney disease, and diabetes. Odds ratio for the association between sudden death and exposure to each antibiotic relative to amoxicillin, after adjustment for predictors of sudden death according to a disease risk index. Of 39,879 sudden deaths, 1027 occurred within seven days of exposure to an antibiotic and were matched to 3733 controls. Relative to amoxicillin, co-trimoxazole was associated with an increased risk of sudden death (adjusted odds ratio 1.38, 95% confidence interval 1.09 to 1.76). The risk was marginally higher at 14 days (adjusted odds ratio 1.54, 1.29 to 1.84). This corresponds to approximately three sudden deaths within 14 days per 1000 co-trimoxazole prescriptions. Ciprofloxacin (a known cause of QT interval prolongation) was also associated with an increased risk of sudden death (adjusted odds ratio 1.29, 1.03 to 1.62), but no such risk was observed with nitrofurantoin or norfloxacin. In older patients receiving angiotensin converting enzyme inhibitors or angiotensin receptor blockers, co-trimoxazole is associated with an increased risk of sudden death. Unrecognized severe hyperkalemia may underlie this finding. When appropriate, alternative antibiotics should be considered in such patients.	f	\N
25372658	In March 2014, the World Health Organization was notified of an outbreak of Zaire ebolavirus in a remote area of Guinea. The outbreak then spread to the capital, Conakry, and to neighboring countries and has subsequently become the largest epidemic of Ebola virus disease (EVD) to date. From March 25 to April 26, 2014, we performed a study of all patients with laboratory-confirmed EVD in Conakry. Mortality was the primary outcome. Secondary outcomes included patient characteristics, complications, treatments, and comparisons between survivors and nonsurvivors. Of 80 patients who presented with symptoms, 37 had laboratory-confirmed EVD. Among confirmed cases, the median age was 38 years (interquartile range, 28 to 46), 24 patients (65%) were men, and 14 (38%) were health care workers; among the health care workers, nosocomial transmission was implicated in 12 patients (32%). Patients with confirmed EVD presented to the hospital a median of 5 days (interquartile range, 3 to 7) after the onset of symptoms, most commonly with fever (in 84% of the patients; mean temperature, 38.6°C), fatigue (in 65%), diarrhea (in 62%), and tachycardia (mean heart rate, >93 beats per minute). Of these patients, 28 (76%) were treated with intravenous fluids and 37 (100%) with antibiotics. Sixteen patients (43%) died, with a median time from symptom onset to death of 8 days (interquartile range, 7 to 11). Patients who were 40 years of age or older, as compared with those under the age of 40 years, had a relative risk of death of 3.49 (95% confidence interval, 1.42 to 8.59; P=0.007). Patients with EVD presented with evidence of dehydration associated with vomiting and severe diarrhea. Despite attempts at volume repletion, antimicrobial therapy, and limited laboratory services, the rate of death was 43%.	f	\N
25375073	As of October 29, 2014, a total of 6,454 Ebola virus disease (Ebola) cases had been reported in Liberia by the Liberian Ministry of Health and Social Welfare, with 2,609 deaths. Although the national strategy for combating the ongoing Ebola epidemic calls for construction of Ebola treatment units (ETUs) in all 15 counties of Liberia, only a limited number are operational, and most of these are within Montserrado County. ETUs are intended to improve medical care delivery to persons whose illnesses meet Ebola case definitions, while also allowing for the safe isolation of patients to break chains of transmission in the community. Until additional ETUs are constructed, the Ministry of Health and Social Welfare is supporting development of community care centers (CCCs) for isolation of patients who are awaiting Ebola diagnostic test results and for provision of basic care (e.g., oral rehydration salts solutions) to patients confirmed to have Ebola who are awaiting transfer to ETUs. CCCs often have less bed capacity than ETUs and are frequently placed in areas not served by ETUs; if built rapidly enough and in sufficient quantity, CCCs will allow Ebola-related health measures to reach a larger proportion of the population. Staffing requirements for CCCs are frequently lower than for ETUs because CCCs are often designed such that basic patient needs such as food are provided for by friends and family of patients rather than by CCC staff. (It is customary in Liberia for friends and family to provide food for hospitalized patients.) Creation of CCCs in Liberia has been led by county health officials and nongovernmental organizations, and this local, community-based approach is intended to destigmatize Ebola, to encourage persons with illness to seek care rather than remain at home, and to facilitate contact tracing of exposed family members. This report describes one Liberian county's approach to establishing a CCC.	f	\N
25378846	The world-wide use of fireworks with their consequent detrimental effect on the air quality is widely recognized with elevated ambient air levels of particulate matter and its several metallic components and gases identified in several studies carried out during such events. Exposed individuals may be at risk following inhalation of such produced pollutants. This review focuses on the impact of fireworks on air quality and the potential effect of fireworks on the respiratory system of healthy individuals as well as those suffering from underlying respiratory diseases, particularly asthma and chronic obstructive pulmonary disease (COPD). This applies not only to spectators including children but also to pyrotechnicians themselves. An extensive Medline search revealed that a strong evidence of the impact of fireworks on respiratory health is lacking in susceptible as well as healthy individuals with no formal studies on COPD or asthma, other than a few case reports in the latter. The implementation of global strategies to control the use of fireworks and hence improve air quality could possibly reduce their likely detrimental effect on human respiratory health in exposed individuals, but clearly a more targeted research is needed.	f	\N
25380207	In this paper a review of the researches on the role of Escherichia coli strain Nissle 1917 (EcN) in gastrointestinal diseases was presented. EcN is a non-pathogenic strain of the Enterobacteriaceae family, which has probiotic properties. In a number of studies conducted among humans and  experimental animals the application of EcN in treatment of gastrointestinal diseases was observed. Most studies about EcN has been devoted to this organism efficacy in ulcerative colitis treatment. Comparable results were obtained, by citied authors, in the treatment (sustaining remission) of EcN and mesalazine in ulcerative colitis. Moreover, this probiotic therapy, compared to placebo, contributes to obtaining a faster remission and improvement of intestinal histopathology. The use of EcN in Crohn's disease has not been the subject of as many studies as in the case of ulcerative colitis. Assessing the importance of EcN in treatment of other gastrointestinal disorders, authors of the studies observed, that in patients with irritable bowel syndrome, who receiving this probiotic there was a pain, nausea and bloating reduction. In studies conducted among children a positive impact of EcN in prevention and treatment of diarrhea was demonstrated. Similar results were obtained in studies conducted in experimental animals. Based on the presented review it can be concluded that the strain of Escherichia coli Nissle 1917 is useful in treatment of gastrointestinal diseases, especially in treatment of ulcerative colitis. This probiotic may constitute a part of treatment of irritable bowel syndrome and diarrhea. The effectiveness of this strain in treatment of Crohn's disease is not clearly established and further research are require.	f	\N
25385258	The objective of this meta-analysis was to determine the association of the apolipoprotein E (ApoE) gene with exceptional longevity (EL) (i.e., reaching 100+ years) by identifying possible unequal distribution of alleles/genotypes in the common variants ε2, ε3, and ε4 among centenarians and younger population. The association of ApoE with EL was analyzed in a total of 2776 centenarians (cases) and 11,941 younger controls (from 13 case-control studies) using the chi-squared test with the Yates correction. We conducted combined and separate analyses for all ethnic groups studied in the literature (Caucasian and Asian). The main result for all ethnic groups combined was that the likelihood of reaching EL was negatively associated with ε4 allele carriage [pooled odds ratio (OR)=0.43; 95% confidence interval (CI) 0.36, 0.50; p<0.001] and with ε4/ε4 (OR=0.18; 95% CI 0.08, 0.39; p<0.001), ε3/ε4 (OR=0.44; 95% CI 0.37, 0.53; p<0.001) and ε2/ε4 genotypes (OR=0.48; 95% CI 0.31, 0.74; p<0.001). In contrast, the ε2/ε3 genotype was positively associated with EL (OR=1.35; 95% CI 1.06, 1.72; p=0.017). When compared with the ε3 allele, the ε2 allele was not associated with increased odds of EL (OR=1.08; 95% CI 0.77, 1.50, p=0.660). The present meta-analysis confirms that, besides its previously documented influence on Alzheimer's and cardiovascular disease risk, the ApoE gene is associated with the likelihood of reaching EL.	f	\N
25386825	Hypertension is the most common cardiovascular disease and remains the most prevalent risk factor for cardiovascular diseases and a major cause of death worldwide. Despite the large number of antihypertensive drugs available, in the majority of patients blood pressure still remains not optimally controlled and persists at high risk of cardiovascular complications. The limitations of current therapies have stimulated the research and development of new classes of antihypertensive agents, with different mechanisms of action, that provide a better blood pressure control, greater protection against organ damage, better tolerability and more effective prevention of cardiovascular diseases. However, essential hypertension is a multifactorial and multigenic disorder, which means that various mechanisms contribute to a greater or lesser extent to increase BP. Recent advances in the understanding of the multiple and complex cellular signalling pathways that modulate vascular smooth muscle cell contraction and growth involved in the regulation of vascular tone and in hypertension-induced end-organ damage have provided valuable insight in identifying new therapeutic targets. This article reviews new antihypertensive drugs under development, focusing on their mechanisms of action and possible advantages compared with traditional drugs.	f	\N
25391248	We demonstrate histological evidence for hyperparathyroidism in patients with gastrectomy. This is, at least in part, explained by impaired calcium absorption, resulting in mineralization defects and secondary hyperparathyroidism. Additionally, we demonstrate improved bone mineralization in patients with gastrectomy after gluconate therapy and showed the effectiveness of calcium gluconate over carbonate to balance impaired calcium hemostasis in mice. Gastrectomy and hypochlorhydria due to long-term proton pump inhibitor therapy are associated with increased fracture risk because of intestinal calcium malabsorption. Hence, our objectives were to histologically investigate bone metabolism in patients with gastrectomy and to analyze the impact of calcium gluconate supplementation on skeletal integrity in the setting of impaired gastric acidification. Undecalcified bone biopsies of 26 gastrectomized individuals were histologically analyzed. In the clinical setting, we retrospectively identified 5 gastrectomized patients with sufficient vitamin D level, who were additionally supplemented with calcium gluconate and had a real bone mineral density (aBMD) follow-up assessments. A mouse model of achlorhydria (ATP4b-/-) was used to compare the effect of calcium gluconate and calcium carbonate supplementation on bone metabolism. Biopsies from gastrectomized individuals showed significantly increased osteoid, osteoclast, and osteoblast indices and fibroosteoclasia (p < 0.05) as well as impaired calcium distribution in mineralized bone matrix compared to healthy controls. Five gastrectomized patients with sufficient vitamin D level demonstrated a significant increase in aBMD after a treatment with calcium gluconate alone for at least 6 months (p < 0.05). Calcium gluconate was superior to calcium carbonate in maintaining calcium metabolism in a mouse model of achlorhydria. Gastrectomy is associated with severe osteomalacia, marrow fibrosis, and impaired calcium distribution within the mineralized matrix. We show that calcium gluconate supplementation can increase bone mineral density in gastrectomized individuals and performs superior to calcium carbonate in restoring calcium/skeletal homoeostasis in a mouse model of achlorhydria.	f	\N
25391854	Genetic polymorphisms in Solute carrier family 1 (glial high affinity glutamate transporter), member 2 (SLC1A2) have been linked with essential tremor. SLC1A2 encodes excitatory amino acid transporter type 2 (EAAT2), which clears glutamate from the synaptic cleft. One postulated mechanism for essential tremor is the over-excitation of glutamatergic olivo-cerebellar climbing fibers, leading to excitotoxic death of Purkinje cells. Other glutamatergic excitatory signals are transmitted to Purkinje cells via parallel fibers of cerebellar granule neurons. Therefore, the expression level of glutamate transporters could be important in essential tremor pathogenesis. Using Western blotting, we compared the expression levels of the two main glutamate transporters in the cerebellar cortex, EAAT1 and EAAT2, in postmortem tissue from 16 essential tremor cases and 13 age-matched controls. We also studied the localization of EAAT1 and EAAT2 using immunohistochemistry in 10 essential tremor cases and 12 controls. EAAT1 protein levels were similar in cases and controls (1.12 ± 0.83 vs. 1.01 ± 0.69, p =0.71) whereas EAAT2 protein levels in essential tremor cases were only 1/3 of that in controls (0.35 ± 0.23 vs. 1.00 ± 0.62, p < 0.01). Interestingly, EAAT2, but not EAAT1, was expressed in astrocytic processes surrounding the Purkinje cell axon initial segment, a region of previously observed pathological changes in essential tremor. Our main finding, a significant reduction in cerebellar cortical EAAT2 protein levels in essential tremor, suggests that Purkinje cells in essential tremor might be more vulnerable to excitotoxic damage than those of controls.	f	\N
25400038	Schistosomiasis, one of the most important neglected tropical diseases worldwide, is caused by flatworms (blood flukes or schistosomes) that live in the bloodstream of humans. The hepatointestinal form of this debilitating disease results from a chronic infection with Schistosoma mansoni or Schistosoma japonicum. No vaccine is available to prevent schistosomiasis, and treatment relies predominantly on the use of a single drug, praziquantel. In spite of considerable research effort over the years, very little is known about the complex in vivo events that lead to granuloma formation and other pathological changes during infection. Here we use, for the first time, a lentivirus-based transduction system to deliver microRNA-adapted short hairpin RNAs (shRNAmirs) into the parasite to silence and explore selected protein-encoding genes of S. mansoni implicated in the disease process. This gene-silencing system has potential to be used for functional genomic-phenomic studies of a range of socioeconomically important pathogens.	f	\N
25400122	We report a 10-year-old male with relapsing Ph-like acute lymphoblastic leukemia (ALL) bearing ATF7IP/PDGFRB translocation. He was refractory to conventional therapy, and was finally treated with single-agent second-generation TKI dasatinib. The therapeutic response was prompt, with the disappearance of minimum residual disease (MRD) based on genomic PCR analysis within 3 months, and he has maintained complete molecular remission for 12 months. This case report describes an early-phase response to TKI monotherapy on Ph-like ALL, and technical tips for MRD monitoring on long-term follow-up.	f	\N
25404522	Untreated human immunodeficiency virus type 1 (HIV) infection is associated with persistent immune activation, which is an independent driver of disease progression in European and United States cohorts. In Uganda, HIV-1 subtypes A and D and recombinant AD viruses predominate and exhibit differential rates of disease progression. HIV-1 seroconverters (n = 156) from rural Uganda were evaluated to assess the effects of T-cell activation, viral load, and viral subtype on disease progression during clinical follow-up. The frequency of activated T cells was increased in HIV-1-infected Ugandans, compared with community matched uninfected individuals, but did not differ significantly between viral subtypes. Higher HIV-1 load, subtype D, older age, and high T-cell activation levels were associated with faster disease progression to AIDS or death. In a multivariate Cox regression analysis, HIV-1 load was the strongest predictor of progression, with subtype also contributing. T-cell activation did not emerge an independent predictor of disease progression from this particular cohort. These findings suggest that the independent contribution of T-cell activation on morbidity and mortality observed in European and North American cohorts may not be directly translated to the HIV epidemic in East Africa. In this setting, HIV-1 load appears to be the primary determinant of disease progression.	f	\N
25406883	Periorbital burns are an infrequent but potentially devastating injury. This study aimed to elucidate the spectrum of such injuries presenting to a UK burns centre and the outcome achieved in the cases requiring periorbital reconstruction for the restoration of function and form. Patients admitted to a UK regional burns centre between January 2005 and January 2011 with periorbital burns were identified from the Patient Administration System (PAS), theatre logs and the International Burns Injury database (IBID). Multiple parameters were assessed using patient notes, ITU and hospital image databases. Over 6 years, 167 patients with facial burns requiring surgery were treated, including 103 patients with eyelid burns. The mean burn size was 33% total body surface area. The eyelid burn depth varied; 67% superficial partial thickness, 17% deep dermal and 16% full thickness. Two patients lost complete vision in one eye, one patient underwent amniotic membrane grafting. In total 16 patients required periorbital reconstruction to maintain eye closure, with 1.8 operations on average per patient. Acute surgery was required in 11 patients, whilst late intervention (>3 months) was needed in 5, 2 patients had both acute and delayed surgery. Of the 5 late intervention patients 4 were treated with full thickness skin grafts and 1 with a Z plasty. Average time for final reconstruction with delayed surgery was 4.5 months. The goal in management of periorbital burns is preservation of vision, prevention of future complications and restoration of an acceptable aesthetic outcome. Total visual loss is thankfully rare, but early ophthalmology intervention is vital given the evidence of corneal damage as a brief therapeutic window exists.	f	\N
25410176	The goal of this cross-sectional observational study was to quantify the pattern-shift visual evoked potentials (VEP) and the thickness as well as the volume of retinal layers using optical coherence tomography (OCT) across a cohort of Parkinson's disease (PD) patients and age-matched controls. Forty-three PD patients and 38 controls were enrolled. All participants underwent a detailed neurological and ophthalmologic evaluation. Idiopathic PD cases were included. Cases with glaucoma or increased intra-ocular pressure were excluded. Patients were assessed by VEP and high-resolution Fourier-domain OCT, which quantified the inner and outer thicknesses of the retinal layers. VEP latencies and the thicknesses of the retinal layers were the main outcome measures. The mean age, with standard deviation (SD), of the PD patients and controls were 63.1 (7.5) and 62.4 (7.2) years, respectively. The patients were predominantly in the initial Hoehn-Yahr (HY) disease stages (34.8% in stage 1 or 1.5, and 55.8 % in stage 2). The VEP latencies and the thicknesses as well as the volumes of the retinal inner and outer layers of the groups were similar. A negative correlation between the retinal thickness and the age was noted in both groups. The thickness of the retinal nerve fibre layer (RNFL) was 102.7 μm in PD patients vs. 104.2 μm in controls. The thicknesses of retinal layers, VEP, and RNFL of PD patients were similar to those of the controls. Despite the use of a representative cohort of PD patients and high-resolution OCT in this study, further studies are required to establish the validity of using OCT and VEP measurements as the anatomic and functional biomarkers for the evaluation of retinal and visual pathways in PD patients.	f	\N
25412555	Ovary cancer is a disease charged of paradigms and a serious health problem. It's important to know its natural history, because has a multifactor origins, and understanding its behavior since risk factors until patient's death because metastatic disease is a challenger for oncology group. In this work we made a bibliographic, analytic review that brings up concepts related to its origin, evolution, risk factors, preclinical horizon, and clinical symptoms until the death of patient.	f	\N
25424781	While a PhD candidate, doing my thesis at the Oak Ridge National Laboratory, Biology Division under Dr. Charles Congdon, my introduction to the immune response was studying graft vs. host (GVH) disease as a consequence of bone marrow transplantation in mice. The sequalae of GVH was impressive, and demonstrated the potential of negative clinical consequences of the immune system. The idea of harnessing this immunological phenomena in cancer therapy was appealing even in the late 1960s. The problem was that at the time T-cells as a component of the immune system were identified but not defined. We moved to soluble antigen stimulation in mice and recognized and described the post antigen stimulation changes in lymphatic tissue germinal centers during the first 48 h after the induction of the humoral immune response. We described the extracellular localization of soluble antigens on the surface of dendritic reticular cells of the stroma, directing a response of B-cells to produce antibody against non-self. The ensuing reaction was the rapid proliferation of B-cells toward antibody secreting plasma cells.	f	\N
25428209	The Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST) is a multicenter randomized trial of stenting versus endarterectomy in patients with symptomatic and asymptomatic carotid disease. This study assesses management of vascular risk factors. Management was provided by the patient's physician, with biannual monitoring results collected by the local site. Therapeutic targets were low-density lipoprotein, cholesterol <100 mg/dL, systolic blood pressure <140 mm Hg, fasting blood glucose <126 mg/dL, and nonsmoking status. Optimal control was defined as achieving all 4 goals concurrently. Generalized estimating equations were used to compare risk factors at baseline with those observed in scheduled follow-up visits for up to 48 months. In the analysis cohort of 2210, significant improvements in risk-factor control were observed across risk factors for all follow-up visits compared with baseline. At 48 months, achievement of the low-density lipoprotein cholesterol goal improved from 59.1% to 73.6% (P<0.001), achievement of the systolic blood pressure goal improved from 51.6% to 65.1% (P<0.001), achievement of the glucose goal improved from 74.9% to 80.7% (P=0.0101), and nonsmoking improved from 74.4% to 80.9% (P<0.0001). The percentage with optimal risk-factor control also improved significantly, from 16.7% to 36.2% (P<0.001), but nearly 2 of 3 study participants did not achieve optimal control during the study. Site-based risk-factor control improved significantly in the first 6 months and over the long term in CREST but was often suboptimal. Intensive medical management should be considered for future trials of carotid revascularization. ClinicalTrials.gov. Unique identifier: NCT00004732.	f	\N
25439075	Gastric cancer is the third cause of cancer death worldwide, and Helicobacter pylori infection causes almost 90% of non-cardia cancers, the predominant type. H. pylori infection is treatable, and in clinical trials there is evidence of a 30-40% reduction in incidence of gastric cancer among treated subjects. However, with a few exceptions, there are no public health programmes for gastric cancer prevention. In December 2013, the International Agency for Research on Cancer (IARC), organized a Working Group of international experts to discuss and make recommendations for gastric cancer control. The Working Group considered that the enormous burden of disease, which is not expected to decline in the coming decades, requires decisive public health action to include gastric cancer in cancer control programmes. Interventions should be tailored to the local conditions and consider population-based screening and eradication of H. pylori, in the context of evaluation of feasibility, efficacy and adverse consequences.	f	\N
25439990	We report a case of KSHV/EBV associated germinotropic lymphoproliferative disorder (LPG) in a 49-year-old African patient, without immunosuppression. LPG is a rare entity arising in immunocompetent patients in opposition to other lymphoproliferative disorders associated to Kaposi sarcoma-associated herpes virus (KSHV). The disease presents itself as localized lymphadenopathy with an infiltration of germinal centers by plasmablastic cells coinfected by KSHV and EBV (Epstein-Barr Virus). After treatment, the outcome is favorable. Differential diagnosis in our case, due to the presence of clusters of Hodgkin-like cells in the mantle zone, included lymphocyte rich classic Hodgkin lymphoma (LHCRL) and nodular lymphocyte predominant Hodgkin lymphoma (LHNPL). Finally, we highlight the differential diagnostic criteria of KSHV lymphoproliferative diseases.	f	\N
25440885	While important efforts were made in the development of positron emission tomography (PET) tracers for the in vivo molecular diagnosis of Alzheimer's disease, very few investigations to develop magnetic resonance imaging (MRI) probes were performed. Here, a new generation of Gd(III)-based contrast agents (CAs) is proposed to detect the amyloid β-protein (Aβ) aggregates by MRI, one of the earliest biological hallmarks of the pathology. A building block strategy was used to synthesize a library of 16 CAs to investigate structure-activity relationships (SARs) on physicochemical properties and binding affinity for the Aβ aggregates. Three types of blocks were used to modulate the CA structures: (i) the Gd(III) chelates (Gd(III)-DOTA and Gd(III)-PCTA), (ii) the biovectors (2-arylbenzothiazole, 2-arylbenzoxazole and stilbene derivatives) and (iii) the linkers (neutrals, positives and negatives with several lengths). These investigations revealed unexpected SARs and a difficulty of these probes to cross the blood-brain barrier (BBB). General insights for the development of Gd(III)-based CAs to detect the Aβ aggregates are described.	f	\N
25445322	Aleutian disease virus (ADV, Amdovirus, Parvoviridae) primarily infects farmed mustelids (mink and ferrets) but also other fur-bearing animals and humans. Three Aleutian disease (AD) cases have been described in captive striped skunks; however, little is known about the relevance of AD in free-ranging carnivores. This work describes the pathological findings and temporospatial distribution in 7 cases of AD in free-ranging striped skunks. All cases showed neurologic disease and were found in a 46-month period (2010-2013) within a localized geographical region in California. Lesions included multisystemic plasmacytic and lymphocytic inflammation (ie, interstitial nephritis, myocarditis, hepatitis, meningoencephalitis, pneumonia, and splenitis), glomerulonephritis, arteritis with or without fibrinoid necrosis in several organs (ie, kidney, heart, brain, and spleen), splenomegaly, ascites/hydrothorax, and/or encephalomalacia with cerebral microangiopathy. ADV infection was confirmed in all cases by specific polymerase chain reaction and/or in situ hybridization. The results suggest that AD is an emerging disease in free-ranging striped skunks in California.	f	\N
25445432	The relationship between pre-hospital care and the prognosis of out-of-hospital cardiac arrest (OHCA) caused by respiratory disease is unclear. This study aimed to assess the impact of pre-hospital care on the prognosis of OHCA caused by respiratory disease. In a nationwide, population-based, observational study, we enrolled 121,081 adults aged ≥18 years who experienced OHCA from January 1, 2010, to December 31, 2010. The primary endpoint was favourable neurological outcomes. Of the 120,256 eligible adult OHCA patients, 7,071 (5.9%) experienced OHCA caused by respiratory disease. Of these 7,071 patients, 3,911 (55.3%) received no cardiopulmonary resuscitation (CPR), 2,403 (34.0%) received chest-compression-only CPR, and 757 (10.7%) received conventional CPR by a bystander. There was no significant difference between the three types of bystander CPR with regard to the neurological outcome (no CPR: OR 0.68, 95%CI 0.39-1.24, p=0.1951; chest-compression-only CPR: OR 0.68, 95%CI 0.37-1.29, p=0.2295; and conventional CPR: as a reference). Pre-hospital administration of epinephrine (OR 0.37, 95%CI 0.13-0.85, p=0.0170) and the implementation of advanced airway management (OR 0.32, 95%CI 0.19-0.52, p<0.0001) were associated with poor neurological outcomes. Even in OHCA caused by respiratory disease, not only pre-hospital epinephrine administration but also pre-hospital advanced airway management and rescue breathing in bystander CPR may not be critical.	f	\N
25456683	Group A streptococcal (GAS) infections are frequent in developing countries but the epidemiology is incompletely known. In 2005, 90 % of symptomatic pharyngitis, 96 % of invasive diseases and 97 % of deaths due to GAS were observed in these countries. Clinical features of GAS invasive infections are identical to those reported in developed countries, but frequency and mortality are higher, as is the number of the different emm types involved. In the world, from 15.6 to 19.6 millions of persons are affected by rheumatic heart disease (282,000 new cases and 233,000-468,000 deaths per year). Incidence of acute post-streptococcal glomerulonephritis varies with time and location: in 2005, 472,000 new cases have been reported in the world (83 % in a developing country). World Heart Federation recently aimed at reducing the burden of rheumatic heart diseases by 25 % among < 25 years persons in 2025.	f	\N
25467562	Patients are increasingly being admitted with chronic atrial fibrillation, and disease-specific management might reduce recurrent admissions and prolong survival. However, evidence is scant to support the application of this therapeutic approach. We aimed to assess SAFETY--a management strategy that is specific to atrial fibrillation. We did a pragmatic, multicentre, randomised controlled trial in patients admitted with chronic, non-valvular atrial fibrillation (but not heart failure). Patients were recruited from three tertiary referral hospitals in Australia. 335 participants were randomly assigned by computer-generated schedule (stratified for rhythm or rate control) to either standard management (n=167) or the SAFETY intervention (n=168). Standard management consisted of routine primary care and hospital outpatient follow-up. The SAFETY intervention comprised a home visit and Holter monitoring 7-14 days after discharge by a cardiac nurse with prolonged follow-up and multidisciplinary support as needed. Clinical reviews were undertaken at 12 and 24 months (minimum follow-up). Coprimary outcomes were death or unplanned readmission (both all-cause), measured as event-free survival and the proportion of actual versus maximum days alive and out of hospital. Analyses were done on an intention-to-treat basis. The trial is registered with the Australian New Zealand Clinical Trials Registry (ANZCTRN 12610000221055). During median follow-up of 905 days (IQR 773-1050), 49 people died and 987 unplanned admissions were recorded (totalling 5530 days in hospital). 127 (76%) patients assigned to the SAFETY intervention died or had an unplanned readmission (median event-free survival 183 days [IQR 116-409]) and 137 (82%) people allocated standard management achieved a coprimary outcome (199 days [116-249]; hazard ratio 0·97, 95% CI 0·76-1·23; p=0·851). Patients assigned to the SAFETY intervention had 99·5% maximum event-free days (95% CI 99·3-99·7), equating to a median of 900 (IQR 767-1025) of 937 maximum days alive and out of hospital. By comparison, those allocated to standard management had 99·2% (95% CI 98·8-99·4) maximum event-free days, equating to a median of 860 (IQR 752-1047) of 937 maximum days alive and out of hospital (effect size 0·22, 95% CI 0·21-0·23; p=0·039). A post-discharge management programme specific to atrial fibrillation was associated with proportionately more days alive and out of hospital (but not prolonged event-free survival) relative to standard management. Disease-specific management is a possible strategy to improve poor health outcomes in patients admitted with chronic atrial fibrillation. National Health and Medical Research Council of Australia.	f	\N
25470167	This article provides a practical clinical approach for the role of exercise in the treatment and management of neurologic disorders. A number of clinical studies have reported positive benefits from exercise in various neurologic disease states, suggesting that this mode of intervention should be considered as another option in clinical management. Significant evidence-based data exists confirming the positive effects of exercise in otherwise healthy populations. Good evidence also exists that physical activity may benefit people with long-term neurologic conditions. Despite this evidence, exercise is often neglected in patients with normal aging or neurologic disease progression. Neurologists should counsel patients on this therapeutic adjunct and provide specific recommendations when possible.	f	\N
25476560	Cardiovascular risk remains uncertain in patients with cardiovascular disease despite achieving target lipid levels. Serum levels of lipoprotein(a) [Lp(a)] can be risk factors for adverse events. The aim of this study was to determine the role of Lp(a) as a residual risk factor in patients who achieve target lipid levels by the time of treatment by percutaneous coronary intervention (PCI). A total of 3,508 patients were treated by PCI from 1997 to 2011 at our institution. Among them, we analyzed consecutive 569 patients who achieved target lipid levels of low-density lipoprotein cholesterol <100 mg/dl, high-density lipoprotein cholesterol ≥40 mg/dl, and triglycerides <150 mg/dl at PCI. A total of 411 eligible patients were assigned to groups according to Lp(a) levels of ≥30 mg/dl (high Lp(a); n = 119) or <30 mg/dl (low Lp(a); n = 292). The primary outcome was a composite of all-cause death and acute coronary syndrome. The median follow-up period was 4.7 years. Cumulative event-free survival was significantly worse for the group with high Lp(a) than with low Lp(a) group (p = 0.04). Multivariate analysis selected a high Lp(a) level as an independent predictor of primary outcomes (hazard ratio 1.68, 95% confidence interval 1.03 to 2.70, p = 0.04). In conclusion, a high Lp(a) value (≥30 mg/dl) could be associated with a poor prognosis after PCI even for patients who achieved target lipid levels.	f	\N
25481243	The presence of somatic mutations in splicing factor 3b subunit 1 (SF3B1) in patients with Myelodysplastic syndromes with ring sideroblasts (MDS-RS) highlights the importance of the RNA-splicing machinery in MDS. We previously reported the presence of bone marrow (BM) RS in Sf3b1 heterozygous (Sf3b1 (+/-)) mice which are rarely found in mouse models of MDS. Sf3b1 (+/-) mice were originally engineered to study the interaction between polycomb genes and other proteins. We used routine blood tests and histopathologic analysis of BM, spleen, and liver to evaluate the hematologic and morphologic characteristics of Sf3b1 (+/-) mice in the context of MDS by comparing the long term follow-up (15 months) of Sf3b1 (+/-) and Sf3b1 (+/+) mice. We then performed a comprehensive RNA-sequencing analysis to evaluate the transcriptome of BM cells from Sf3b1 (+/-) and Sf3b1 (+/+) mice. Sf3b1 (+/-) exhibited macrocytic anemia (MCV: 49.5 ± 1.6 vs 47.2 ± 1.4; Hgb: 5.5 ± 1.7 vs 7.2 ± 1.0) and thrombocytosis (PLTs: 911.4 ± 212.1 vs 878.4 ± 240.9) compared to Sf3b1 (+/+) mice. BM analysis showed dyserythropoiesis and occasional RS in Sf3b1 (+/-) mice. The splenic architecture showed increased megakaryocytes with hyperchromatic nuclei, and evidence of extramedullary hematopoiesis. RNA-sequencing showed higher expression of a gene set containing Jak2 in Sf3b1 (+/-) compared to Sf3b1 (+/+). Our study indicates that Sf3b1 (+/-) mice manifest features of low risk MDS-RS and may be relevant for preclinical therapeutic studies.	f	\N
25482988	Cancer cell metabolism is deregulated, and signalling pathways can be involved. For instance, PI3K/Akt/mTOR is associated with normal proliferation and differentiation, and its alteration is detectable in cancer cells, that exploit the normal mechanisms to overcome apoptosis. On the other hand, also the family of Phospholipase C (PLC) enzymes play a critical role in cell growth, and any change concerning these enzymes or their downstream targets can be associated with neoplastic transformation. Here, we review the role of PLC and PI3K/Akt/mTOR signal transduction pathways in pathophysiology.	f	\N
25486686	The current economic difficulties and the changed epidemiological picture, characterized by an increase in life expectancy, which shows in the elderly, chronically ill and disabled the main, both health and social, care needs,r equires a remark on the hospital network and organization. Today, most of the application assistance is usually at low intensity of care, whereas the acute event is shrinking. The prevalence of hospital admissions concern the elderly, who get into acute events but on a substrate of chronicity and co-morbidity conditions. There must be a new model of hospital network, with the possibility of converting some hospital centres for medium intensity care and selecting few centres for high intensity care, where concentrating the more expensive technology and the skill and expertise of the professional. The -suggestion is a renewed health planning that detects:- hospitals for widespread disease, equipped with emergency war for minor codes-hospital at high intensity of care for emergency-urgency- hospital for particular fields of medical speciality and research.	f	\N
25497401	We present a Dutch family with a novel disease-causing mutation in the mitochondrial tRNA(Ser(UCN)) gene, m.7507A>G. The index patient died during the neonatal period due to cardio-respiratory failure and fatal lactic acidosis. A second patient, his cousin, has severe hearing loss necessitating cochlear implants and progressive exercise intolerance. Laboratory investigations of both patients revealed combined deficiencies of the enzyme complexes of the mitochondrial respiratory chain in several tissues. Reduced levels of fully assembled complexes I and IV in fibroblasts by BN-PAGE associated with (near) homoplasmic levels of the m.7507A>G mutation in several tissues and a severe reduction in the steady-state level of mt-tRNA(Ser(UCN)) in fibroblasts were observed. The novel mitochondrial DNA mutation was shown to segregate with disease; several healthy maternal family members showed high heteroplasmy levels (up to 76 ± 4% in blood and 68 ± 4% in fibroblasts) which did not lead to any alterations in the activities of the enzyme complexes of the respiratory chain in fibroblasts or clinical signs and symptoms. We hereby conclude that the m.7507A>G mutation causes a heterogeneous clinical phenotype and is only pathogenic at very high levels of mtDNA heteroplasmy.	f	\N
25500436	The abnormal formation and insufficient clearance of neutrophil extracellular traps (NETs) has been reported to be involved in the pathogenesis of lupus nephritis (LN). The abnormal regulation of NETs may contribute to increases in the levels of circulating cell-free DNA (cfDNA). The present study tested the hypothesis that elevated plasma cfDNA levels are related to LN. Fifty-four systemic lupus erythematosus (SLE) patients and 43 control subjects were included in this study. The cfDNA concentrations were measured using the Picogreen Kit, the low-density granulocyte (LDG) percentage in peripheral blood mononuclear cells (PBMCs) was tested using a flow cytometer and the DNase I activity was measured according to the radial enzyme-diffusion method. The mean cfDNA concentration in the SLE group was 236.66±40.09 ng/mL, which was significantly higher than that observed in the healthy control group (187.96±40.55 ng/mL, p<0.0001). Meanwhile, the mean cfDNA concentration in the patients with LN was significantly higher than that observed in the patients without LN (247.27±46.79 ng/mL vs. 213.56±31.34 ng/mL, p=0.0094), and the mean cfDNA concentration in the patients with active LN was significantly higher than that observed in the patients with inactive LN (254.22±50.16 ng/mL vs. 215.93±29.10 ng/mL, p=0.0349). In the SLE group, the cfDNA concentration was to positively correlate with the quantitative 24-hour urinary protein (r=0.350, p=0.013), LDG (r=0.6361, p=0.0019) and neutrophil (r=0.5990, p<0.0001) levels and inversely correlate with the albumin level (r=-0.500, p<0.0001) and endogenous creatinine clearance rate (r=-0.354, p=0.044). Compared to that observed in the control group, the SLE group exhibited a significantly increased percentage of LDGs in PBMCs and a significantly decreased DNase I activity. Our data indicate that elevated plasma cfDNA concentrations may be associated with active LN and partially attributed to the abnormal regulation of NETs in SLE patients, thus suggesting that NETs constitute an intrinsic link between cfDNA and active LN.	f	\N
25524212	The cause of type 1 diabetes remains unknown. To dissect the link between hyperexpression of human leukocyte antigen (HLA) class I on the islet cells, we examined its expression in subjects with recent-onset type 1 diabetes. IHC showed seemingly pronounced hyperexpression in subjects with recent-onset type 1 diabetes, as well as in some nondiabetic subjects. In all subjects, HLA class I expression on exocrine tissue was low. However, no difference in the level of HLA class I expression was found between islet and exocrine tissue using Western blot, flow cytometry, real-time quantitative PCR, or RNA sequencing analyses. Also, the level of HLA class I expression on the messenger level was not increased in islets from subjects with recent-onset type 1 diabetes compared with that in nondiabetic subjects. Consistently, the HLA class I specific enhanceosome (NLRC5) and related transcription factors, as well as interferons, were not enhanced in islets from recent-onset type 1 diabetic subjects. In conclusion, a discrepancy in HLA class I expression in islets assessed by IHC was observed compared with that using quantitative techniques showing similar expression of HLA class I in islets and exocrine tissue in subjects with recent-onset type 1 diabetes, nor could any differences be found between type 1 diabetic and nondiabetic subjects. Results presented provide important clues for a better understanding on how this complex disease develops.	f	\N
25536728	Brucellosis is an important disease in developing countries. We aimed to determine the epidemiologic, clinical, and laboratory characteristics of brucellosis, which still has a high morbidity in Turkey. Seventy-two patients with brucellosis, monitored at our clinic from January 2004 to July 2010, were reviewed retrospectively. The average age was determined to be 44.8 ± 18 years, and 40 of the patients were female (55.6%). The most frequent transmission route was the use of raw milk and dairy products, in 45 of the patients (62.5%). The most frequent complaints were joint pain, high fever, weakness, low back pain, and gastrointestinal symptoms, whereas the most frequent physical examination findings were fever, osteoarticular involvement, splenomegaly, hepatomegaly, and lymphadenopathy. All of the patients were positive for Rose Bengal testing. The standard tube agglutination titer was 1/160 or higher in 64 (88.9%) patients. Brucella melitensis was isolated from blood cultures of 13 (18.1%) patients and bone marrow cultures of 7 (9.7%) patients. Complications of sacroiliitis in 6 (8.3%), spondylodiscitis in 4 (5.6%), endocarditis in 2 (2.8%), neurobrucellosis in 1 (1.4%), and epididymo-orchitis in 1 (1.4%) of the patients were observed. Brucellosis has various clinical presentations. It should be included in the differential diagnosis of high fever and joint pains in endemic countries.	f	\N
25539271	Pancreatic adenocarcinoma is a rapidly progressive malignancy characterized by its tendency for early metastatic spread. MDCT is the primary diagnostic modality for the preoperative staging of patients with pancreatic cancer, with an accuracy established in multiple studies. However, for a variety of reasons, there is often a prolonged interval between staging MDCT and the surgical intervention. This study examines the relationship between the interval between imaging and surgery and the accuracy of MDCT in determining the presence or absence of metastatic disease at surgery in patients with pancreatic cancer. Patients were identified who had undergone surgery for pancreatic cancer at our institution with a dedicated preoperative pancreas-protocol MDCT performed in our department. Findings from the preoperative MDCT report were correlated with the operative findings, as well as the time between imaging and surgery. Two hundred ninety-two MDCT scans were performed on 256 patients who underwent exploration for pancreatic adenocarcinoma. The patients had a median age of 67 years (range, 30-95 years), and 51.6% (132/256) were male. The median time between MDCT and surgical exploration was 15.5 days (range, 1-198 days). MDCT correctly predicted the absence of metastatic disease at surgery in 233 of 274 (85.0%) studies. MDCT was more accurate in predicting the absence of metastatic disease if the study was performed within 25 days of surgery than it was if the study was performed within more than 25 days of surgery (89.3% vs 77.0%; p = 0.0097). Furthermore, regression models showed that the negative predictive value of a given MDCT significantly decreased after approximately 4 weeks. MDCT is an accurate method to stage patients with pancreatic cancer, but its accuracy in excluding distant metastatic disease depreciates over time. Patients should undergo a repeat MDCT within 25 days of any planned definitive operative intervention for pancreatic cancer to avoid unexpectedly finding metastatic disease at surgery.	f	\N
25545990	Dependence on invasive procedures for classification of patients with Sjögren's syndrome (SS) hampers timely diagnosis and suitable patient followup. The aim of this study was to recapitulate the diagnosis of SS through noninvasive means and to define the biologic state of SS patients' salivary glands. Using a 187-plex capture antibody-based assay, salivary proteomic biomarker profiles were generated from patients with primary SS, patients with rheumatoid arthritis, and asymptomatic controls. Discriminant function analyses and Gene Ontology-based network analyses allowed data analyses with a reductionist approach and with a focus on systems biology. Characterized by significant changes in 61 and 55 proteins, respectively, the salivary proteome of SS patients appeared profoundly altered compared to that of individuals without SS. On this basis, 4-plex and 6-plex biomarker signatures, both including interleukin-4 (IL-4), IL-5, and clusterin, achieved accurate prediction of an individual's group membership for at least 94% of cases. Of note, all misclassified SS patients presented with ectopic germinal center-like structures. Systematic inference of biologic meaning identified SS-related protein patterns delineating B cell-dominated immune responses, macrophage differentiation, and signs of T cell chemotaxis. In addition, proteomic Multi-Analyte Profiles provided insight about proteins related to collagen, cytokine, and growth factor synthesis as well as lipid transport. The SS-related molecular landscape conveyed by saliva showed great congruence with histopathologic features found in SS and advances understanding of this disease at a molecular level. Such salivary biomarker signatures harbor great potential for improving timeliness of SS diagnosis and enabling suitable patient followup.	f	\N
25546563	Sjögren's Syndrome (SS) is an autoimmune disease that causes sicca (dryness) symptoms by affecting secretions most notably of the lacrimal and salivary glands. Voice disorders have been documented in patients with SS, but the true prevalence and relationships among possible contributing factors remain unknown. This preliminary epidemiological investigation examined prevalence and risk factors for voice disorders in SS. Self-report epidemiological questionnaire. One hundred and one (101) patients with SS (94 females, 7 males; M age = 59.4 years; standard deviation [SD] = 14.1 years) completed an extensive interview using a previously validated questionnaire involving the patient's medical, family, occupational, psychosocial, social/lifestyle, voice use, and general health histories. Summary statistics, chi-squares, risk ratios, and multiple logistic regression were used to determine the frequency and severity of voice disorders in individuals with SS, as well as associations with demographic, lifestyle, health, disease severity, and voice use factors. The prevalence of a current voice disorder in individuals with SS was 59.4%. In general, voice disorders began gradually; were chronic; and correlated with SS disease severity independent of age, sex, duration of the disease, comorbid autoimmune conditions, and use of SS-related medication. Specific voice symptoms including chronic throat dryness and soreness were significantly associated with SS disease severity. Voice disorders are relatively common in SS and are more frequent as disease severity worsens. These findings have important implications for evaluation and treatment of patients with SS. 4.	f	\N
25549186	After injection into muscle and peripheral nerves, a variety of viral vectors undergo retrograde transport to lower motor neurons. However, because of its attractive safety profile and durable gene expression, adeno-associated virus (AAV) remains the only vector to have been applied to the human nervous system for the treatment of neurodegenerative disease. Nonetheless, only a very small fraction of intramuscularly injected AAV vector arrives at the spinal cord. To engineer a novel AAV vector by inserting a neuronal targeting peptide (Tet1), with binding properties similar to those of tetanus toxin, into the AAV1 capsid. Integral to this approach was the use of structure-based design to increase the effectiveness of functional capsid engineering. This approach allowed the optimization of scaffolding regions for effective display of the foreign epitope while minimizing disruption of the native capsid structure. We also validated an approach by which low-titer tropism-modified AAV vectors can be rescued by particle mosaicism with unmodified capsid proteins. Importantly, our rationally engineered AAV1-based vectors exhibited markedly enhanced transduction of cultured motor neurons, diminished transduction of nontarget cells, and markedly superior retrograde delivery compared with unmodified AAV1 vector. This approach promises a significant advancement in the rational engineering of AAV vectors for diseases of the nervous system and other organs.	f	\N
25549677	To explore the clinical features of neuromyelitis optica (NMO) spectrum disease (NMOSD) with connective tissue disease (CTD). The clinical features of 184 NMO/NMOSD patients (NMO/NMOSD: 119/184, 64.7%; NMO/NMOSD-CTD: 65/184, 35.3%) from May 2013 to May 2014 were analyzed retrospectively. And the effectiveness of long-term treatment of immunosuppressive drugs in NMOSD was evaluated. NMO/NMOSD-CTD patients had significantly higher female percentage (93.8% vs 83.2%, P < 0.05) and significantly higher percentage of patients with cerebral spinal fluid (CSF)-restricted oligoclonal band (OB)(41.5% vs 21.9%, P < 0.05). As compared with NMO/NMOSD-CTD counterparts, NMO/NMOSD patients had significantly higher percentage of non-specific lesions on brain MRI (62.5% vs 35.9%, P < 0.01). After >6 months consecutive long-term treatment of immunosuppressive drugs, the relapse rate post-treatment (0.36 ± 0.85) was significantly lower than that pre-treatment (2.91 ± 4.10, P < 0.01). And no significant difference existed in expanded disability status scale (EDSS) score between pre-and post-treatment. When using azathioprine (AZA), the percentage of relapse was significantly higher in NMO/NMOSD-CTD patients (50.0%) versus NMO/NMOSD ones (18.5%, P = 0.064); When using cyclophosphamide (CTX), there was no such significant difference. Female patients are more susceptible to have NMO/NMOSD with CTD. NMO/NMOSD-CTD patients tend to have higher percentage of CSF-restricted OB and fewer non-specific lesions on brain MRI. AZA and CTX may effectively reduce relapses in both NMO/NMOSD and NMO/NMOSD-CTD patients. However CTX is superior to AZA for reducing relapses in NMO/NMOSD-CTD patients.	f	\N
25551964	The aim of this study was to investigate if vaginal preparation procedure affects the occurrence of oocyte pickup-associated pelvic inflammation (OPU-PI) and the reproductive outcome in an in vitro fertilization (IVF) program. The occurrence of OPU-PI and the reproductive outcome were compared between 956 infertile patients undergoing vaginal preparation with saline douching alone versus 1,216 infertile patients undergoing a combination ofpovidone iodine disinfection and subsequent saline douching in an IVF program. OPU-PI occurred in four patients (0.042%) in the saline douching alone group, whereas there were no cases in the combination group (p = 0.016). There were no significant differences in the rate of fertilization, morphologically good embryo acquisition, clinical and ongoing pregnancy between the two groups (p > 0.23). This large cohort study demonstrated that a combination of vaginal povidone iodine disinfection and subsequent saline douching is more effective procedure than saline douching alone to prevent OPU-PI, without spoiling the oocyte quality.	f	\N
25553466	Hemophilia is an X-linked inherited bleeding disorder consisting of two classifications, hemophilia A and hemophilia B, depending on the underlying mutation. Although the disease is currently treatable with intravenous delivery of replacement recombinant clotting factor, this approach represents a significant cost both monetarily and in terms of quality of life. Gene therapy is an attractive alternative approach to the treatment of hemophilia that would ideally provide life-long correction of clotting activity with a single injection. In this review, we will discuss the multitude of approaches that have been explored for the treatment of both hemophilia A and B, including both in vivo and ex vivo approaches with viral and nonviral delivery vectors.	f	\N
25553772	Farnesoid x receptor (FXR) belongs to the group of nuclear receptors (NRs), which regulate the expression of various genes by binding to DNA either as a monomer or a heterodimer with retinoid x receptor. FXR affects several metabolic pathways through its specific target genes, regulating bile acid (BA) synthesis and homeostasis, glucose and lipid metabolism, also exhibiting a crucial role in intestinal bacterial growth and liver regeneration. Additionally, FXR is involved in the pathogenesis of different cholestatic diseases, as well as non-alcoholic fatty liver disease, inflammatory bowel disease (IBD) and primary idiopathic BA malabsorption. Analyses of certain FXR polymorphisms revealed associations with clinical phenotypes and susceptibility to various human diseases. FXR single-nucleotide polymorphisms seem to be correlated with differences in glucose homeostasis, gallstone formation, intrahepatic cholestasis of pregnancy, IBD and therapeutic response to hypolipidemic therapy, among studied populations. Unfortunately, little data are still available and more studies remain to be done to determine the contribution of FXR polymorphisms in estimating risk factors and clinical outcomes for several diseases.	f	\N
25575898	The Hundred Person Wellness Project is an ambitious pilot undertaking, which aims to intensely monitor 100 individuals over 10 months. Patients with abnormal findings will be treated, in hopes that this early intervention will avoid, or delay, symptomatic disease. Google's "Baseline Study" is of similar scope and will enroll 10,000 people over 2 to 3 years. I here speculate that these approaches will likely not be effective in preventing disease, but instead, lead to unnecessary and potentially harmful interventions. Examples from the cancer screening experience over the last 30 years are provided, which show that intensive testing may uncover indolent disease or incidental findings which, when treated, may cause more harm than good. Additional examples show that aggressive treatments for cancer and other diseases do not always lead to better patient outcomes. I conclude that the recent advances in omics provide us with unprecedented opportunities for high content clinical testing, but such testing should be used with caution to avoid the harmful consequences of over-diagnosis and over-treatment. Despite the detailed rebuttals by Hood and colleagues in another commentary in BMC Medicine, time will show the actual benefits and harms of these ambitious initiatives.	f	\N
25585384	In 2014, a major epidemic of human Ebola virus disease emerged in West Africa, where human-to-human transmission has now been sustained for greater than 12 months. In the summer of 2014, there was great uncertainty about the answers to several key policy questions concerning the path to containment. What is the relative importance of nosocomial transmission compared with community-acquired infection? How much must hospital capacity increase to provide care for the anticipated patient burden? To which interventions will Ebola transmission be most responsive? What must be done to achieve containment? In recent years, epidemic models have been used to guide public health interventions. But, model-based policy relies on high quality causal understanding of transmission, including the availability of appropriate dynamic transmission models and reliable reporting about the sequence of case incidence for model fitting, which were lacking for this epidemic. To investigate the range of potential transmission scenarios, we developed a multi-type branching process model that incorporates key heterogeneities and time-varying parameters to reflect changing human behavior and deliberate interventions in Liberia. Ensembles of this model were evaluated at a set of parameters that were both epidemiologically plausible and capable of reproducing the observed trajectory. Results of this model suggested that epidemic outcome would depend on both hospital capacity and individual behavior. Simulations suggested that if hospital capacity was not increased, then transmission might outpace the rate of isolation and the ability to provide care for the ill, infectious, and dying. Similarly, the model suggested that containment would require individuals to adopt behaviors that increase the rates of case identification and isolation and secure burial of the deceased. As of mid-October, it was unclear that this epidemic would be contained even by 99% hospitalization at the planned hospital capacity. A new version of the model, updated to reflect information collected during October and November 2014, predicts a significantly more constrained set of possible futures. This model suggests that epidemic outcome still depends very heavily on individual behavior. Particularly, if future patient hospitalization rates return to background levels (estimated to be around 70%), then transmission is predicted to remain just below the critical point around Reff = 1. At the higher hospitalization rate of 85%, this model predicts near complete elimination in March to June, 2015.	f	\N
25590983	Pseudomonas aeruginosa, the predominant cause of chronic airway infections of patients with cystic fibrosis, exhibits extensive phenotypic diversity among isolates within and between sputum samples, but little is known about the underlying genetic diversity. To characterize the population genetic structure of transmissible P. aeruginosa Liverpool Epidemic Strain in chronic infections of nine patients with cystic fibrosis, and infer evolutionary processes associated with adaptation to the cystic fibrosis lung. We performed whole-genome sequencing of P. aeruginosa isolates and pooled populations and used comparative analyses of genome sequences including phylogenetic reconstructions and resolution of population structure from genome-wide allele frequencies. Genome sequences were obtained for 360 isolates from nine patients. Phylogenetic reconstruction of the ancestry of 40 individually sequenced isolates from one patient sputum sample revealed the coexistence of two genetically diverged, recombining lineages exchanging potentially adaptive mutations. Analysis of population samples for eight additional patients indicated coexisting lineages in six cases. Reconstruction of the ancestry of individually sequenced isolates from all patients indicated smaller genetic distances between than within patients in most cases. Our population-level analysis demonstrates that coexistence of distinct lineages of P. aeruginosa Liverpool Epidemic Strain within individuals is common. In several cases, coexisting lineages may have been present in the infecting inoculum or assembled through multiple transmissions. Divergent lineages can share mutations via homologous recombination, potentially aiding adaptation to the airway during chronic infection. The genetic diversity of this transmissible strain within infections, revealed by high-resolution genomics, has implications for patient segregation and therapeutic strategies.	f	\N
25595571	Noonan Syndrome (NS) is characterized by short stature, typical facial dysmorphology and congenital heart defects. The incidence of NS is estimated to be between 1:1000 and 1:2500 live births. The syndrome is transmitted as an autosomal dominant trait. In approximately 50% of cases, the disease is caused by missense mutations in the PTPN11 gene on chromosome 12, resulting in a gain of function of the non-receptor protein tyrosine phosphatase SHP-2 protein. Autoimmune Hepatitis (AIH) is a cryptogenic, chronic and progressive necroinflammatory liver disease. Common features of AIH are hypergammaglobulinemia (IgG), presence of circulating autoantibodies, histological picture of interface hepatitis and response to immunosuppressant drugs. Conventional treatment with Prednisone and Azathioprine is effective in most patients. We describe the case of a 6 years-old girl with Noonan Syndrome and Autoimmune Hepatitis type 1. Molecular analysis of PTPN11 gene showed heterozygous mutation c.923A>G (Asn308Ser) in exon 8. Though association between NS and autoimmune disorders is known, this is the second case of association between Noonan Syndrome and Autoimmune Hepatitis type 1 described in literature. In the management of NS, an accurate clinical evaluation would be recommended. When there is a clinical suspicion of autoimmune phenomena, appropriate laboratory tests should be performed with the aim of clarifying whether the immune system is involved in NS. We think that autoimmunity represents a characteristic of NS, even if the etiopathogenesis is still unknown.	f	\N
25600917	Hepatitis B virus surface antigen (HBsAg) levels reflect disease status and can predict the clinical response to antiviral treatment; however, the emergence of HBsAg mutant strains has become a challenge. The Abbott HBsAg quantification assay provides enhanced detection of HBsAg and HBsAg mutants. We aimed to evaluate the performance of the Abbott HBsAg quantification assay with automatic sample dilutions (shortened as automatic Architect assay), compared with the Abbott HBsAg quantification assay with manual sample dilutions (shortened as manual Architect assay) and the Roche HBsAg quantification assay with automatic sample dilutions (shortened as Elecsys). A total of 130 sera samples obtained from 87 hepatitis B virus (HBV)-infected patients were collected to assess the correlation between the automatic and manual Architect assays. Among the 87 patients, 41 provided 42 sera samples to confirm the linearity and reproducibility of the automatic Architect assay, and find out the correlation among the Elecsys and two Architect assays. The coefficients of variation (0.44-9.53%) and R(2) = 0.996-1, which were both determined using values obtained from the automatic Architect assay, showed good reproducibility and linearity. Results of the two Architect assays demonstrated a feasible correlation (n = 130 samples; R = 0.898, p < 0.01). With regard to subgroups, correlations between the two Architect assays were better in the hepatitis B e antigen (HBeAg)-negative group (HBeAg-negative group vs. HBeAg-positive group: R = 0.885 vs. R = 0.865, both p < 0.01) and low HBV DNA group (low DNA group vs. high DNA group: R = 0.886 vs. R = 0.844, both p < 0.01). Significant correlations were also found between the results of the Elecsys and Architect assays (R > 0.93 in all cases). In conclusion, the correlation between the automatic and manual dilution Architect assays was feasible, particularly in the HBeAg-negative and low DNA groups. With lower labor costs and less human error than the manual version, the Abbott automatic dilution Architect assay provided a good clinical performance with regard to the HBsAg levels.	f	\N
25601965	Many cancer patients receive supplemental ascorbate (vitamin C) in the belief that it synergizes the anticancer effects of chemotherapy and reduces its toxicity. A systematic review was performed to evaluate the antitumor effects and toxicity of ascorbate treatment. Medline (1946 to March 2014), EMBASE (1947 to March 2014), and the Cochrane central register (1993 to March 2014) were searched for randomized and observational studies. Of 696 identified records, 61 full-text articles were screened and 34 were included. In total, 5 randomized controlled trials (RCTs) (n = 322), 12 phase I/II trials (n = 287), 6 observational studies (n = 7,599), and 11 case reports (n = 267) were identified. Because of study heterogeneity, no meta-analyses were performed. No RCTs reported any statistically significant improvements in overall or progression-free survival or reduced toxicity with ascorbate relative to control arm. Evidence for ascorbate's antitumor effects was limited to case reports and observational and uncontrolled studies. There is no high-quality evidence to suggest that ascorbate supplementation in cancer patients either enhances the antitumor effects of chemotherapy or reduces its toxicity. Given the high financial and time costs to patients of this treatment, high-quality placebo-controlled trials are needed.	f	\N
25602998	No current therapy for relapsing-remitting multiple sclerosis (MS) results in significant reversal of disability. To determine the association of nonmyeloablative hematopoietic stem cell transplantation with neurological disability and other clinical outcomes in patients with MS. Case series of patients with relapsing-remitting MS (n = 123) or secondary-progressive MS (n = 28) (mean age, 36 years; range, 18-60 years; 85 women) treated at a single US institution between 2003 and 2014 and followed up for 5 years. Final follow-up was completed in June 2014. Treatment with cyclophosphamide and alemtuzumab (22 patients) or cyclophosphamide and thymoglobulin (129 patients) followed by infusion of unmanipulated peripheral blood stem cells. Primary end point was reversal or progression of disability measured by change in the Expanded Disability Status Scale (EDSS) score of 1.0 or greater (score range, 0-10). Secondary outcomes included changes in the Neurologic Rating Scale (NRS) score of 10 or greater (score range, 0-100), Multiple Sclerosis Functional Composite (MSFC) score, quality-of-life Short Form 36 questionnaire scores, and T2 lesion volume on brain magnetic resonance imaging scan. Outcome analysis was available for 145 patients with a median follow-up of 2 years and a mean of 2.5 years. Scores from the EDSS improved significantly from a pretransplant median of 4.0 to 3.0 (interquartile range [IQR], 1.5 to 4.0; n = 82) at 2 years and to 2.5 (IQR, 1.9 to 4.5; n = 36) at 4 years (P < .001 at each assessment). There was significant improvement in disability (decrease in EDSS score of ≥1.0) in 41 patients (50%; 95% CI, 39% to 61%) at 2 years and in 23 patients (64%; 95% CI, 46% to 79%) at 4 years. Four-year relapse-free survival was 80% and progression-free survival was 87%. The NRS scores improved significantly from a pretransplant median of 74 to 88.0 (IQR, 77.3 to 93.0; n = 78) at 2 years and to 87.5 (IQR, 75.0 to 93.8; n = 34) at 4 years (P < .001 at each assessment). The median MSFC scores were 0.38 (IQR, -0.01 to 0.64) at 2 years (P < .001) and 0.45 (0.04 to 0.60) at 4 years (P = .02). Total quality-of-life scores improved from a mean of 46 (95% CI, 43 to 49) pretransplant to 64 (95% CI, 61 to 68) at a median follow-up of 2 years posttransplant (n = 132) (P < .001). There was a decrease in T2 lesion volume from a pretransplant median of 8.57 cm3 (IQR, 2.78 to 22.08 cm3) to 5.74 cm3 (IQR, 1.88 to 14.45 cm3) (P < .001) at the last posttransplant assessment (mean follow-up, 27 months; n = 128). Among patients with relapsing-remitting MS, nonmyeloablative hematopoietic stem cell transplantation was associated with improvement in neurological disability and other clinical outcomes. These preliminary findings from this uncontrolled study require confirmation in randomized trials.	f	\N
25622254	The accumulation and aggregation of misfolded proteins in the brain, such as amyloid-β (Aβ) and hyperphosphorylated tau, is a neuropathological hallmark of Alzheimer's disease (AD). Previously, we developed and validated a novel non-human primate model for sporadic AD (sAD) research using intracerebroventricular administration of streptozotocin (icv STZ). To date, no characterization of AD-related genes in different brain regions has been performed. Therefore, in the current study, the expression of seven amyloid precursor protein (APP) pathway-related and five tau phosphorylation-related genes was investigated by quantitative real-time PCR experiments, using two matched-pair brain samples from control and icv STZ-treated cynomolgus monkeys. The genes showed similar expression patterns within the control and icv STZ-treated groups; however, marked differences in gene expression patterns were observed between the control and icv STZ-treated groups. Remarkably, other than β-secretase (BACE1) and cyclin-dependent kinase 5 (CDK5), all the genes tested showed similar expression patterns in AD models compared to controls, with increased levels in the precuneus and occipital cortex. However, significant changes in gene expression patterns were not detected in the frontal cortex, hippocampus, or posterior cingulate. Based on these results, we conclude that APP may be cleaved via the general metabolic mechanisms of increased α- and γ-secretase levels, and that hyperphosphorylation of tau could be mediated by elevated levels of tau protein kinase, specifically in the precuneus and occipital cortex.	f	\N
25631478	The dihydropteroate sulfate (DHPS) gene is associated with resistance to sulfa/sulfone drugs in Pneumocystis jirovecii. We investigated the DHPS mutation rate in three groups of Iranian HIV-positive and HIV-negative patients by polymerase chain reaction-restricted fragment length polymorphism analysis. Furthermore, an association between P. jirovecii DHPS mutations and strain typing was investigated based on direct sequencing of internal transcribed spacer region 1 (ITS1) and ITS2. The overall P. jirovecii DHPS mutation rate was (5/34; 14.7%), the lowest rate identified was in HIV-positive patients (1/16; 6.25%) and the highest rate was in malignancies patients (3/11; 27.3%). A moderate rate of mutation was detected in chronic obstructive pulmonary disease (COPD) patients (1/7; 14.3%). Most of the isolates were wild type (29/34; 85.3%). Double mutations in DHPS were detected in patients with malignancies, whereas single mutations at codons 55 and 57 were identified in the HIV-positive and COPD patients, respectively. In this study, two new and rare haplotypes were identified with DHPS mutations. Additionally, a positive relationship between P. jirovecii strain genotypes and DHPS mutations was identified. In contrast, no DHPS mutations were detected in the predominant (Eg) haplotype. This should be regarded as a warning of an increasing incidence of drug-resistant P. jirovecii strains.	f	\N
25636578	Psoriasis is a T cell-dependent immune-mediated disease of the skin and joints. It is clear that co-stimulatory and co-inhibitory molecules (currently named co-signaling molecules collectively) synergize with TCR signaling to promote or inhibit T cell activation and function. In recent years, enthusiasm in the field of co-signaling research has been fueled by the success of co-stimulatory and co-inhibitory immunotherapy for the treatment of human diseases. This review outlines the involvement of several sets of co-signaling molecules in the immunopathogenesis of psoriasis. We then describe the relevant preclinical studies and summarize recent clinical findings on targeting these molecules for the treatment of psoriasis.	f	\N
25648029	Western blot is the gold standard method to determine individual protein expression levels. However, western blot is technically difficult to perform in large sample sizes because it is a time consuming and labor intensive process. Dot blot is often used instead when dealing with large sample sizes, but the main disadvantage of the existing dot blot techniques, is the absence of signal normalization to a housekeeping protein. In this study we established a one dot two development signals (ODTDS) dot blot method employing two different signal development systems. The first signal from the protein of interest was detected by horseradish peroxidase (HRP). The second signal, detecting the housekeeping protein, was obtained by using alkaline phosphatase (AP). Inter-assay results variations within ODTDS dot blot and western blot and intra-assay variations between both methods were low (1.04-5.71%) as assessed by coefficient of variation. ODTDS dot blot technique can be used instead of western blot when dealing with large sample sizes without a reduction in results accuracy.	f	\N
25656590	The purpose of this study was to examine the practice patterns of intraoperative completion imaging (CI) for lower extremity bypass (LEB) in the Vascular Quality Initiative (VQI). A retrospective review of all LEB procedures in the VQI database from January 2003 to October 2013 was performed. Regions with fewer than 200 LEB procedures were excluded from the regional analysis. The modality of CI was defined as duplex ultrasound, angiography, or both. A total of 14,140 LEBs were captured, with the rate of CI being 43%. After exclusion of three regions for insufficient volume (<200 LEBs), 13,945 LEB operations across 13 regions were available for regional analysis. Use of any type of intraoperative CI varied across regions from a low of 8% to a high of 70%, with angiography being performed most frequently. When CI was performed, the type of imaging modality varied between regions from a high of 99% for angiography to a high of 75% for duplex ultrasound. CI was more common in male patients (44% of male patients vs 42% of female patients; P = .032), diabetics (44% of diabetic patients vs 42% of nondiabetic patients; P = .026), and patients with coronary artery disease (45% of patients with coronary artery disease vs 42% of patients with no coronary artery disease; P = .0015). CI was performed less frequently in LEB using single-segment great saphenous vein vs LEB using lesser saphenous, arm, or composite vein (48% vs 57%; P < .0001). CI was used in 51% of LEBs with a tibial or pedal target vessel vs 38% of LEBs with a more proximal target vessel (P < .0001). Patients with an indication of critical limb ischemia underwent CI in 45% of LEBs vs 39% with an indication other than critical limb ischemia (P < .0001). Within the VQI database, considerable practice pattern variation exists in the use of CI. Currently, CI is most commonly employed for patients with critical limb ischemia, infrageniculate target vessel, and disadvantaged venous conduit. Further study is required to standardize and to define the appropriate use of CI for LEBs.	f	\N
25659158	Dengue virus infection is a leading cause of morbidity among children in the Philippines in recent years. In order to investigate the association of HLA Class I and II alleles and dengue disease severity in a cohort of Filipino children, we performed a case control study in 2 hospitals in Metro Manila from June 2008 to December 2009. A total of 250 laboratory confirmed dengue patients and 300 healthy individuals aged 5 to 15 years old were typed for HLA-A, B and DRB1 alleles. The frequency of HLA-A*33:01 was significantly decreased in severe dengue (DHF/ DSS; Pc = 0.0016)) and DSS (Pc = 0.0032) compared to the background population. These findings support a previous study that this allele may confer protection against the severe form of dengue and provide the first evidence of HLA association with dengue in the Philippines. Future studies should be directed in investigating the possible mechanisms of protection.	f	\N
25659380	The 18th WHO Global Tuberculosis Annual Report indicates that there were an estimated 8.6 million incident cases of tuberculosis (TB) in 2012, which included 2.9 million women and 530,000 children. TB caused 1.3 million deaths including 320,000 human immunodeficiency virus (HIV)-infected people; three-quarters of deaths occurred in Africa and Southeast Asia. With one-third of the world's population latently infected with Mycobacterium tuberculosis (Mtb), active TB disease is primarily associated with a break down in immune surveillance. This explains the strong link between active TB disease and other communicable diseases (CDs) or noncommunicable diseases (NCDs) that exert a toll on the immune system. Comorbid NCD risk factors include diabetes, smoking, malnutrition, and chronic lung disease, all of which have increased relentlessly over the past decade in developing countries. The huge overlap between killer infections such as TB, HIV, malaria, and severe viral infections with NCDs, results in a "double burden of disease" in developing countries. The current focus on vertical disease programs fails to recognize comorbidities or to encourage joint management approaches. This review highlights major disease overlaps and discusses the rationale for better integration of tuberculosis care with services for NCDs and other infectious diseases to enhance the overall efficiency of the public health responses.	f	\N
25662376	To determine the number, distribution and cost of hospital admissions for chronic obstructive pulmonary disease (COPD) in New Zealand. National patient-level routine data on admissions with a principal diagnosis of COPD (mostly ICD-10- AN J440 and J441) were obtained for the period July 1st 2008 to June 30th 2013. Admissions with length of stay (LOS) = 90 days were excluded. There were 61,516 admissions in 5 years. Admission rates and budget impact (in 2012/13 dollar values) were stable but the average length of stay (ALOS) declined from 5.09 to 4.37 days. In FY2012/13 the admission rate was 2.82 per 1000 population, with age standardised rate (ASR) 4.4- and 3.6-fold higher for Maori and Pacific peoples respectively than for European/others. For age = 15 years the ASR was 2.55 per 1000. Admission rates were higher for men than women and increased steeply with age and socioeconomic deprivation (NZDep06). The mean age at discharge was lower for Maori and Pacific peoples than for European/Others (63.4, 67.1 and 72.3 years). The mean 30-day readmission rate was 6.7%. The average LOS increased with age and was shorter for Maori (3.6 days) and Pacific peoples (3.5 days) than for European/Others (4.7 days). Admission rates varied widely across District Health Boards, and were higher in rural than urban regions. The estimated cost of admissions in FY2012/13 was $NZ59.6m. Hospital admissions for COPD are costly and are over-represented in high risk groups including rural, elderly, socioeconomically deprived and Maori and Pacific peoples. Effective interventions that are targeted to high risk groups are required to improve equity and reduce the burden of COPD.	f	\N
25664604	A novel oral octreotide formulation was tested for efficacy and safety in a phase III, multicenter, open-label, dose-titration, baseline-controlled study in patients with acromegaly. We enrolled 155 complete or partially controlled patients (IGF-1 <1.3 × upper limit of normal [ULN], and 2-h integrated GH <2.5 ng/mL) receiving injectable somatostatin receptor ligand (SRL) for ≥ 3 months. Subjects were switched to 40 mg/d oral octreotide capsules (OOCs), and the dose escalated to 60 and then up to 80 mg/d to control IGF-1. Subsequent fixed doses were maintained for a 7-month core treatment, followed by a voluntary 6-month extension. Of 151 evaluable subjects initiating OOCs, 65% maintained response and achieved the primary endpoint of IGF-1 <1.3 × ULN and mean integrated GH <2.5 ng/mL at the end of the core treatment period and 62% at the end of treatment (up to 13 mo). The effect was durable, and 85 % of subjects initially controlled on OOCs maintained this response up to 13 months. When controlled on OOCs, GH levels were reduced compared to baseline, and acromegaly-related symptoms improved. Of 102 subjects completing the core treatment, 86% elected to enroll in the 6-month extension. Twenty-six subjects who were considered treatment failures (IGF-1 ≥ 1.3 × ULN) terminated early, and 23 withdrew for adverse events, consistent with those known for octreotide or disease related. OOC, an oral therapeutic peptide, achieves efficacy in controlling IGF-1 and GH after switching from injectable SRLs for up to 13 months, with a safety profile consistent with approved SRLs. OOC appears to be effective and safe as an acromegaly monotherapy.	f	\N
25675517	Rheumatoid arthritis (RA) is an inflammatory autoimmune disease characterized by joint destruction and severe morbidity. Methotrexate (MTX) is the standard first-line therapy of RA. However, about 40% of RA patients are unresponsive to MTX treatment. Regulatory T cells (Tregs, CD4(+)CD25(+)FoxP3(+)) are thought to play an important role in attenuating RA. To investigate the role of Tregs in MTX resistance, we recruited 122 RA patients (53 responsive, R-MTX; 69 unresponsive, UR-MTX) and 33 healthy controls. Three months after MTX treatment, R-MTX but not UR-MTX showed higher frequency of peripheral blood CD39(+)CD4(+)CD25(+)FoxP3(+) Tregs than the healthy controls. Tregs produce adenosine (ADO) through ATP degradation by sequential actions of two cell surface ectonucleotidases: CD39 and CD73. Tregs from UR-MTX expressed a lower density of CD39, produced less ADO, and had reduced suppressive activity than Tregs from R-MTX. In a prospective study, before MTX treatment, UR-MTX expressed a lower density of CD39 on Tregs than those of R-MTX or control (P < 0.01). In a murine model of arthritis, CD39 blockade reversed the antiarthritic effects of MTX treatment. Our results demonstrate that MTX unresponsiveness in RA is associated with low expression of CD39 on Tregs and the decreased suppressive activity of these cells through reduced ADO production. Our findings thus provide hitherto unrecognized mechanism of immune regulation in RA and on mode of action of MTX. Furthermore, our data suggest that low expression of CD39 on Tregs could be a noninvasive biomarker for identifying MTX-resistant RA patients.	f	\N
25675716	Cardiorehabilitation of patients with multivessel coronary lesions is an obligatory component of ambulatory stage of care. With the aim of potentiating cardioprotective and antiischemic impact of rehabilitative preventive measures in 36 patients with ischemic heart disease (IHD) and multivessel coronary artery involvement who had undergone percutaneous coronary intervention we studied cardioprotective and antiischemic effect of long-term (24 weeks) administration of 70 mg/day trimetazidine in combination with moderate intensity physical training with the use of distance surveillance by a physician. The chosen therapeutic approach in patients with residual ischemia after incomplete anatomical revascularization provided early persistent formation of cardioprotective and antiischemic effect proven by increase of tolerance to physical exercise, improvement of diastolic function, and positive dynamics of both ECG parameters and biochemical markers of myocardial ischemia.	f	\N
25678847	5-Fluorouracil (5Fu) chemotherapy is the first treatment of choice for advanced gastric cancer (GC), but its effectiveness is limited by drug resistance. Emerging evidence suggests that the existence of cancer stem cells (CSCs) contributes to chemoresistance. The aim of the present study was to determine whether 5Fu chemotherapy generates residual cells with CSC-like properties in GC. Human GC cell lines, SGC7901 and AGS, were exposed to increasing 5Fu concentrations. The residual cells were assessed for both chemosensitivity and CSC-like properties. B lymphoma Mo-MLV insertion region 1 (BMI1), a putative CSC protein, was analyzed by immunohistochemical staining and subjected to pairwise comparison in GC tissues treated with or without neoadjuvant 5Fu-based chemotherapy. The correlation between BMI1 expression and recurrence-free survival in GC patients who received 5Fu-based neoadjuvant chemotherapy was then examined. The residual cells exhibited 5Fu chemoresistance. These 5Fu-resistant cells displayed some CSC features, such as a high percentage of quiescent cells, increased self-renewal ability and tumorigenicity. The 5Fu-resistant cells were also enriched with cells expressing cluster of differentiation (CD)133+, CD326+ and CD44+CD24-. Moreover, the BMI1 gene was overexpressed in 5Fu-resistant cells, and BMI1 knockdown effectively reversed chemoresistance. The BMI1 protein was highly expressed consistently in the remaining GC tissues after 5Fu-based neoadjuvant chemotherapy, and BMI1 levels were correlated positively with recurrence-free survival in GC patients who received 5Fu-based neoadjuvant chemotherapy. Our data provided molecular evidence illustrating that 5Fu chemotherapy in GC resulted in acquisition of CSC-like properties. Moreover, enhanced BMI1 expression contributed to 5Fu resistance and may serve as a potential therapeutic target to reverse chemoresistance in GC patients.	f	\N
25679282	There is inconsistency among the perioperative management strategies currently used for chronic subdural hematoma (cSDH). Moreover, postoperative complications such as acute intracranial bleeding and cSDH recurrence affect clinical outcome of cSDH surgery. This study evaluated the risk factors associated with acute intracranial bleeding and cSDH recurrence and identified an effective perioperative strategy for cSDH patients. A retrospective study of patients who underwent bur hole craniostomy for cSDH between 2008 and 2012 was performed. A consecutive series of 303 cSDH patients (234 males and 69 females; mean age 67.17 years) was analyzed. Postoperative acute intracranial bleeding developed in 14 patients (4.57%) within a mean of 3.07 days and recurrence was observed in 37 patients (12.21%) within a mean of 31.69 days (range 10-104 days) after initial bur hole craniostomy. The comorbidities of hematological disease and prior shunt surgery were clinical factors associated with acute bleeding. There was a significant risk of recurrence in patients with diabetes mellitus, but recurrence did not affect the final neurological outcome (p = 0.776). Surgical details, including the number of operative bur holes, saline irrigation of the hematoma cavity, use of a drain, and type of postoperative ambulation, were not significantly associated with outcome. However, a large amount of drainage was associated with postoperative acute bleeding. Bur hole craniostomy is an effective surgical procedure for initial and recurrent cSDH. Patients with hematological disease or a history of prior shunt surgery are at risk for postoperative acute bleeding; therefore, these patients should be carefully monitored to avoid overdrainage. Surgeons should consider informing patients with diabetes mellitus that this comorbidity is associated with an increased likelihood of recurrence.	f	\N
25680251	The orbital manifestations of acquired immunodeficiency syndrome(AIDS) are uncommon. To provide a review of orbital manifestations of AIDS, the predisposing factors, investigations, treatment and outcome. Meticulous and systematic literature search of Pubmed to identify manuscripts describing orbital manifestations of AIDS was done and the articles were reviewed.The keywords used in the search were “orbit and AIDS”, “HIV positive and orbit”,“orbit manifestations in AIDS”, “orbital disease and AIDS” and “orbital infections and AIDS”. The orbital involvement in AIDS may present with opportunistic infections from organisms like fungi, viruses, bacteria and protozoa or with malignancies like Kaposi’s sarcoma, squamous cell carcinoma, smooth muscle cell tumors and lymphoma.The predisposing factors for orbital involvement in AIDS are low CD4+ cell count and the immunosuppressive states like diabetes, diabetic ketoacidosis, intravenous drug abuse and neutropenia. A patient may present with fever, headache, nausea, vomiting,decreased vision, ocular pain, and, in cases of mass formation, there is periorbital swelling, axial proptosis, globe displacement and swollen optic disc. Radiologically,mass formation, orbital bony destruction, and spread of disease to contiguous structures including the central nervous system may be seen. The medical management includes therapy for infection and HIV-1 protease inhibitors (highly active antiretroviral therapy)to suppress HIV-1 replication. For tumors, radical surgery including debulking followed by postoperative radiotherapy is generally needed. Orbital involvements with AIDS in any form, infective or malignancy, causes significant morbidity and mortality and should be diagnosed and managed as early as possible.	f	\N
25682204	The goal of this study is to validate a new, continuous, noninvasive stroke volume (SV) method, known as transbrachial electrical bioimpedance velocimetry (TBEV). TBEV SV was compared to SV obtained by cardiac magnetic resonance imaging (cMRI) in normal humans devoid of clinically apparent heart disease. Thirty-two (32) volunteers were enrolled in the study. Each subject was evaluated by echocardiography to assure that no aortic or mitral valve disease was present. Subsequently, each subject underwent electrical interrogation of the brachial artery by means of a high frequency, low amplitude alternating current. A first TBEV SV estimate was obtained. Immediately after the initial TBEV study, subjects underwent cMRI, using steady-state precession imaging to obtain a volumetric estimate of SV. Following cMRI, the TBEV SV study was repeated. Comparing the cMRI-derived SV to that of TBEV, the two TBEV estimates were averaged and compared to the cMRI standard. CO was computed as the product of SV and heart rate. Statistical methods consisted of Bland-Altman and linear regression analysis. TBEV SV and CO estimates were obtained in 30 of the 32 subjects enrolled. Bland-Altman analysis of pre- and post-cMRI TBEV SV showed a mean bias of 2.87 % (2.05 mL), precision of 13.59% (11.99 mL) and 95% limits of agreement (LOA) of +29.51% (25.55 mL) and -23.77% (-21.45 mL). Regression analysis for pre- and post-cMRI TBEV SV values yielded y = 0.76x + 25.1 and r(2) = 0.71 (r = 0.84). Bland-Altman analysis comparing cMRI SV with averaged TBEV SV showed a mean bias of -1.56% (-1.53 mL), precision of 13.47% (12.84 mL), 95% LOA of +24.85% (+23.64 mL) and -27.97% (-26.7 mL) and percent error = 26.2 %. For correlation analysis, the regression equation was y = 0.82x + 19.1 and correlation coefficient r(2) = 0.61 (r = 0.78). Bland-Altman analysis of averaged pre- and post-cMRI TBEV CO versus cMRI CO yielded a mean bias of 5.01% (0.32 L min(-1)), precision of 12.85% (0.77 L min(-1)), 95% LOA of +30.20 % (+0.1.83 L min(-1)) and -20.7% (-1.19 L min(-1)) and percent error = 24.8%. Regression analysis yielded y = 0.92x + 0.78, correlation coefficient r(2) = 0.74 (r = 0.86). TBEV is a novel, noninvasive method, which provides satisfactory estimates of SV and CO in normal humans.	f	\N
25713121	Lyme disease is the most important vector-borne disease in the Northern hemisphere and represents a major public health challenge with insufficient means of reliable diagnosis. Skin is rarely investigated in proteomics but constitutes in the case of Lyme disease the key interface where the pathogens can enter, persist, and multiply. Therefore, we investigated proteomics on skin samples to detect Borrelia proteins directly in cutaneous biopsies in a robust and specific way. We first set up a discovery gel prefractionation-LC-MS/MS approach on a murine model infected by Borrelia burgdorferi sensu stricto that allowed the identification of 25 Borrelia proteins among more than 1300 mouse proteins. Then we developed a targeted gel prefractionation-LC-selected reaction monitoring (SRM) assay to detect 9/33 Borrelia proteins/peptides in mouse skin tissue samples using heavy labeled synthetic peptides. We successfully transferred this assay from the mouse model to human skin biopsies (naturally infected by Borrelia), and we were able to detect two Borrelia proteins: OspC and flagellin. Considering the extreme variability of OspC, we developed an extended SRM assay to target a large set of variants. This assay afforded the detection of nine peptides belonging to either OspC or flagellin in human skin biopsies. We further shortened the sample preparation and showed that Borrelia is detectable in mouse and human skin biopsies by directly using a liquid digestion followed by LC-SRM analysis without any prefractionation. This study thus shows that a targeted SRM approach is a promising tool for the early direct diagnosis of Lyme disease with high sensitivity (<10 fmol of OspC/mg of human skin biopsy).	f	\N
25716730	Allogeneic bone marrow transplantation (allo-BMT) is currently the only way to cure many hematoproliferative disorders. However, allo-BMT use is limited by severe complications, the foremost being graft-versus-host disease (GVHD). Due to the lack of efficiency of the existing methods of GVHD prophylaxis, new methods are being actively explored, including the use of donors' multipotent mesenchymal stromal cells (MMSC). In this work, we analyzed the results of acute GVHD (aGVHD) prophylaxis by means of MMSC injections after allo-BMT in patients with hematological malignancies. The study included 77 patients. They were randomized into two groups - those receiving standard prophylaxis of aGVHD and those who were additionally infused with MMSC derived from the bone marrow of hematopoietic stem cell donors. We found that the infusion of MMSC halves the incidence of aGVHD and increases the overall survival of patients. Four of 39 MMSC samples were ineffective for preventing aGVHD. Analysis of individual donor characteristics (gender, age, body mass index) and the MMSC properties of these donors (growth parameters, level of expression of 30 genes involved in proliferation, differentiation, and immunomodulation) revealed no significant difference between the MMSC that were effective or ineffective for preventing aGVHD. We used multiple logistic regression to establish a combination of features that characterize the most suitable MMSC samples for the prevention of aGVHD. A model predicting MMSC sample success for aGVHD prophylaxis was constructed. Significant model parameters were increased relative expression of the FGFR1 gene in combination with reduced expression levels of the PPARG and IGF1 genes. Depending on the chosen margin for probability of successful application of MMSC, this model correctly predicts the outcome of the use of MMSC in 82-94% of cases. The proposed model of prospective evaluation of the effectiveness of MMSC samples will enable prevention of the development of aGVHD in the maximal number of patients.	f	\N
25721731	Two recent genome-wide association studies in Asians have reported the association between the PSCA (prostate stem cell antigen) rs2294008C>T gene polymorphism and two Helicobacter pylori infection-related diseases such as gastric cancer (GC) and duodenal ulcer (DU). Since rs2294008 allele frequencies differ notably among ethnicities, we aimed to assess the role of rs2294008 on the susceptibility to GC and DU in a Caucasian population in Spain. Moreover, the relevance of rs2294008 on GC prognosis was evaluated. Genomic DNA from 603 Spanish patients with primary GC, 139 with DU and 675 healthy controls was typed for the PSCA rs2294008C>T polymorphism by PCR-TaqMan assays. H. pylori infection [odds ratio (OR): 8.27; 95% confidence interval (CI): 3.45-15.33] and nonsteroidal anti-inflammatory drugs (OR: 6.54; 95% CI: 3.19-12.43) were identified as independent risk factors for DU whereas the rs2294008T allele was associated with reduced risk of developing the disease (OR: 0.52; 95% CI: 0.33-0.82). Infection with CagA strains (OR: 2.10; 95% CI: 1.63-2.34), smoking (OR: 1.93; 95% CI: 1.54-2.61), family history of GC (OR: 2.83; 95% CI: 2.01-3.83), and the rs2294008T allele (OR: 1.46; 95% CI: 1.07-1.99) were associated with increased risk of GC. Interestingly, the association with the rs2294008T allele was restricted to noncardia GC (OR: 1.43; 95% CI: 1.12-1.82), particularly of the diffuse histotype (OR: 1.59; 95% CI: 1.16-1.92). Finally, Cox regression analysis identified the rs2294008T variant as a prognosis factor associated with worse overall survival in patients with diffuse-type GC (hazard ratio: 1.85; 95% CI: 1.12-3.06). From these results we conclude that the PSCA rs2294008 polymorphism is involved in the susceptibility to GC and DU, as well as in the prognosis of the diffuse-type of GC in Caucasians.	f	\N
25727171	In this study, we investigated the vasorelaxant and antihypertensive effects of gallic acid (GA), a polyphenol isolated from the green alga Spirogyra sp., to assess its suitability as a therapeutic for cardiovascular diseases (CVDs). We examined the effect of GA on endothelium-dependent vasorelaxation in human umbilical vein endothelial cells (HUVECs). GA increased nitric oxide (NO) levels by increasing phosphorylation of endothelial nitric oxide synthase (eNOS), and its effect on NO production was attenuated by pretreatment with the eNOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME). We also investigated its antihypertensive effect by examining GA-mediated inhibition of angiotensin-I converting enzyme (ACE). GA inhibited ACE with a half-maximal inhibitory concentration (IC50) value of 37.38 ± 0.39 μg/ml. In silico simulations revealed that GA binds to the active site of ACE (PDB: 1O86) with a binding energy of -270.487 kcal/mol. Furthermore, GA clearly reduced blood pressure in spontaneously hypertensive rats (SHR) to an extent comparable to captopril. These results suggest that GA isolated from Spirogyra sp. exerts multiple therapeutic effects and has potential as a CVD treatment.	f	\N
25728727	The American Heart Association (AHA) established recommendations based on 7 ideal health behaviors and factors with the goal of improving cardiovascular health (CVH) and reducing both morbidity and mortality from cardiovascular disease by 20% by 2020. Few studies have investigated their association with subclinical coronary heart disease. We sought to examine whether the 7 AHA CVH metrics were associated with calcified atherosclerotic plaque in the coronary arteries. In a cross-sectional design, we studied 1,731 predominantly white men and women from the National Heart, Lung, and Blood Institute Family Heart Study without prevalent coronary heart disease. Diet was assessed by a semiquantitative food frequency questionnaire. Coronary artery calcium (CAC) was measured by cardiac computed tomography. We defined prevalent CAC using an Agatston score of 100+ and fitted generalized estimating equations to calculate prevalence odds ratios of CAC. Mean age was 56.8 years, and 41% were male. The median number of ideal CVH metrics was 3, and no participant met all 7. There was a strong inverse relationship between number of ideal CVH metrics and prevalent CAC. Odds ratios (95% CI) for CAC of 100+ were 1.0 (reference), 0.37 (0.29-0.45), 0.35 (0.26-0.44), and 0.27 (0.20-0.36) among subjects with 0 to 1, 2, 3, and 4+ ideal CVH metrics, respectively (P = .0001), adjusting for sex, age, field center, alcohol, income, education, and energy consumption. These data demonstrate a strong and graded inverse relationship between AHA ideal CVH metrics and prevalent CAC in adult men and women.	f	\N
25738293	Celiac disease (CD) is an autoimmune disease induced by an autoimmune reaction to indigested gluten, which occurs in genetically predisposed population. The etiology of CD is linked to innate and adaptive immunity, mostly mediated by lymphocytes, especially T cells, infiltrating into the small intestinal wall. The subpopulations of T cells that infiltrate inflamed intestinal tissues comprise various CD4+ T cells and CD8+ T cells. The plethora of T cell subtypes activated in CD leads to simultaneous activation of different signaling cascades including GATA1, NF-kB, JAK or STAT5 the activity of which may be modified by diet or drugs. It was recently showed that food allergens may accelerate CD by altering the interaction between IL-15 and CD4+ T cells in the activation of CD8+ T cells. Increased levels of cytokines like IL-15 are considered to play a role in CD development. Furthermore it was showed that some drugs like tofacitinib or ruxolitinib may influence CD by blocking IL-15 signaling and CD8+ T cell activity. This mini-review will summarize the current knowledge on the role of CD4+ T cell and CD8+ T cell in clinical and experimental CD and will describe how T cell-activated signaling pathways and locally released proteins may be influenced by dietary factors and drugs used in CD treatment.	f	\N
25750286	Herpesvirus entry mediator (HVEM) has been recently suggested to play certain roles in cancer biology. We examined HVEM expression in human colorectal cancer (CRC) to reveal its clinical importance. Immunohistochemical staining was carried-out in normal epithelium, benign and malignant lesions. While intense HVEM expression was not observed in normal epithelium and hyperplastic polyps, 24% of adenoma and more than half of CRCs had high HVEM expression. In 234 CRCs, HVEM expression was significantly associated with tumor status and pathological stage. Patients with high HVEM expression had a significantly poorer prognosis than those with low expression. Importantly, HVEM status had an independent prognostic value in CRC. Furthermore, HVEM status was inversely corrected with the presence of tumor-infiltrating T-cells. HVEM may play a critical role in tumor progression and immune evasion, and may also be a novel prognostic marker and potential therapeutic target in human CRC.	f	\N
25770253	Although obesity has been viewed traditionally as a disease of excess nutrition, evidence suggests that it may also be a disease of malnutrition. Specifically, thiamin deficiency was found in 15.5-29% of obese patients seeking bariatric surgery. It can present with vague signs and symptoms and is often overlooked in patients without alcohol use disorders. This review explores the relatively new discovery of high rates of thiamin deficiency in certain populations of people with obesity, including the effects of thiamin deficiency and potential underlying mechanisms of deficiency in people with obesity. The 2 observational studies that examined the prevalence in preoperative bariatric surgery patients and gaps in our current knowledge (including the prevalence of thiamin deficiency in the general obese population and whether the current RDA for thiamin meets the metabolic needs of overweight or obese adults) are reviewed. Suggestions for future areas of research are included.	f	\N
25774918	We sought to determine whether genomic polymorphism in collagen IX genes (COL9A) was associated with Kashin-Beck disease (KBD). Twenty seven single nucleotide polymorphisms (SNPs) in COL9AI, COL9A2 and COL9A3 were genotyped in 274 KBD cases and 248 healthy controls using the Sequenom MassARRAY system. Associations between the COL9A polymorphism and KBD risk were detected using an unconditional logistic regression model. Linkage disequilibrium (LD) and haplotypes analysis were performed with the Haploview software. After Bonferroni correction, the frequency distribution of genotypes in rs6910140 in COL9A1 was significantly different between the KBD and the control groups (X2 = 16.74, df = 2, P = 0.0002). Regression analysis showed that the allele "C" in SNP rs6910140 had a significant protective effect on KBD [odds ratio (OR) = 0.49, 95% confidence interval (CI) = 0.34-0.70, P = 0.0001]. The frequencies of alleles and genotypes in rs6910140 were significantly different among subjects of different KBD stages (allele: X2 = 7.82, df = 2, P = 0.02, genotype: X2 = 14.81, df = 4, P = 0.005). However, haplotype analysis did not detect any significant association between KBD and COL9A1, COL9A2 and COL9A3. We observed a significant association between rs6910140 of COL9A1 and KBD, suggesting a role of COL9A1 in the development of KBD.	f	\N
25795200	The study aims to compare the efficacy and safety of capecitabine plus oxaliplatin (XELOX) with 5-fluorouracil/leucovorin plus oxaliplatin (FOLFOXs) in patients with advanced gastric cancer. Five databases were searched up to June 2014, without language restrictions. The outcomes included overall response rate (ORR), clinical benefit rate (CBR), and toxicity. Twenty-six eligible trials were selected from 178 studies that initially were identified. All trials were published in Chinese journals between 2005 and 2014 and included 1585 patients (787 in XELOX group and 798 in FOLFOXs group). The pooled results failed to show statistical significance of XELOX regimen on ORR (OR 1.18, 95% CIs 1.00-1.41, P = 0.057) and CBR (OR 1.10, 95% CIs 0.95-1.28, P = 0.191) as compared with FOLFOXs regimen. None of the 26 clinical trials reported progression-free survival, and only one reported overall survival rate. The meta-analysis demonstrated that XELOX regimen was associated with a significant lower risk with nausea, stomatitis, diarrhea and alopecia, and a significant higher risk of hand-foot syndrome. The evidence is limited to suggest that XELOX may share similar efficacy as FOLFOXs and reduce toxicities of chemotherapy in advanced gastric cancer therapy. However, owing to limited data and potential bias of the included studies, further rigorously controlled trials are required.	f	\N
25801012	Eccentric distribution of atheroma has been associated with plaques likely to rupture and cause an acute coronary syndrome, but the factors responsible for the development of eccentricity remain unknown. Endothelial shear stress (ESS) drives plaque formation. We aimed to investigate the role of the local ESS characteristics in the de novo development and progressive worsening of plaque eccentricity in humans. Vascular profiling (3-vessel 3D coronary reconstruction by angiography/intravascular ultrasound, and blood flow simulation for ESS computation) was performed in 374 patients at baseline & 6-10 months follow-up. At baseline, we identified (i) disease-free segments (n=2157), and (ii) diseased regions of luminal obstructions (n=408). In disease-free regions, baseline low ESS magnitude (p<0.001), marked ESS circumferential heterogeneity (p=0.001), and their interaction (p=0.026) were associated with an increased probability of de novo eccentric plaque formation at follow-up. In diseased regions, baseline low ESS (odds ratio [OR]: 2.33, p=0.003) and large plaque burden (OR: 2.46, p=0.002) were independent predictors of substantially increasing plaque eccentricity index with worsening lumen encroachment. This combined outcome was more frequent in obstructions with both features vs. all others (33 vs. 12%; p<0.001). The incidence of percutaneous coronary intervention in worsening obstructions with increasing plaque eccentricity was higher (13.3 vs. 4.3%, p=0.011). The local hemodynamic environment has a critical effect on the development of eccentric coronary plaques at both an early and advanced stage of atherosclerosis. Local ESS assessment could help in predicting sites prone to plaque disruption and acute coronary syndromes in humans.	f	\N
25811383	Nephropathic cystinosis is a lysosomal storage disorder caused by mutations in the CTNS gene encoding cystine transporter cystinosin that results in accumulation of amino acid cystine in the lysosomes throughout the body and especially affects kidneys. Early manifestations of the disease include renal Fanconi syndrome, a generalized proximal tubular dysfunction. Current therapy of cystinosis is based on cystine-lowering drug cysteamine that postpones the disease progression but offers no cure for the Fanconi syndrome. We studied the mechanisms of impaired reabsorption in human proximal tubular epithelial cells (PTEC) deficient for cystinosin and investigated the endo-lysosomal compartments of cystinosin-deficient PTEC by means of light and electron microscopy. We demonstrate that cystinosin-deficient cells had abnormal shape and distribution of the endo-lysosomal compartments and impaired endocytosis, with decreased surface expression of multiligand receptors and delayed lysosomal cargo processing. Treatment with cysteamine improved surface expression and lysosomal cargo processing but did not lead to a complete restoration and had no effect on the abnormal morphology of endo-lysosomal compartments. The obtained results improve our understanding of the mechanism of proximal tubular dysfunction in cystinosis and indicate that impaired protein reabsorption can, at least partially, be explained by abnormal trafficking of endosomal vesicles.	f	\N
25813338	Poor data regarding skin involvement in Myotonic Dystrophy, also named Dystrophia Myotonica type 1, have been reported. This study aimed to investigate the prevalence and types of skin disorders in adult patients with Myotonic Dystrophy type 1. Fifty-five patients and one hundred age- and sex-matched healthy subjects were referred to a trained dermatologist for a complete skin examination to check for potential cutaneous hallmarks of disease. No difference in prevalence of preneoplastic, neoplastic, and cutaneous lesions was detected between the two groups. Among morphofunctional, proliferative and inflammatory lesions, focal hyperhidrosis (p < 0.0001), follicular hyperkeratosis (p = 0.0003), early androgenic alopecia (p = 0.01), nail pitting (p = 0.003), pedunculus fibromas (p = 0. 01), twisted hair (p = 0.01), seborrheic dermatitis (p = 0.02), macules of hyperpigmentation (p = 0.03) were significantly more frequent in patients compared with controls. In patients with Myotonic Dystrophy type 1 significant differences according to sex were found for: early androgenic alopecia, twisted hair and seborrheic dermatitis, whose prevalence was higher in males (p < 0.0001). Our preliminary results seem to rule out an increased prevalence of pre-neoplastic, and neoplastic skin lesions in Myotonic Dystrophy type 1. On the other hand, an increased prevalence of morphofunctional, inflammatory, and proliferative diseases involving adnexal structures seems to characterize adult patients with Myotonic Dystrophy type 1.	f	\N
25834326	To investigate whether transarterial chemoembolization (TACE) before liver transplantation (LT) improves long-term survival in hepatocellular carcinoma (HCC) patients. A retrospective study was conducted among 204 patients with HCC who received LT from January 2002 to December 2010 in PLA General Hospital. Among them, 88 patients received TACE before LT. Prognostic factors of serum α-fetoprotein (AFP), intraoperative blood loss, intraoperative blood transfusion, disease-free survival time, survival time with tumor, number of tumor nodules, tumor size, tumor number, presence of blood vessels and bile duct invasion, lymph node metastasis, degree of tumor differentiation, and preoperative liver function were determined in accordance with the Child-Turcotte-Pugh (Child) classification and model for end-stage liver disease. We also determined time of TACE before transplant surgery and tumor recurrence and metastasis according to different organs. Cumulative survival rate and disease-free survival rate curves were prepared using the Kaplan-Meier method, and the log-rank and χ(2) tests were used for comparisons. In patients with and without TACE before LT, the 1, 3 and 5-year cumulative survival rate was 70.5% ± 4.9% vs 91.4% ± 2.6%, 53.3% ± 6.0% vs 83.1% ± 3.9%, and 46.2% ± 7.0% vs 80.8% ± 4.5%, respectively. The median survival time of patients with and without TACE was 51.857 ± 5.042 mo vs 80.930 ± 3.308 mo (χ(2) = 22.547, P < 0.001, P < 0.05). The 1, 3 and 5-year disease-free survival rates for patients with and without TACE before LT were 62.3% ± 5.2% vs 98.9% ± 3.0%, 48.7% ± 6.7% vs 82.1% ± 4.1%, and 48.7% ± 6.7% vs 82.1% ± 4.1%, respectively. The median survival time of patients with and without TACE before LT was 50.386 ± 4.901 mo vs 80.281 ± 3.216 mo (χ(2) = 22.063, P < 0.001, P < 0.05). TACE before LT can easily lead to pulmonary or distant metastasis of the primary tumor. Although there was no significant difference between the two groups, the chance of metastasis of the primary tumor in the group with TACE was significantly higher than that of the group without TACE. TACE pre-LT for HCC patients increased the chances of pulmonary or distant metastasis of the primary tumor, thus reducing the long-term survival rate.	f	\N
25836637	The pathologic correlates of interstitial lung disease (ILD) secondary to connective tissue disease (CTD) comprise a diverse group of histologic patterns. Lung biopsies in patients with CTD-associated ILD tend to demonstrate simultaneous involvement of multiple anatomic compartments of the lung. Certain histologic patterns tend to predominate in each defined CTD, and it is possible in many cases to confirm connective tissue-associated lung disease and guide patient management using surgical lung biopsy. This article will cover the pulmonary pathologies seen in rheumatoid arthritis, systemic sclerosis, myositis, systemic lupus erythematosus, Sjögren syndrome, and mixed CTD.	f	\N
25857492	Mitochondrial dysfunctions are known to be responsible for a number of heterogenous clinical presentations with multi-systemic involvement. Impaired oxidative phosphorylation leading to a decrease in cellular energy (ATP) production is the most important cause underlying these disorders. Despite significant progress made in the field of mitochondrial medicine during the last two decades, the molecular mechanisms underlying these disorders are not fully understood. Since the identification of first mitochondrial DNA (mtDNA) mutation in 1988, there has been an exponential rise in the identification of mtDNA and nuclear DNA mutations that are responsible for mitochondrial dysfunction and disease. Genetic complexity together with ever widening clinical spectrum associated with mitochondrial dysfunction poses a major challenge in diagnosis and treatment. Effective therapy has remained elusive till date and is mostly efficient in relieving symptoms. In this review, we discuss the important clinical and genetic features of mitochondrials disorders with special emphasis on diagnosis and treatment.	f	\N
25861414	Chronic kidney disease (CKD) is characterized by increased levels of oxidative stress and inflammation. Oxidative stress and inflammation promote renal injury via damage to molecular components of the kidney. Unfortunately, relationships between inflammation and oxidative stress are cyclical in that the inflammatory processes that exist to repair radical-mediated damage may be a source of additional free radicals, resulting in further damage to renal tissue. Oxidative stress and inflammation also have the ability to become systemic, serving to injure tissues distal to the site of original insult. This review describes select mediators in the exacerbatory relationship between oxidative stress, inflammation, and CKD. This review also discusses oxidative stress, inflammation, and CKD as they pertain to the development and progression of common CKD-associated comorbidities. Lastly, the utility of several widely accessible and cost-effective lifestyle interventions and their ability to reduce oxidative stress and inflammation are discussed and recommendations for future research are provided.	f	\N
25897458	As of late 2014, interferon beta injection was the standard "disease-modifying" treatment for patients with relapsing-remitting multiple sclerosis, in the absence of a better alternative. Alemtuzumab (Lemtrada degree, Genzyme Therapeutics), an antilymphocyte monoclonal antibody first used in some types of leukaemia, is authorised in the European Union, at a different dosage, for patients with multiple sclerosis. Clinical evaluation in multiple sclerosis is based on three unblinded trials comparing alemtuzumab with interferon beta-1a. These trials were all biased in favour of alemtuzumab and thus fail to establish the potential value of this immunosuppressant. Overall, adverse effects, including the most severe, were more frequent with alemtuzumab than with interferon beta-1a. The adverse effects of alemtuzumab reported in these trials had already been observed in cancer patients. They included potentially severe reactions to the infusion, as well as a risk of infections and cancer due to profound and prolonged immunosuppression. At the dosage authorised in multiple sclerosis, autoimmune disorders such as thyroid disorders and immune thrombocytopenic purpura are particularly frequent and serious. In practice, patients with multiple sclerosis already have difficulty coping with the troublesome consequences of their underlying disease. They should not be subjected to the serious adverse effects of alemtuzumab, especially given the absence of any proven benefit.	f	\N
25924288	The paper describes the development of alopecia with a patient with echinocccosis alveolaris during treatment with Nemozole (albandazole). To decide to continue or to discontinue Nemozole treatment in the development of alopecia, the patient should be given full information on the risk of alopecia to his life and quality of life as compared to the sequels of recurrent hydatid disease when Nemozole is discontinued.	f	\N
25924757	Hypercalcaemia is a common biochemical abnormality in the blood that can be caused by malignancy, hyperparathyroidism, medications or underlying medical conditions. Initial signs and symptoms are often vague, however, if someone has severe hypercalcaemia it is treated as an emergency, requiring prompt management to prevent life-threatening complications such as dehydration, cardiac arrhythmias or coma. Understanding the pathophysiology, signs and symptoms of hypercalcaemia enables effective diagnosis and holistic management of the patient with complex health needs.	f	\N
25925920	Celiac disease (CD) is a chronic small intestinal immune-mediated enteropathy precipitated by exposure to dietary gluten in genetically susceptible individuals. CD-related enteropathy leads to multiple nutritional deficiencies involving macro- and micronutrients. Currently, medical nutrition therapy consisting of the gluten-free diet (GFD) is the only accepted treatment for CD. The GFD is the cornerstone of treatment for CD. Prior published studies have concluded that maintenance of the GFD results in improvement of the majority of nutritional deficiencies. In the past, counseling for CD focused mainly on the elimination of gluten in the diet. However, the GFD is not without its inadequacies; compliance to the GFD may result in certain deficiencies such as fiber, B vitamins, iron, and trace minerals. Paucity of fortified gluten-free foods may be responsible for certain deficiencies which develop on the GFD. Weight gain and obesity have been added to the list of nutritional consequences while on the GFD and have been partially attributed to hypercaloric content of commercially available gluten-free foods. Follow-up of patients diagnosed with CD after starting the GFD has been reported to be irregular and, hence, less than ideal. Monitoring of the nutritional status using blood tests and use of appropriate gluten-free supplementation are integral components in the management of CD. The ideal GFD should be nutrient-dense with naturally gluten-free foods, balanced with macro- and micronutrients, reasonably priced, and easily accessible. Rotation of the pseudo-cereals provides a good source of complex carbohydrates, protein, fiber, fatty acids, vitamins and minerals. Fortification/enrichment of commonly consumed gluten-free commercial grain products should be encouraged. Dietitians specializing in CD play a critical role in the education and maintenance of the GFD for patients with CD.	f	\N
25934387	C5a plays a central role in antineutrophil cytoplasmic antibody (ANCA)-mediated neutrophil recruitment and activation. A previous study showed that C5a played a crucial role in the regulation of high mobility group box 1 (HMGB1) release from human neutrophils. The current study further investigated the interaction between C5a and HMGB1 in ANCA-induced neutrophil activation. The effects of HMGB1 inhibitors on the translocation of ANCA antigens, ANCA-induced respiratory burst and degranulation of C5a-primed neutrophils were tested. We found that blocking HMGB1 decreased C5a-mediated translocation of ANCA antigens, as well as ANCA-induced respiratory burst and degranulation of C5a-primed neutrophils. Further study showed that supernatant of C5a-primed neutrophils, which contained HMGB1, also caused translocation of ANCA antigens of primary neutrophils, whereas blocking HMGB1 decreased the translocation. In conclusion, blocking HMGB1 may attenuate ANCA-induced activation of C5a-primed neutrophils. The interaction between HMGB1 and C5a might play an important role in ANCA-induced neutrophil activation.	f	\N
25945002	To compare ultrasound-based acoustic structure quantification (ASQ) with established non-invasive techniques for grading and staging fatty liver disease. Type 2 diabetic patients at risk of non-alcoholic fatty liver disease (n = 50) and healthy volunteers (n = 20) were evaluated using laboratory analysis and anthropometric measurements, transient elastography (TE), controlled attenuation parameter (CAP), proton magnetic resonance spectroscopy ((1)H-MRS; only available for the diabetic cohort), and ASQ. ASQ parameters mode, average and focal disturbance (FD) ratio were compared with: (1) the extent of liver fibrosis estimated from TE and non-alcoholic fatty liver disease (NAFLD) fibrosis scores; and (2) the amount of steatosis, which was classified according to CAP values. Forty-seven diabetic patients (age 67.0 ± 8.6 years; body mass index 29.4 ± 4.5 kg/m²) with reliable CAP measurements and all controls (age 26.5 ± 3.2 years; body mass index 22.0 ± 2.7 kg/m²) were included in the analysis. All ASQ parameters showed differences between healthy controls and diabetic patients (P < 0.001, respectively). The ASQ FD ratio (logarithmic) correlated with the CAP (r = -0.81, P < 0.001) and (1)H-MRS (r = -0.43, P = 0.004) results. The FD ratio [CAP < 250 dB/m: 107 (102-109), CAP between 250 and 300 dB/m: 106 (102-114); CAP between 300 and 350 dB/m: 105 (100-112), CAP ≥ 350 dB/m: 102 (99-108)] as well as mode and average parameters, were reduced in cases with advanced steatosis (ANOVA P < 0.05). However, none of the ASQ parameters showed a significant difference in patients with advanced fibrosis, as determined by TE and the NAFLD fibrosis score (P > 0.08, respectively). ASQ parameters correlate with steatosis, but not with fibrosis in fatty liver disease. Steatosis estimation with ASQ should be further evaluated in biopsy-controlled studies.	f	\N
25971299	Cancer recurrence and disease-free survival are key outcomes for measuring the burden of illness, assessing the quality of cancer care, and informing decisions about increasingly costly cancer therapies. Yet information about recurrence is not collected in cancer registries or other population-based data sources. To address the lack of population-based recurrence information, researchers are increasingly using algorithms applied to health claims to infer recurrence. However, the validity of these approaches has not been comprehensively evaluated. In this commentary, we review existing studies and discuss options for improving the availability of recurrence data. We found that the validity of claims-based approaches appears promising in small, single institution studies, but larger population-based studies have identified substantial limitations with using claims to identify recurrence. With the increasing availability of health data, there are potential options that can be implemented to enhance information about recurrence. These options include design of software for the electronic medical record that enables rapid and standardized reporting of recurrence, use of electronic pathology reports to facilitate streamlined collection of recurrence by cancer registries, and mandates by insurers to require reporting of recurrence on health claims submitted by physicians. All of these options will require that governmental agencies, health insurers, professional societies, and other groups recognize the importance of population-based recurrence data and determine that this information is a priority for assessing cancer outcomes and costs.	f	\N
25972525	Relations of the 25 mammalian selenoprotein genes with obesity and the associated inflammation remain unclear. This study explored impacts of high-fat diet-induced obesity on inflammation and expressions of selenoprotein and obesity-related genes in 10 tissues of pigs. Plasma and 10 tissues were collected from pigs (n = 10) fed a corn-soy-based control diet or that diet containing 3-7% lard from weanling to finishing (180 d). Plasma concentrations (n = 8) of cytokines and thyroid hormones and tissue mRNA abundance (n = 4) of 25 selenoprotein genes and 16 obesity-related genes were compared between the pigs fed the control and high-fat diets. Stepwise regression was applied to analyze correlations among all these measures, including the previously reported body physical and plasma biochemical variables. The high-fat diet elevated (P < 0.05) plasma concentrations of tumor necrosis factor α, interleukin-6, leptin, and leptin receptor by 29-42% and affected (P < 0.05-0.1) tissue mRNA levels of the selenoprotein and obesity-related genes in 3 patterns. Specifically, the high-fat diet up-regulated 12 selenoprotein genes in 6 tissues, down-regulated 13 selenoprotein genes in 7 tissues, and exerted no effect on 5 genes in any tissue. Body weights and plasma triglyceride concentrations of pigs showed the strongest regressions to tissue mRNA abundances of selenoprotein and obesity-related genes. Among the selenoprotein genes, selenoprotein V and I were ranked as the strongest independent variables for the regression of phenotypic and plasma measures. Meanwhile, agouti signaling protein, adiponectin, and resistin genes represented the strongest independent variables of the obesity-related genes for the regression of tissue selenoprotein mRNA. The high-fat diet induced inflammation in pigs and affected their gene expression of selenoproteins associated with thioredoxin and oxidoreductase systems, local tissue thyroid hormone activity, endoplasmic reticulum protein degradation, and phosphorylation of lipids. This porcine model may be used to study interactive mechanisms between excess fat intake and selenoprotein function.	f	\N
25998164	In atopic dermatitis (AD), the inflammatory response between skin-infiltrating T cells and keratinocytes is fundamental to the development of chronic lesional eczema. The aim of this study was to investigate whether skin-derived T cells from AD patients could induce an inflammatory response in mice through keratinocyte activation and consequently cause the development of eczematous lesions. Punch biopsies of the lesional skin from AD patients were used to establish skin-derived T cell cultures, which were transferred to NOD.Cg-Prkd(scid) Il2rg(tm1Sug) /JicTac (NOG) mice. We found that the subcutaneous injection of the human AD skin-derived T cells resulted in the migration of the human T cells from subcutis to the papillary dermis followed by the development of erythema and oedema in the mouse skin. Furthermore, the human T cells induced a transient proliferative response in the mouse keratinocytes shown as increased numbers of Ki-67(+) keratinocytes and increased epidermal thickness. Out of six established AD skin-derived T cell cultures, two were superior at inducing a skin reaction in the mice, and these cultures were found to contain >10% CCR10(+) T cells compared to <2% for the other cultures. In comparison, blood-derived in vitro-differentiated Th2 cells only induced a weak response in a few of the mice. Thus, we conclude that human AD skin-derived T cells can induce a reaction in the mouse skin through the induction of a proliferative response in the mouse keratinocytes.	f	\N
26026650	The aim of the Activating Schoolyards Study is to develop, implement, document and assess a comprehensive schoolyard intervention to promote physical activity (PA) during school recess for primary school children (grade 4-8). The intervention is designed to implement organizational and structural changes in the physical environment. The study builds on a quasi-experimental study design using a mixed method approach including: 1) an exploratory study aimed at providing input for the developing process; 2) an evaluation of the effect of the interventions using a combination of accelerometer, GPS and GIS; 3) a process evaluation facilitating the intervention development process and identifying barriers and facilitators in the implementation process; 4) a post-intervention end-user evaluation aimed at exploring who uses the schoolyards and how the schoolyards are used. The seven project schools (cases) were selected by means of an open competition and the interventions were developed using a participatory bottom-up approach. The participatory approach and case selection strategy make the study design novel. The use of a mixed methods design including qualitative as well as quantitative methods can be seen as a strength, as the different types of data complement each other and results of one part of the study informed the following parts. A unique aspect of our study is the use of accelerometers in combination with GPS and GIS in the effect evaluation to objectively determine where and how active the students are in the schoolyard, before and after the intervention. This provides a type of data that, to our knowledge, has not been used before in schoolyard interventions. Exploring the change in behavior in relation to specific intervention elements in the schoolyard will lead to recommendations for schools undergoing schoolyard renovations at some point in the future.	f	\N
26029704	Many common diseases have a complex genetic basis in which large numbers of genetic variations combine with environmental factors to determine risk. However, quantifying such polygenic effects has been challenging. In order to address these difficulties we developed a global measure of the information content of an individual's genome relative to a reference population, which may be used to assess differences in global genome structure between cases and appropriate controls. Informally this measure, which we call relative genome information (RGI), quantifies the relative "disorder" of an individual's genome. In order to test its ability to predict disease risk we used RGI to compare single-nucleotide polymorphism genotypes from two independent samples of women with early-onset breast cancer with three independent sets of controls. We found that RGI was significantly elevated in both sets of breast cancer cases in comparison with all three sets of controls, with disease risk rising sharply with RGI. Furthermore, these differences are not due to associations with common variants at a small number of disease-associated loci, but rather are due to the combined associations of thousands of markers distributed throughout the genome. Our results indicate that the information content of an individual's genome may be used to measure the risk of a complex disease, and suggest that early-onset breast cancer has a strongly polygenic component.	f	\N
26037125	Vaginal inflammation (vaginitis) is the most common disease caused by the human-pathogenic fungus Candida albicans. Secretory aspartyl proteinases (Sap) are major virulence traits of C. albicans that have been suggested to play a role in vaginitis. To dissect the mechanisms by which Sap play this role, Sap2, a dominantly expressed member of the Sap family and a putative constituent of an anti-Candida vaccine, was used. Injection of full-length Sap2 into the mouse vagina caused local neutrophil influx and accumulation of the inflammasome-dependent interleukin-1β (IL-1β) but not of inflammasome-independent tumor necrosis factor alpha. Sap2 could be replaced by other Sap, while no inflammation was induced by the vaccine antigen, the N-terminal-truncated, enzymatically inactive tSap2. Anti-Sap2 antibodies, in particular Fab from a human combinatorial antibody library, inhibited or abolished the inflammatory response, provided the antibodies were able, like the Sap inhibitor Pepstatin A, to inhibit Sap enzyme activity. The same antibodies and Pepstatin A also inhibited neutrophil influx and cytokine production stimulated by C. albicans intravaginal injection, and a mutant strain lacking SAP1, SAP2, and SAP3 was unable to cause vaginal inflammation. Sap2 induced expression of activated caspase-1 in murine and human vaginal epithelial cells. Caspase-1 inhibition downregulated IL-1β and IL-18 production by vaginal epithelial cells, and blockade of the IL-1β receptor strongly reduced neutrophil influx. Overall, the data suggest that some Sap, particularly Sap2, are proinflammatory proteins in vivo and can mediate the inflammasome-dependent, acute inflammatory response of vaginal epithelial cells to C. albicans. These findings support the notion that vaccine-induced or passively administered anti-Sap antibodies could contribute to control vaginitis. Candidal vaginitis is an acute inflammatory disease that affects many women of fertile age, with no definitive cure and, in its recurrent forms, causing true devastation of quality of life. Unraveling the fungal factors causing inflammation is important to be able to devise novel tools to fight the disease. In an experimental murine model, we have discovered that aspartyl proteinases, particularly Sap2, may cause the same inflammatory signs of vaginitis caused by the fungus and that anti-Sap antibodies and the protease inhibitor Pepstatin A almost equally inhibit Sap- and C. albicans-induced inflammation. Sap-induced vaginitis is an early event during vaginal infection, is uncoupled from fungal growth, and requires Sap and caspase-1 enzymatic activities to occur, suggesting that Sap or products of Sap activity activate an inflammasome sensor of epithelial cells. Our data support the notion that anti-Sap antibodies could help control the essence of candidal vaginitis, i.e., the inflammatory response.	f	\N
26041263	Several mutations in nuclear genes encoding for mitochondrial components have been associated with an increased cancer risk or are even causative, e.g. succinate dehydrogenase (SDHB, SDHC and SDHD genes) and iso-citrate dehydrogenase (IDH1 and IDH2 genes). Recently, studies have suggested an eminent role for mitochondrial DNA (mtDNA) mutations in the development of a wide variety of cancers. Various studies associated mtDNA abnormalities, including mutations, deletions, inversions and copy number alterations, with mitochondrial dysfunction. This might, explain the hampered cellular bioenergetics in many cancer cell types. Germline (e.g. m.10398A>G; m.6253T>C) and somatic mtDNA mutations as well as differences in mtDNA copy number seem to be associated with cancer risk. It seems that mtDNA can contribute as driver or as complementary gene mutation according to the multiple-hit model. This can enhance the mutagenic/clonogenic potential of the cell as observed for m.8993T>G or influences the metastatic potential in later stages of cancer progression. Alternatively, other mtDNA variations will be innocent passenger mutations in a tumor and therefore do not contribute to the tumorigenic or metastatic potential. In this review, we discuss how reported mtDNA variations interfere with cancer treatment and what implications this has on current successful pharmaceutical interventions. Mutations in MT-ND4 and mtDNA depletion have been reported to be involved in cisplatin resistance. Pharmaceutical impairment of OXPHOS by metformin can increase the efficiency of radiotherapy. To study mitochondrial dysfunction in cancer, different cellular models (like ρ(0) cells or cybrids), in vivo murine models (xenografts and specific mtDNA mouse models in combination with a spontaneous cancer mouse model) and small animal models (e.g. Danio rerio) could be potentially interesting to use. For future research, we foresee that unraveling mtDNA variations can contribute to personalized therapy for specific cancer types and improve the outcome of the disease.	f	\N
26083239	Dual-isotope simultaneous-acquisition (DISA) rest-stress myocardial perfusion SPECT (MPS) protocols offer a number of advantages over separate acquisition. However, crosstalk contamination due to scatter in the patient and interactions in the collimator degrade image quality. Compensation can reduce the effects of crosstalk, but does not entirely eliminate image degradations. Optimizing acquisition parameters could further reduce the impact of crosstalk. In this paper we investigate the optimization of the rest Tl-201 energy window width and relative injected activities using the ideal observer (IO), a realistic digital phantom population and Monte Carlo (MC) simulated Tc-99m and Tl-201 projections as a means to improve image quality. We compared performance on a perfusion defect detection task for Tl-201 acquisition energy window widths varying from 4 to 40 keV centered at 72 keV for a camera with a 9% energy resolution. We also investigated 7 different relative injected activities, defined as the ratio of Tc-99m and Tl-201 activities, while keeping the total effective dose constant at 13.5 mSv. For each energy window and relative injected activity, we computed the IO test statistics using a Markov chain Monte Carlo (MCMC) method for an ensemble of 1,620 triplets of fixed and reversible defect-present, and defect-absent noisy images modeling realistic background variations. The volume under the 3-class receiver operating characteristic (ROC) surface (VUS) was estimated and served as the figure of merit. For simultaneous acquisition, the IO suggested that relative Tc-to-Tl injected activity ratios of 2.6-5 and acquisition energy window widths of 16-22% were optimal. For separate acquisition, we observed a broad range of optimal relative injected activities from 2.6 to 12.1 and acquisition energy window of widths 16-22%. A negative correlation between Tl-201 injected activity and the width of the Tl-201 energy window was observed in these ranges. The results also suggested that DISA methods could potentially provide image quality as good as that obtained with separate acquisition protocols. We compared observer performance for the optimized protocols and the current clinical protocol using separate acquisition. The current clinical protocols provided better performance at a cost of injecting the patient with approximately double the injected activity of Tc-99m and Tl-201, resulting in substantially increased radiation dose.	f	\N
26086077	Biological systems consist of multiple organizational levels all densely interacting with each other to ensure function and flexibility of the system. Simultaneous analysis of cross-sectional multi-omics data from large population studies is a powerful tool to comprehensively characterize the underlying molecular mechanisms on a physiological scale. In this study, we systematically analyzed the relationship between fasting serum metabolomics and whole blood transcriptomics data from 712 individuals of the German KORA F4 cohort. Correlation-based analysis identified 1,109 significant associations between 522 transcripts and 114 metabolites summarized in an integrated network, the 'human blood metabolome-transcriptome interface' (BMTI). Bidirectional causality analysis using Mendelian randomization did not yield any statistically significant causal associations between transcripts and metabolites. A knowledge-based interpretation and integration with a genome-scale human metabolic reconstruction revealed systematic signatures of signaling, transport and metabolic processes, i.e. metabolic reactions mainly belonging to lipid, energy and amino acid metabolism. Moreover, the construction of a network based on functional categories illustrated the cross-talk between the biological layers at a pathway level. Using a transcription factor binding site enrichment analysis, this pathway cross-talk was further confirmed at a regulatory level. Finally, we demonstrated how the constructed networks can be used to gain novel insights into molecular mechanisms associated to intermediate clinical traits. Overall, our results demonstrate the utility of a multi-omics integrative approach to understand the molecular mechanisms underlying both normal physiology and disease.	f	\N
26109487	The aim of this study was to evaluate the long-term outcomes of patients with colorectal cancer liver metastasis (CRCLM) exhibiting disease progression after portal vein embolization (PVE). Patients with CRCLM requiring PVE before hepatectomy between 2003 and 2014 were included. Clinical variables, and liver and tumour volumes determined by three-dimensional CT volumetry were assessed before and after PVE. Overall and disease-free survival data were obtained. Univariable and multivariable logistic regression analyses were performed to identify predictors of tumour progression after PVE. Of 141 patients who underwent PVE, 93 (66.0 per cent) had tumour progression and 17 (12.1 per cent) developed new contralateral lesions. Significantly fewer patients had resectable disease in the group with disease progression than among those with stable disease: 43 (46 per cent) of 93 versus 36 (75 per cent) of 48 respectively (P = 0.001). Median survival was similar in patients with and without tumour growth after PVE: 22.5 versus 26.0 months for patients with unresectable tumours (P = 0.706) and 46.2 versus 52.2 months for those with resectable disease (P = 0.953). However, disease-free survival for patients with tumour progression after PVE was shorter than that for patients with stable disease (6.0 versus 20.2 months; P = 0.045). Response to neoadjuvant chemotherapy was the only significant factor associated with tumour progression in multivariable analysis. Tumour progression after PVE did not affect overall survival, but patients with resected tumours who had tumour growth after embolization experienced earlier recurrence. A borderline response to neoadjuvant chemotherapy seemed to be associated with tumour progression after PVE.	f	\N
26118068	There has been a significant increase in diabetes morbidity in the past years. Prolonged asymptomatic progression of disease presents a problem and leads to late diagnosis and development of complications. Present study shows efficiency of screening measures to determine actual spread of carbohydrate metabolism disorders among residents of Odessa, frequency of type 2 diabetes mellitus risk factors determination and prevention of complications.	f	\N
26141335	In the past few years, new biological insights into the myelodysplastic syndromes (MDS) resulting from molecular genetic analysis have improved pathologic understanding, but treatment advances have not kept pace. More than 40 genes are now known to be recurrently mutated in MDS. However, because most of these genes encode spliceosome components, chromatic remodeling factors, epigenetic pattern modulators, or transcription factors rather than more easily inhibited activated tyrosine kinases, there are as of yet few narrowly targeted therapies available for MDS. Three drugs--azacitidine, decitabine, and lenalidomide--were approved by the US Food and Drug Administration for MDS indications a decade ago, and these agents can improve hematopoiesis, delay disease progression, and improve survival and quality of life for a subset of patients. However, only a few patients with MDS respond to these agents, and their benefit is temporary. The only potentially curative therapy for MDS is allogeneic hematopoietic stem cell transplant, but owing to the advanced age of many patients with MDS and the frequency of serious comorbid conditions, less than 10% of patients currently undergo stem cell transplant. This narrative review summarizes the current understanding of MDS and treatment options for these challenging disorders.	f	\N
26143070	Human T-lymphotropic virus type 1 (HTLV-1), a retrovirus, is the causative agent of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and adult T-cell leukaemia/lymphoma (ATLL). The reported association with pulmonary disease such as bronchiectasis is less certain. A retrospective case review of a HTLV-1 seropositive cohort attending a national referral centre. The cohort was categorised into HTLV-1 symptomatic patients (SPs) (ATLL, HAM/TSP, Strongyloidiasis and HTLV associated inflammatory disease (HAID)) and HTLV-1 asymptomatic carriers (ACs). The cohort was reviewed for diagnosis of bronchiectasis. 34/246 ACs and 30/167 SPs had been investigated for respiratory symptoms by computer tomography (CT) with productive cough +/- recurrent chest infections the predominant indications. Bronchiectasis was diagnosed in one AC (1/246) and 13 SPs (2 HAID, 1 ATLL, 10 HAM/TSP) (13/167, RR 19.2 95 % CI 2.5-14.5, p = 0.004) with high resolution CT. In the multivariate analysis ethnicity (p = 0.02) and disease state (p < 0.001) were independent predictors for bronchiectasis. The relative risk of bronchiectasis in SPs was 19.2 (95 % CI 2.5-14.5, p = 0.004) and in HAM/TSP patients compared with all other categories 8.4 (95 % CI 2.7-26.1, p = 0.0002). Subjects not of African/Afro-Caribbean ethnicity had an increased prevalence of bronchiectasis (RR 3.45 95 % 1.2-9.7, p = 0.02). Bronchiectasis was common in the cohort (3.4 %). Risk factors were a prior diagnosis of HAM/TSP and ethnicity but not HTLV-1 viral load, age and gender. The spectrum of HTLV-associated disease should now include bronchiectasis and HTLV serology should be considered in patients with unexplained bronchiectasis.	f	\N
26148061	In humans, neurodegenerative disorders such as Huntington's disease (HD) and many spinocerebellar ataxias (SCAs) have been found to be associated with CAG trinucleotide repeat expansion. An important RNA-mediated mechanism that causes these diseases involves the binding of the splicing regulator protein MBNL1 (Muscleblind-like 1 protein) to expanded r(CAG) repeats. Moreover, mutant huntingtin protein translated from expanded r(CAG) also yields toxic effects. To discern the role of mutant RNA in these diseases, it is essential to gather information about its structure. Detailed insight into the different structures and conformations adopted by these mutant transcripts is vital for developing therapeutics targeting them. Here, we report the crystal structure of an RNA model with a r(CAG) motif, which is complemented by an NMR-based solution structure obtained from restrained Molecular Dynamics (rMD) simulation studies. Crystal structure data of the RNA model resolved at 2.3 Å reveals non-canonical pairing of adenine in 5´-CAG/3´-GAC motif samples in different syn and anti conformations. The overall RNA structure has helical parameters intermediate to the A- and B-forms of nucleic acids due to the global widening of major grooves and base-pair preferences near internal AA loops. The comprehension of structural behaviour by studying the spectral features and the dynamics also supports the flexible nature of the r(CAG) motif.	f	\N
26149802	The importance of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for survival outcomes in patients with acute myeloid leukemia (AML) currently remains unclear. The study aimed to compare measures of clinical treatment for patients with AML in CR1 (the first complete remission) with or without being subjected to allo-HSCT. These consisted of leukemia-free survival (LFS), overall survival (OS), cumulative incidence of relapse (CIR), and non-relapse mortality disease (NRM). Subjects were 622 patients, median age of 44, forming part of the prospective, randomized, and multicenter clinical Polish Adult Leukemia Group trials during 1999-2008. The Mantel-Byar approach was used to assess allo-HSCT on survival endpoints, accounting for a changing transplant status. Undergoing allo-HSCT significantly improved the LFS and OS for the entire group of patients with AML in CR1, along with the DAC induction subgroup and for the group with unfavorable cytogenetics aged 41-60. The CIR demonstrated that allo-HSCT reduced the risk of relapse for patients with AML in CR1 and those with an unfavorable cytogenetic risk. In addition, the NRM analysis showed that allo-HSCT significantly reduced the risk of death unrelated to relapse for the entire group of AML patients in CR1 and aged 41-60. The allo-HSCT treatment particularly benefitted survival for the AML in CR1 group having an unfavorable cytogenetic prognosis.	f	\N
26160211	The objective of this study was to compare the efficacy and comfort of inelastic bandages (IBs) and adjustable Velcro compression devices (AVCDs) in reducing venous leg edema in the initial treatment phase. Forty legs from 36 patients with untreated venous edema (C3EpsAsdPr) were randomized to two groups. Patients in the first group received IBs (n = 20) and those in the second AVCDs (n = 20). Both compression devices were left on the leg day and night, and were renewed after 1 day. Patients in the AVCD group were asked to re-adjust the device as needed when it felt loose. Leg volume was calculated using the truncated cone formula at baseline (T0), after 1 day (T1) and after 7 days (T7). The interface pressure of the two compression devices was measured by an air filled probe, and the static stiffness index calculated after applying compression at T0 and T1, and just before removal of compression on T1 and T7. Patient comfort with regard to the two compression systems was assessed by grading signs and symptoms using a visual analog scale. At T1, the median percent volume reduction was 13% for the IB group versus 19% for the AVCD group; at T7 it was 19% versus 26%, respectively (p < .001). The pressure of the IBs was significantly higher compared with the AVCDs at T0 (63 vs. 43 mmHg) but dropped by > 50% over time, while it remained unchanged with AVCDs owing to the periodic readjustment by the patient. Comfort was reported to be similar with the two compression devices. Re-adjustable AVCDs with a resting pressure of around 40 mmHg are more effective in reducing chronic venous edema than IBs with a resting pressure of around 60 mmHg. AVCDs are effective and well tolerated, not only during maintenance therapy, but also in the initial decongestive treatment phase of patients with venous leg edema.	f	\N
26163286	Thymic stromal lymphopoietin (TSLP) is an IL-7-related cytokine that has been studied extensively in atopic diseases and more recently in various rheumatic disorders. It is involved in T cell development in the thymus and promotes homeostatic T cell expansion by classical dendritic cells. However, deregulated TSLP expression in various rheumatic diseases has implicated this cytokine as a strong mediator in immunopathology. Overexpressed TSLP induces strong T cell activation and production of pro-inflammatory cytokines in human cells and animal models for RA, SSc and LN, underscoring the therapeutic potential of targeting the TSLP-TSLP receptor axis.	f	\N
26174498	The 14(th) -century Black Death was one of the most devastating epidemics in human history, killing tens of millions of people in a short period of time. It is not clear why mortality rates during the epidemic were so high. One possibility is that the affected human populations were particularly stressed in the 14(th) century, perhaps as a result of repeated famines in areas such as England. This project examines survival and mortality in two pre-Black Death time periods, 11-12(th) centuries vs 13(th) century CE, to determine if demographic conditions were deteriorating before the epidemic occurred. This study is done using a sample of individuals from several London cemeteries that have been dated, in whole or in part, either to the 11-12(th) centuries (n = 339) or 13(th) century (n = 258). Temporal trends in survivorship and mortality are assessed via Kaplan-Meier survival analysis and by modeling time period as a covariate affecting the Gompertz hazard of adult mortality. The age-at-death distributions from the two pre-Black Death time periods are significantly different, with fewer older adults in 13(th) century. The results of Kaplan-Meier survival analysis indicate reductions in survival before the Black Death, with significantly lower survival in the 13(th) century (Mantel Cox p < 0.001). Last, hazard analysis reveals increases in mortality rates before the Black Death. Together, these results suggest that health in general was declining in the 13(th) century, and this might have led to high mortality during the Black Death. This highlights the importance of considering human context to understand disease in past and living human populations.	f	\N
26175069	Dengue hemorrhagic fever (DHF), although predominantly associated with secondary infections, has also been reported in primary infections. An enhanced immune response including antibodies and cytokines is implicated in the pathogenesis of secondary DHF. However, the factors operating in primary DHF are poorly understood. To understand the role of the antibody response, the relative levels of different antibody isotypes during the acute phase of infection in primary and secondary dengue infections were determined. Levels of DENV-specific IgM, IgG, IgA and IgE were measured in the serum samples of 200 dengue patients and 20 dengue-naïve individuals. Samples were collected within 15 days of onset of illness. The DENV-specific IgM levels were significantly higher in DF cases compared to DHF, which was more evident in secondary infections and in post-defervescence samples. The levels of IgG, IgA and IgE were higher in DHF cases, with greater significance in primary infections. A higher level of IgG in DHF cases was evident in pre-defervescence samples, whilst the IgE level was higher in pre- and post-defervescence samples. There was a significant correlation of IgG titres with platelet counts, with higher titres associated with lower platelet counts. It is speculated that IgG, IgA and IgE produced in response to primary infections may contribute to pathogenesis, whilst IgM produced in response to secondary infections may protect against progression to severe disease.	f	\N
26189088	To determine the statistical correlation between visual acuity (VA) and various quantitative parameters relevant to birdshot retinochoroidopathy (BRC) evaluation. Hospital-based retrospective observational study. setting: Institutional. Consecutive HLA29+ BRC patients were included between May and August 2013 at a single tertiary center (Pitié-Salpétrière Hospital, Paris). Demographic data and quantitative parameters relevant to BRC at baseline were collected: VA, degree of anterior and posterior inflammatory reaction, foveal thickness measured by optical coherence tomography (OCT), Arden ratio, and electrooculography (EOG) light peak. Correlation between VA and the other parameters of the ipsilateral and fellow eye was performed using Spearman rank correlation coefficients. Fifty-five patients were included. Mean VA was 6/9.5 in the right eye (OD) and 6/12 in the left eye (OS). Mean foveal thickness was 240 μm OD (range: 112-606) and 251 μm OS (range: 85-662). Mean Arden ratio was 159% OD and 160% OS. EOG light peak was 714 mV OD (range: 316-1379) and 746 mV OS (range: 272-1652). VA of a given eye was moderately correlated with VA of the contralateral eye (r = 0.4). On the contrary, all other parameters showed a strong correlation between both eyes (all r > 0.7, P < .01). Overall, none of the studied parameters was correlated with its VA (all r < 0.5). In BRC, visual acuity alone does not seem to fully reflect the disease severity in terms of clinical or ancillary quantitative findings at baseline.	f	\N
26204159	Dividing cells that experience chromosome mis-segregation generate aneuploid daughter cells, which contain an incorrect number of chromosomes. Although aneuploidy interferes with the proliferation of untransformed cells, it is also, paradoxically, a hallmark of cancer, a disease defined by increased proliferative potential. These contradictory effects are also observed in mouse models of chromosome instability (CIN). CIN can inhibit and promote tumorigenesis. Recent work has provided insights into the cellular consequences of CIN and aneuploidy. Chromosome mis-segregation per se can alter the genome in many more ways than just causing the gain or loss of chromosomes. The short- and long-term effects of aneuploidy are caused by gene-specific effects and a stereotypic aneuploidy stress response. Importantly, these recent findings provide insights into the role of aneuploidy in tumorigenesis.	f	\N
26211602	Small cell carcinoma of head and neck region (SmCCHN) represents a rare entity and its management remains a significant clinical challenge. Complete initial response to primary therapy poses a difficult and controversial scenario for radiation oncologists. Prophylactic cranial irradiation (PCI) has long been established in the management of small cell lung cancer; however, its role in SmCCHN is still called into question. The rationale behind PCI lies in the eradication of possible micro-metastatic brain disease, which is often documented in this type of cancer. No randomized trials on this topic are available. This review, based on 20 retrospective studies, addresses the controversies in the use of PCI in SmCCHN management.	f	\N
26253469	Under distinct pathological heart conditions, the expression of a single miRNA can display completely opposite patterns. However, the mechanism underlying the bidirectional regulation of a single miRNA and the clinical implications of this regulation remain largely unknown. To address this issue, we examined the regulation of miR-1, one of the most abundant miRNAs in the heart, during cardiac hypertrophy and ischemia/reperfusion (I/R). Our data indicated that different magnitudes and chronicities of ROS levels in cardiomyocytes resulted in differential expression of miR-1, subsequently altering the expression of myocardin. In animal models, the administration of a miR-1 mimic attenuated cardiac hypertrophy by suppressing the transverse aortic constriction-induced increase in myocardin expression, whereas the administration of anti-miR-1 ameliorated I/R-induced cardiac apoptosis and deterioration of heart function. Our findings indicated that a pathologic stimulus such as ROS can bidirectionally alter the expression of miRNA to contribute to the development of pathological conditions exhibiting distinct phenotypes and that the meticulous adjustment of the pathological miRNA levels is required to improve clinical outcomes.	f	\N
26285805	VEGFs (vascular endothelial growth factors) are a family of conserved disulfide-linked soluble secretory glycoproteins found in higher eukaryotes. VEGFs mediate a wide range of responses in different tissues including metabolic homoeostasis, cell proliferation, migration and tubulogenesis. Such responses are initiated by VEGF binding to soluble and membrane-bound VEGFRs (VEGF receptor tyrosine kinases) and co-receptors. VEGF and receptor splice isoform diversity further enhances complexity of membrane protein assembly and function in signal transduction pathways that control multiple cellular responses. Different signal transduction pathways are simultaneously activated by VEGFR-VEGF complexes with membrane trafficking along the endosome-lysosome network further modulating signal output from multiple enzymatic events associated with such pathways. Balancing VEGFR-VEGF signal transduction with trafficking and proteolysis is essential in controlling the intensity and duration of different intracellular signalling events. Dysfunction in VEGF-regulated signal transduction is important in chronic disease states including cancer, atherosclerosis and blindness. This family of growth factors and receptors is an important model system for understanding human disease pathology and developing new therapeutics for treating such ailments.	f	\N
26292522	At the death of Cardinal Pietro Basadonna in 1684, his personal physician Romolo Spezioli wrote a report describing the disease, circumstances of death and autopsy findings of the illustrious prelate. This document, kept in the Biblioteca Civica at Jesi, is a significant attestation of the medical terminology and diagnostic and therapeutic procedures of the time. Even with the constraints that interpretation of a clinical account dating back over 300 years inevitably imposes, perusal of this report suggests that Cardinal Basadonna's demise could have been due to septic shock, consequent to a urinary infection caused by a bulky bladder stone.	f	\N
26293802	Leptin is an adipocytokine produced by adipocytes and controlling body weight. It is unclear whether leptin works as a proinflammatory or an anti-inflammatory cytokine. We investigated the effects of hyperleptinemia on leptin transgenic (LepTg) mice in terms of cartilage destruction, bone destruction, joint synovitis, and serum cytokine levels by using a mouse model of collagen-antibody-induced arthritis (CAIA). CAIA was induced for female age-matched 6- to 8-week-old C57BL/6 J control mice and LepTg mice. Mice were injected intraperitoneally with 5 mg of a combination of monoclonal antibody specific for type II collagen on day 0 and 12.5 mg of lipopolysaccharide (LPS) on day 3. Clinical evaluation of arthritis was monitored for 14 days, and hind paws were examined clinically and histologically. Serum cytokine levels of interleukin (IL)-1β, IL-6, IL-10, and IL-17 and tumor necrosis factor alpha (TNF-α) were also analyzed on days 0 and 5. Moreover, THP-1 cells, which are human monocytic cell line derived from an acute monocytic leukemia patient, were cultured and differentiated into macrophages. The effects of leptin on messenger RNA (mRNA) expression of IL-6 were examined by real-time quantitative polymerase chain reaction (RT-PCR). Serum leptin concentrations were approximately ninefold higher in LepTg mice (62.0 ± 20.7 ng/ml) than in control mice (7.2 ± 0.5 ng/ml). Severity of clinical paw swelling, arthritis score, synovial hyperplasia, and cartilage damage were suppressed in LepTg mice with CAIA. Although serum cytokine levels of IL-1β, IL-17, and IL-10 and TNF-α showed no significant changes in two mice, serum levels of IL-6 in LepTg mice were suppressed at day 5. Moreover, in vitro study showed that IL-6 elevation following LPS exposure in THP-1 cells was suppressed with high leptin concentrations. Our finding suggests that hyperleptinemia suppress IL-6 responses and progression of joint inflammation. Leptin may play an anti-inflammatory role under hyperleptinemia.	f	\N
26299076	The aim of this study is to observe the association between venous thromboembolism (VTE) and oxidative stress and to see if there is a diagnostic value in the oxidative/antioxidative balance parameters like total oxidant status (TOS), total antioxidant status (TAS), paraoxonase-(PON1), and arylesterase (ARE) enzyme activities in this specific disease. Sixty-nine patients with deep vein thrombosis and/or pulmonary embolism and 40 control subjects were included in the study. Oxidative stress index, total oxidant status, and antioxidant status were examined in addition to the PON1 and ARE enzyme activities in both groups. Serum PON1 and ARE activities were significantly lower in the VTE patients, whereas total oxidant status was higher in patients compared to the controls. This preliminary study showed that oxidative/antioxidative balance shifted towards the oxidative status in venous thromboembolism. ROC analysis results suggested that the parameters used in this study were not good enough to be used in the diagnosis of VTE.	f	\N
26310351	Google Flu Trends (GFT) was the first application of big data in the public health field. GFT was open online in 2009 and attracted worldwide attention immediately. However, GFT failed catching the 2009 pandemic H1N1 and kept overestimating the intensity of influenza-like illness in the 2012-2014 season in the United States. GFT model has been updated for three times since 2009, making its prediction bias controlled. Here, we summarized the mechanism GFT worked, the strategy GFT used to update, and its influence on public health.	f	\N
26357715	Anal cancer is a relatively uncommon disease, accounting for only 4% of cancers of the lower gastrointestinal tract. To summarize a single-center experience in the treatment of anal carcinoma using various radiation techniques. We conducted a retrospective chart review of consecutive patients who were treated for anal cancer between the years 2002 and 2011. The data extracted included demographics, type of radiation technique, treatment-associated acute toxicity, and patterns of failure and survival. For statistical analysis purposes, the patients were divided into two groups according to radiotherapy technique: 2D (group A) and 3D (group B). A total of 42 patients--25 (59.5%) females and 17 males (40.5%)--underwent definitive chemo-radiation treatment (CRT) for anal cancer. Group A comprised 26 patients and group B 14 patients. Toxicity did not differ significantly between the groups; only in grade 1-2 skin toxicity which was more common in group B. There were significant differences in the unplanned interruptions in treatment, in both the number of patients who needed a treatment break and the number of days needed (more in group A). There were no differences in treatment response and patterns of failure between these two techniques, or in overall survival between the two groups. Our study results are consistent with reported large randomized trials, indicating that current treatments for anal carcinomas are associated with high grade acute toxicity that may result in significant treatment interruptions. The 2D technique was associated with significantly more treatment interruptions but did not differ from 3D with regard to treatment efficacy.	f	\N
26375933	There has been considerable effort over the last 25 years to understand the emergence of complexity in motor output and how this relates to properties of the individual (e.g., age, disease state, etc.), environment (e.g., information) and task (e.g., movement, posture, isometric force). This paper addresses the behavioral dimension of motor complexity in movement and posture from a degrees of freedom (DF) perspective together with the change of complexity through aging, disease and fatigue. The dimension of behavior for a given perceptual-motor output is shown to be relatively low, dependent on the interaction between the individual, environmental, and task constraints and varies within a limited adaptive range for a given motor task. The determination of dimension in movement and posture has taken us beyond the traditional motor performance scores of behavior but it is not a sufficient characterization of the adaptive and emergent processes of complexity.	f	\N
26381985	Assessment of the global burden of disease is based on epidemiological cohort studies that connect premature mortality to a wide range of causes, including the long-term health impacts of ozone and fine particulate matter with a diameter smaller than 2.5 micrometres (PM2.5). It has proved difficult to quantify premature mortality related to air pollution, notably in regions where air quality is not monitored, and also because the toxicity of particles from various sources may vary. Here we use a global atmospheric chemistry model to investigate the link between premature mortality and seven emission source categories in urban and rural environments. In accord with the global burden of disease for 2010 (ref. 5), we calculate that outdoor air pollution, mostly by PM2.5, leads to 3.3 (95 per cent confidence interval 1.61-4.81) million premature deaths per year worldwide, predominantly in Asia. We primarily assume that all particles are equally toxic, but also include a sensitivity study that accounts for differential toxicity. We find that emissions from residential energy use such as heating and cooking, prevalent in India and China, have the largest impact on premature mortality globally, being even more dominant if carbonaceous particles are assumed to be most toxic. Whereas in much of the USA and in a few other countries emissions from traffic and power generation are important, in eastern USA, Europe, Russia and East Asia agricultural emissions make the largest relative contribution to PM2.5, with the estimate of overall health impact depending on assumptions regarding particle toxicity. Model projections based on a business-as-usual emission scenario indicate that the contribution of outdoor air pollution to premature mortality could double by 2050.	f	\N
26383059	Multiple sclerosis (MS) is a demyelinating disease that affects young adults; in that age group, it represents the second leading cause of disability in our setting. Its precise aetiology has not been elucidated, but it is widely accepted to occur in genetically predisposed patients who are exposed to certain environmental factors. The discovery of the regulatory role played by intestinal microbiota in various autoimmune diseases has opened a new line of research in this field, which is discussed in this review. We reviewed published studies on the role of the microbiota in the development of both MS and its animal model, experimental autoimmune encephalomyelitis (EAE). In mice, it has been shown that intestinal microorganisms regulate the polarisation of T helper cells from Th1-Th17 up to Th2, the function of regulatory T cells, and the activity of B cells; they participate in the pathogenesis of EAE and contribute to its prevention and treatment. In contrast, evidence in humans is still scarce and mainly based on case-control studies that point to the presence of differences in certain bacterial communities. Multiple evidence points to the role of microbiota in EAE. Extrapolation of these results to MS is still in the early stages of research, and studies are needed to define which bacterial populations are associated with MS, the role they play in pathogenesis, and the therapeutic possibilities this knowledge offers us.	f	\N
26402460	Perforin-2 (MPEG1) is a pore-forming, antibacterial protein with broad-spectrum activity. Perforin-2 is expressed constitutively in phagocytes and inducibly in parenchymal, tissue-forming cells. In vitro, Perforin-2 prevents the intracellular replication and proliferation of bacterial pathogens in these cells. Perforin-2 knockout mice are unable to control the systemic dissemination of methicillin-resistant Staphylococcus aureus (MRSA) or Salmonella typhimurium and perish shortly after epicutaneous or orogastric infection respectively. In contrast, Perforin-2-sufficient littermates clear the infection. Perforin-2 is a transmembrane protein of cytosolic vesicles -derived from multiple organelles- that translocate to and fuse with bacterium containing vesicles. Subsequently, Perforin-2 polymerizes and forms large clusters of 100 Å pores in the bacterial surface with Perforin-2 cleavage products present in bacteria. Perforin-2 is also required for the bactericidal activity of reactive oxygen and nitrogen species and hydrolytic enzymes. Perforin-2 constitutes a novel and apparently essential bactericidal effector molecule of the innate immune system.	f	\N
26427384	The ubiquitin-proteasome pathway (UPP) is the primary degradation system of short-lived regulatory proteins. Cellular processes such as the cell cycle, signal transduction, gene expression, DNA repair and apoptosis are regulated by this UPP and dysfunctions inthis system have important implications in the development of cancer, neurodegenerative, cardiac and other human pathologies. UPP seems also to be very important in the function of eukaryote cells of the human parasites like Plasmodium falciparum, thecausal agent of the neglected disease Malaria. Hence, the UPP could be considered as an attractive target for the development of compounds with Anti-Malarial or Anti-cancer properties. Recent online databases like ChEMBL contains a larger quantity of information in terms of pharmacological assay protocols and compounds tested as UPP inhibitors under many different conditions. This large amount of data give new openings for the computer-aided identification of UPP inhibitors, but the intrinsic data diversity is an obstacle for the development of successful classifiers. To solve this problem here we used the Bob-Jenkins moving average operators and the atom-based quadratic molecular indices calculated with the software TOMOCOMD-CARDD (TC) to develop a quantitative model for the prediction of the multiple outputs in this complex dataset. Our multi-target model can predict results for drugs against 22 molecular or cellular targets of different organisms with accuracies above 70% in both training and validation sets.	f	\N
26432016	The continuous search for drugs targeting type 2 diabetes mellitus (T2DM) has led to the identification of small molecules that disrupt the binding between glucokinase and glucokinase regulatory protein (GKRP). Although mice studies are encouraging, it will take years before these disruptors can be introduced to T2DM patients. Recently, genome-wide association studies (GWASs) have shown that variants in the gene encoding GKRP protect against T2DM and kidney disease but predispose to gout, nonalcoholic fatty liver disease, and dyslipidemia. These genetic data, together with previous experience with systemic and hepatospecific glucokinase activators, provide insight into the anticipated efficacy and safety of small-molecule disruptors in humans. Interestingly, they suggest that the opposite--enhanced GKRP-glucokinase binding--could be beneficial in selected patients.	f	\N
26470622	Hidradenitis suppurativa (HS) is a chronic inflammatory disease that commonly develops painful, deep dermal abscesses and chronic, draining sinus tracts. Classically, pharmacologic and surgical therapies have been effective for reducing lesion activity and inflammation, but provide only modest success in the prevention of future recurrences and disease progression. Adjunctive therapies, such as laser and light-based therapies, have become more commonly used in the management of HS. These therapies work to reduce the occurrence of painful HS flare-ups by decreasing the number of hair follicles, sebaceous glands, and bacteria in affected areas, and by ablatively debulking chronic lesions. The best results are seen when treatment is individualized, taking disease severity into consideration when selecting specific energy-based approaches. This article will discuss various light-based therapies and the evidence supporting their use in the management of HS.	f	\N
26525918	Micrographia is a common symptom in Parkinson's disease, which manifests as either a consistent or progressive reduction in the size of handwriting or both. Neural correlates underlying micrographia remain unclear. We used functional magnetic resonance imaging to investigate micrographia-related neural activity and connectivity modulations. In addition, the effect of attention and dopaminergic administration on micrographia was examined. We found that consistent micrographia was associated with decreased activity and connectivity in the basal ganglia motor circuit; while progressive micrographia was related to the dysfunction of basal ganglia motor circuit together with disconnections between the rostral supplementary motor area, rostral cingulate motor area and cerebellum. Attention significantly improved both consistent and progressive micrographia, accompanied by recruitment of anterior putamen and dorsolateral prefrontal cortex. Levodopa improved consistent micrographia accompanied by increased activity and connectivity in the basal ganglia motor circuit, but had no effect on progressive micrographia. Our findings suggest that consistent micrographia is related to dysfunction of the basal ganglia motor circuit; while dysfunction of the basal ganglia motor circuit and disconnection between the rostral supplementary motor area, rostral cingulate motor area and cerebellum likely contributes to progressive micrographia. Attention improves both types of micrographia by recruiting additional brain networks. Levodopa improves consistent micrographia by restoring the function of the basal ganglia motor circuit, but does not improve progressive micrographia, probably because of failure to repair the disconnected networks.	f	\N
26527069	Cancer, more than any other human disease, now has a surfeit of potential molecular targets poised for therapeutic exploitation. Currently, a number of attractive and validated cancer targets remain outside of the reach of pharmacological regulation. Some have been described as undruggable, at least by traditional strategies. In this article, we outline the basis for the undruggable moniker, propose a reclassification of these targets as undrugged, and highlight three general classes of this imposing group as exemplars with some attendant strategies currently being explored to reclassify them. Expanding the spectrum of disease-relevant targets to pharmacological manipulation is central to reducing cancer morbidity and mortality.	f	\N
26574670	The neurodegenerative synucleinopathies, which include Parkinson disease, multiple-system atrophy, and Lewy body disease, are characterized by the presence of abundant neuronal inclusions called Lewy bodies and Lewy neurites. These disorders remain incurable, and a greater understanding of the pathologic processes is needed for effective treatment strategies to be developed. Recent data suggest that pathogenic misfolding of the presynaptic protein, α-synuclein (α-syn), and subsequent aggregation and accumulation are fundamental to the disease process. It is hypothesized that the misfolded isoform is able to induce misfolding of normal endogenous α-syn, much like what occurs in the prion diseases. Recent work highlighting the seeding effect of pathogenic α-syn has largely focused on the detergent-insoluble species of the protein. In this study, we performed intracerebral inoculations of the sarkosyl-insoluble or sarkosyl-soluble fractions of human Lewy body disease brain homogenate and show that both fractions induce CNS pathology in mice at 4 months after injection. Disease-associated deposits accumulated both near and distal to the site of the injection, suggesting a cell-to-cell spread via recruitment of α-syn. These results provide further insight into the prion-like mechanisms of α-syn and suggest that disease-associated α-syn is not homogeneous within a single patient but might exist in both soluble and insoluble isoforms.	f	\N
26622256	Endometriosis is a frequent gynecologic disease with a severe impact on the quality of life in the affected women; its pathogenesis is yet to be fully understood, with an altered immunity as a possible key factor. The present study aimed to investigate the serum anti-inflammatory cytokine profile in the patients with endometriosis compared with the healthy controls. One hundred and sixty women were included, divided into two study groups (Group I - endometriosis; Group 2 - healthy women). We evaluated the serum levels of interleukin-1 receptor antagonist (IL-1Ra), IL-2, IL-2R, IL-4, IL-10, IL-13, and IL-15 with the use of Human multiplex cytokine panels. Statistical analyses (normality distribution analysis, independent t-test, Mann-Whitney U-test) were performed using IBM SPSS software (version 22.0) and GraphPad Prism (version 5.00); receiver operating characteristic curve were used to demonstrate the diagnostic performance of the studied markers. The mean serum level of IL-1Ra, IL-4, and IL-10 were significantly higher in women with endometriosis compared to women free of disease from the control group (30.155, 138.459, and 1.489, respectively, compared to 14.109, 84.710, and 0.688, respectively; P < 0.001, P < 0.001, and P = 0.002, respectively.). No significant differences in the mean serum levels of IL-2, IL-13, and IL-15 were observed between the studied groups and IL-2R had a very low detection rate. Endometriosis is associated with elevated levels of anti-inflammatory cytokines, IL-1Ra, IL-4, and IL-10, markers that have a potential role as a prognostic factor for endometriosis.	f	\N
26628350	Adult tissue-derived mesenchymal stromal cells (MSCs) are showing promise in clinical trials for systemic lupus erythematosus (SLE). However, the inability to manufacture large quantities of functional cells from a single donor as well as donor-dependent variability in quality limits their clinical utility. Human embryonic stem cell (hESC)-derived MSCs are an alternative to adult MSCs that can circumvent issues regarding scalability and consistent quality due to their derivation from a renewable starting material. Here, we show that hESC-MSCs prevent the progression of fatal lupus nephritis (LN) in NZB/W F1 (BWF1) mice. Treatment led to statistically significant reductions in proteinuria and serum creatinine and preserved renal architecture. Specifically, hESC-MSC treatment prevented disease-associated interstitial inflammation, protein cast deposition, and infiltration of CD3(+) lymphocytes in the kidneys. This therapy also led to significant reductions in serum levels of tumor necrosis factor alpha (TNFα) and interleukin 6 (IL-6), two inflammatory cytokines associated with SLE. Mechanistically, in vitro data support these findings, as co-culture of hESC-MSCs with lipopolysaccharide (LPS)-stimulated BWF1 lymphocytes decreased lymphocyte secretion of TNFα and IL-6, and enhanced the percentage of putative regulatory T cells. This study represents an important step in the development of a commercially scalable and efficacious cell therapy for SLE/LN.	f	\N
26633764	Ebola emerged in West Africa around December 2013 and swept through Guinea, Sierra Leone and Liberia, giving rise to 27,748 confirmed, probable and suspected cases reported by 29 July 2015. Case diagnoses during the epidemic have relied on polymerase chain reaction-based tests. Owing to limited laboratory capacity and local transport infrastructure, the delays from sample collection to test results being available have often been 2 days or more. Point-of-care rapid diagnostic tests offer the potential to substantially reduce these delays. We review Ebola rapid diagnostic tests approved by the World Health Organization and those currently in development. Such rapid diagnostic tests could allow early triaging of patients, thereby reducing the potential for nosocomial transmission. In addition, despite the lower test accuracy, rapid diagnostic test-based diagnosis may be beneficial in some contexts because of the reduced time spent by uninfected individuals in health-care settings where they may be at increased risk of infection; this also frees up hospital beds. We use mathematical modelling to explore the potential benefits of diagnostic testing strategies involving rapid diagnostic tests alone and in combination with polymerase chain reaction testing. Our analysis indicates that the use of rapid diagnostic tests with sensitivity and specificity comparable with those currently under development always enhances control, whether evaluated at a health-care-unit or population level. If such tests had been available throughout the recent epidemic, we estimate, for Sierra Leone, that their use in combination with confirmatory polymerase chain-reaction testing might have reduced the scale of the epidemic by over a third.	f	\N
26646939	Non-alcoholic fatty liver disease (NAFLD) is a consequence of sedentary life style and high fat diets with an estimated prevalence of about 30% in western countries. It is associated with insulin resistance, obesity, glucose intolerance and drug toxicity. Additionally, polymorphisms within, e.g., APOC3, PNPLA3, NCAN, TM6SF2 and PPP1R3B, correlate with NAFLD. Several studies have already investigated later stages of the disease. This study explores the early steatosis stage of NAFLD with the aim of identifying molecular mechanisms underlying the etiology of NAFLD. We analyzed liver biopsies and serum samples from patients with high- and low-grade steatosis (also pre-disease states) employing transcriptomics, ELISA-based serum protein analyses and metabolomics. Here, we provide a detailed description of the various related datasets produced in the course of this study. These datasets may help other researchers find new clues for the etiology of NAFLD and the mechanisms underlying its progression to more severe disease states.	f	\N
26666493	Studies have addressed the immunomodulatory effects of helminths and their protective effects upon asthma. However, anti-Ascaris IgE has been reported to be associated with an increased risk of asthma symptoms. We examined the association between serum levels of anti-Ascaris IgE and bronchial hyper-responsiveness (BHR) in children living in rural Bangladesh. Serum anti-Ascaris IgE level was measured and the BHR test done in 158 children aged 9 years selected randomly from a general population of 1705 in the Matlab Health and Demographic Surveillance Area of the International Centre for Diarrhoeal Disease Research, Bangladesh. We investigated wheezing symptoms using a questionnaire from the International Study of Asthma and Allergies in Childhood. BHR tests were successfully done on 152 children (108 'current wheezers'; 44 'never-wheezers'). We examined the association between anti-Ascaris IgE level and wheezing and BHR using multiple logistic regression analyses. Of 108 current-wheezers, 59 were BHR-positive; of 44 never-wheezers, 32 were BHR-negative. Mean anti-Ascaris IgE levels were significantly higher (12.51 UA/ml; 95% confidence interval (CI), 9.21-17.00) in children with current wheezing with BHR-positive than in those of never-wheezers with BHR-negative (3.89; 2.65-5.70; t test, p < 0.001). A BHR-positive test was independently associated with anti-Ascaris IgE levels with an odds ratio (OR) = 7.30 [95% CI, 2.28-23.33], p = 0.001 when adjusted for total IgE, anti-Dermatophagoides pteronyssinus IgE, pneumonia history, parental asthma, Trichuris infection, forced expiratory volume in one second, eosinophilic leukocyte count, and sex. Anti-Ascaris IgE level is associated with an increased risk of BHR among 9-year-old rural Bangladeshi children.	f	\N
26685524	In the first century B.C.E., a group of Greek physicians called the Methodists denied that medicine could be based on such "hidden causes" as humors, atoms, or elements. They argued that the inner workings of the body were ultimately unknowable, existing beyond the limits of human knowledge and inference. Yet they insisted that medical certainty was still possible, claiming that every disease shared one of three directly apprehensible "manifest commonalities"--stricture, laxity, or some mixture of the two. Medicine could therefore be a science; it was simply noncausal in structure. This essay examines these medical theories in light of Herbert Simon's concept of "bounded rationality," suggesting that the Methodists were proposing a type of medical "heuristic" in response to the limitations of human knowledge and processing power. At the same time, the essay suggests that such an epistemology had its consequences, setting up an ontological crunch whereby the demands formerly placed on diseases and their causes transferred to "affections" and the commonalities, with successive generations of Methodists disagreeing about the status of symptoms, signs, and diseased states. Borrowing vocabulary from the Methodists themselves, the essay calls the consequent ontological slippage between causes and effects "metalepsis".	f	\N
26700806	Colorectal cancer remains a major unmet medical need, prompting large-scale genomics efforts in the field to identify molecular drivers for which targeted therapies might be developed. We previously reported the identification of recurrent translocations in R-spondin genes present in a subset of colorectal tumours. Here we show that targeting RSPO3 in PTPRK-RSPO3-fusion-positive human tumour xenografts inhibits tumour growth and promotes differentiation. Notably, genes expressed in the stem-cell compartment of the intestine were among those most sensitive to anti-RSPO3 treatment. This observation, combined with functional assays, suggests that a stem-cell compartment drives PTPRK-RSPO3 colorectal tumour growth and indicates that the therapeutic targeting of stem-cell properties within tumours may be a clinically relevant approach for the treatment of colorectal tumours.	f	\N
26722363	Matrix metalloproteinases (MMPs) play intricate roles in cancer progression; some promote invasion and angiogenesis while others suppress tumor growth. For example, human MMP-26/endometase/matrilysin-2 was reported to be either protective or pro-tumorigenic. Our previous reports suggested pro-invasion and anti-inflammation properties in prostate cancer. Here, we provide evidence for a protective role of MMP-26 in the prostate. MMP-26 expression levels in androgen-repressed human prostate cancer (ARCaP) cells, transfected with sense or anti-sense MMP-26 cDNA, are directly correlated with those of the pro-apoptotic marker Bax. Immunohistochemical staining of prostate cancer tissue samples shows similar protein expression patterns, correlating the expression levels of MMP-26 and Bax in benign, neoplastic, and invasive prostate cancer tissues. The MMP-26 protein levels were upregulated in high grade prostate intraepithelial neoplasia (HGPIN) and decreased during the course of disease progression. Further analysis using an indirect terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay showed that many tumor cells expressing MMP-26 were undergoing apoptosis. This study showed that the high level of MMP-26 expression is positively correlated with the presence of apoptotic cells. This pro-apoptotic role of MMP-26 in human prostate cancer cells and tissues may enhance our understanding of the paradoxical roles of MMP-26 in tumor invasion and progression.	f	\N
26749833	Twenty bromotyrosine alkaloids, including a new compound, 13-oxosubereamolline D (5), were isolated from the Thai sponge Acanthodendrilla sp. Their structures were determined by analyses of 1D- and 2D-NMR, high-resolution mass, and circular dichroism data. The complete 1H and 13C NMR assignments of 5,7β-dichlorocavernicolin (19) and 5,7α-dichlorocavernicolin (20) are described herein for the first time. The acetylcholinesterase (AChE) inhibitory activity of all isolated compounds was evaluated. Only homoaerothionin (7) and fistularin 1 (10) exhibited inhibitory activity against human recombinant AChE (hrAChE) with IC50s of 4.5 and 47.5 µM, respectively. The hrAChE inhibition kinetics of 7, the most potent alkaloid, showed increased Km and unchanged Vmaxvalues, suggesting its competitive mode of inhibition. The spirocyclohexadienylisoxazole and the length of the alkyl diamine linkage were proposed as the crucial parts for its strong inhibitory activity. This finding indicates a therapeutic potential for 7 in acetylcholine-related diseases, most importantly Alzheimer's disease.	f	\N
26769066	Genetic ancestry, sex, and individual alleles have been associated with multiple sclerosis (MS) susceptibility. To determine whether established risk factors for disease onset are associated with relapse rate in pediatric MS. Whole-genome genotyping was performed for 181 MS or high-risk clinically isolated syndrome patients from two pediatric MS centers. Relapses and disease-modifying therapies were recorded as part of continued follow-up. Participants were characterized for 25-hydroxyvitamin D serum status. Ancestral estimates (STRUCTURE v2.3.1), human leukocyte antigen (HLA)-DRB1*15 carrier status (direct sequencing), sex, and a genetic risk score (GRS) of 110 non-HLA susceptibility single-nucleotide polymorphisms (SNPs) were evaluated for association with relapse rate with Cox and negative binomial regression models. Over 622 patient-years, 408 relapses were captured. Girls had greater relapse rate than boys (incident rate ratio (IRR) = 1.40, 95% confidence interval (CI) = 1.04-1.87, p = 0.026). Participants were genetically diverse; ~40% (N = 75) had <50% European ancestry. HLA-DRB1*15 status modified the association of vitamin D status (pixn = 0.022) with relapse rate (per 10 ng/mL, in DRB1*15+ hazard ratio (HR) = 0.72, 95% CI = 0.58-0.88, p = 0.002; in DRB1*15- HR = 0.96, 95% CI = 0.83-1.12, p = 0.64). Neither European ancestry nor GRS was associated with relapse rate. We demonstrate that HLA-DRB1*15 modifies the association of vitamin D status with relapse rate. Our findings emphasize the need to pursue disease-modifying effects of MS genes in the context of environmental factors.	f	\N
26789921	Viruses are obligate parasites and thus require the machinery of the host cell to replicate. Inhibition of host factors co-opted during active infection is a strategy hosts use to suppress viral replication and a potential pan-antiviral therapy. To define the cellular proteins and processes required for a virus during infection is thus crucial to understanding the mechanisms of virally induced disease. In this report, we generated fully infectious tagged influenza viruses and used infection-based proteomics to identify pivotal arms of cellular signaling required for influenza virus growth and infectivity. Using mathematical modeling and genetic and pharmacologic approaches, we revealed that modulation of Sec61-mediated cotranslational translocation selectively impaired glycoprotein proteostasis of influenza as well as HIV and dengue viruses and led to inhibition of viral growth and infectivity. Thus, by studying virus-human protein-protein interactions in the context of active replication, we have identified targetable host factors for broad-spectrum antiviral therapies.	f	\N
22511225	The proteasome was first identified as a high MW protease complex that gets resolved into a series of low MW protein species upon denaturation. As the dominant protease dedicated to protein turnover, the proteasome shapes the cellular protein repertoire. Our knowledge of proteasome regulation and activity has improved considerably over the past decade. Novel inhibitors, in particular, have helped to advance our understanding of proteasome biology. They range from small peptide-based structures that can be modified to vary target specificity to large macromolecular inhibitors that include proteins. Although these reagents have an important role in establishing our current knowledge of the proteasome's catalytic mechanism, many questions remain. The future lies in designing compounds that can function as drugs to target processes involved in disease progression. Our focus in this chapter is to highlight the use of various classes of inhibitors to probe the mechanism of the proteasome and to identify its physiological significance in the cell, so that the mechanism of inhibition of proteasome will work as a definite source for design of protocols for newer therapeutic agents for the treatment of inflammation and in cancer therapy.	f	\N
20047084	Compared to high school graduates, adolescents who drop out of school are more likely to have a range of negative outcomes, including lower verbal capacities; however, the true nature of this association is not well-understood. Dropping out of school could have an important effect on reducing verbal skills, or the link between dropping out of school and diminished verbal skills could be a spurious association that is the result of unmeasured confounding variables. The current study tested these two competing perspectives by using propensity-score-matching (PSM) to unpack the association between school dropout and verbal skills among 7,317 respondents from the National Longitudinal Study of Adolescent Health (51% female, 49% male; 62% Caucasian, 38% minority). The results of the PSM models indicated a small yet meaningful statistically significant effect of dropout on verbal skills in adulthood even after taking into account a range of confounders. We conclude by discussing the implications of our results.	\N	\N
20236795	To determine the effectiveness of gore-tex medialization thyroplasty for the management of glottic incompetence (GI) in patients with mobile vocal folds. Twenty patients with glottic incompetence (GI) and mobile vocal folds were retrospectively analyzed after gore-tex medialization laryngoplasty. Pre- and postoperative outcome measures including grade, roughness, breathiness, asthenia, strain of the voice (GRBAS), glottal function index (GFI), and voice-related quality of life (VRQOL) were compared to detect surgical effectiveness. Two anesthetic subgroups were identified and compared: general anesthesia, via laryngeal mask airway (LMA) anesthetic, and local anesthesia. Statistically significant differences were identified between pre- and postoperative VRQOL (P<0.0001), GFI (P<0.01), and composite GRBAS (P<0.0001) after a mean follow-up time of 7.8 months. Both the LMA and the local anesthetic subgroups demonstrated similar significance across these measures. GFI and VRQOL scores demonstrate a moderate correlation (ρ=0.71). Perceptual voice quality (GRBAS) correlates slightly better with VRQOL scores (ρ=-0.6; P<0.01) than qualitative measures of glottal function (GFI) (ρ=0.43). Gore-tex thyroplasty provides reliable medium-term improvement in both perceptual and subjective voice parameters in the setting of GI with mobile vocal folds.	\N	\N
20388591	Electroencephalogram (EEG) recordings, and especially the Mu-rhythm over the sensorimotor cortex that relates to the activation of the mirror neuron system (MNS), were acquired from two subject groups (orchestral musicians and nonmusicians), in order to explore action representation processes involved in the perception and performance of musical pieces. Two types of stimuli were used, i.e., an auditory one consisting of an excerpt of Beethoven's fifth symphony and a visual one presenting a conductor directing an orchestra performing the same excerpt of the piece. Three tasks were conducted including auditory stimulation, audiovisual stimulation, and visual stimulation only, and the acquired signals were processed using fractal [time-dependent fractal dimension (FD) estimation] and statistical analysis (analysis of variance, Mann-Whitney). Experimental results showed significant differences between the two groups while desychronization of the Mu-rhythm, which can be linked to MNS activation, was observed during all tasks for the musicians' group, as opposed to the nonmusicians' group who exhibited similar response only when the visual stimulus was present. The mobility of the conductor was also correlated to the estimated FD signals, showing significantly higher correlation for the case of musicians compared to nonmusicians' one. The present study sheds light upon the difference in action representation in auditory perception between musicians and nonmusicians and paves the way for better comprehension of the underlying mechanisms of the MNS.	\N	\N
20447726	The purpose of the study was to compare the speech recognition capacity between listeners with and without acoustic reflex using different types of noises and intensities. We studied 18 women allocated to 2 groups: acoustic reflex present (20 ears) and absent (16 ears). They were presented with 180 disyllable words (90 to each ear), emitted randomly at a fixed intensity of 40 dB above the pure tone average hearing level. At the same time, 3 types of noises were presented ipsilaterally (white, pink, and speech), one at a time, at 3 intensities: 40, 50, and 60 dB above the pure tone average hearing level. The ages and auditory thresholds were statistically equal between the groups. There was a significant difference in mean number of hits between the 2 groups for the 3 types of noises used. There was also a significant difference in mean number of hits for noise type and intensity when white and pink noise was used at 40 and 50 dB and for all the intensities when speech was used. Acoustic reflex helps communication in high-noise environments and is more efficient for speech sounds.	\N	\N
20507830	On its 43rd anniversary the Simon effect can look back at a long and varied history. First treated as a curious observation with implications for human factors research, it slowly evolved not only into a valuable target of psychological theorizing itself but also into a handy means to investigate attentional operations, the representation of space and of one's body, the cognitive representation of intentional action, and executive control. This article discusses the major characteristics of the Simon effect and the Simon task that laid the ground for this success and reviews the major lines of research, theoretical developments, and ongoing controversies on and around the Simon Effect and the cognitive processes it reflects.	\N	\N
20557486	Predominantly, the impact of environmental noise is measured using sound level, ignoring the influence of other factors on subjective experience. The present study tested physiological responses to natural urban soundscapes, using functional magnetic resonance imaging and vector cardiogram. City-based recordings were matched in overall sound level (71 decibel A-weighted scale), but differed on ratings of pleasantness and vibrancy. Listening to soundscapes evoked significant activity in a number of auditory brain regions. Compared with soundscapes that evoked no (neutral) emotional response, those evoking a pleasant or unpleasant emotional response engaged an additional neural circuit including the right amygdala. Ratings of vibrancy had little effect overall, and brain responses were more sensitive to pleasantness than was heart rate. A novel finding is that urban soundscapes with similar loudness can have dramatically different effects on the brain's response to the environment.	\N	\N
20562170	Estrogen may be involved in schizophrenia by inhibiting serotonin-1A (5-HT(1A)) receptor function. We examined the effects of estrogen pre-treatment on modulation of loudness dependence of the auditory evoked potential (LDAEP) and mismatch negativity by the 5-HT(1A) receptor partial agonist, buspirone. Using a double-blind, placebo-controlled, repeated-measures design in healthy female volunteers, we observed that buspirone treatment significantly increased LDAEP slope. Estrogen increased LDAEP slope on its own, and a further LDAEP increase by buspirone was not seen after estrogen pre-treatment. Similar results were observed for mismatch negativity, where buspirone caused a small increase of latency, although not amplitude, after placebo but not estrogen pre-treatment, which enhanced mismatch negativity latency on its own. These results are in line with our previous findings on prepulse inhibition showing an inhibitory effect of estrogen on the action of buspirone. Taken together, these data suggest that estrogen may inhibit 5-HT(1A) receptor-mediated disruptions of auditory processing.	\N	\N
20570253	An increasing number of neuroimaging studies in music cognition research suggest that "language areas" are involved in the processing of musical syntax, but none of these studies clarified whether these areas are a prerequisite for normal syntax processing in music. The present electrophysiological experiment tested whether patients with lesions in Broca's area (N=6) or in the left anterior temporal lobe (N=7) exhibit deficits in the processing of structure in music compared to matched healthy controls (N=13). A chord sequence paradigm was applied, and the amplitude and scalp topography of the Early Right Anterior Negativity (ERAN) was examined, an electrophysiological marker of musical syntax processing that correlates with activity in Broca's area and its right hemisphere homotope. Left inferior frontal gyrus (IFG) (but not anterior superior temporal gyrus - aSTG) patients with lesions older than 4 years showed an ERAN with abnormal scalp distribution, and subtle behavioural deficits in detecting music-syntactic irregularities. In one IFG patient tested 7 months post-stroke, the ERAN was extinguished and the behavioural performance remained at chance level. These combined results suggest that the left IFG, known to be crucial for syntax processing in language, plays also a functional role in the processing of musical syntax. Hence, the present findings are consistent with the notion that Broca's area supports the processing of syntax in a rather domain-general way.	\N	\N
20672879	The purpose of the present study was to investigate the relationship between perception and production of metrical patterns in Swedish children with language impairment (LI), in order to add to the knowledge on underlying explanations of LI. A further aim was to explore whether omissions are mainly related to prosodic aspects or to linguistic function. Children with LI omitted significantly more unstressed syllables than did children with typical language development. Exploration of the relationship between perception and production of phrasal stress patterns demonstrated that children with LI might be divided into three subgroups: Group a: children who perform better on perception than production; Group b: children who perform better on production than perception; and Group c: children with rather poor results on both perception and production.	\N	\N
20689026	To use eye tracking to investigate age differences in real-time lexical processing in quiet and in noise in light of the fact that older adults find it more difficult than younger adults to understand conversations in noisy situations. Twenty-four younger and 24 older adults followed spoken instructions referring to depicted objects, for example, "Look at the candle." Eye movements captured listeners' ability to differentiate the target noun (candle) from a similar-sounding phonological competitor (e.g., candy or sandal). Manipulations included the presence/absence of noise, the type of phonological overlap in target-competitor pairs, and the number of syllables. Having controlled for age-related differences in word recognition accuracy (by tailoring noise levels), similar online processing profiles were found for younger and older adults when targets were discriminated from competitors that shared onset sounds. Age-related differences were found when target words were differentiated from rhyming competitors and were more extensive in noise. Real-time spoken word recognition processes appear similar for younger and older adults in most conditions; however, age-related differences may be found in the discrimination of rhyming words (especially in noise), even when there are no age differences in word recognition accuracy. These results highlight the utility of eye movement methodologies for studying speech processing across the life span.	\N	\N
20689036	In this study, the authors investigated the effects of age on the use of fundamental frequency differences (ΔF(0)) in the perception of competing synthesized vowels in simulations of electroacoustic and cochlear-implant hearing. Twelve younger listeners with normal hearing and 13 older listeners with (near) normal hearing were evaluated in their use of ΔF(0) in the perception of competing synthesized vowels for 3 conditions: unprocessed synthesized vowels (UNP), envelope-vocoded synthesized vowels that simulated a cochlear implant (VOC), and synthesized vowels processed to simulate electroacoustic stimulation (EAS) hearing. Tasks included (a) multiplicity, which required listeners to identify whether a stimulus contained 1 or 2 sounds and (b) double-vowel identification, which required listeners to attach phonemic labels to the competing synthesized vowels. Multiplicity perception was facilitated by ΔF(0) in UNP and EAS but not in VOC, with no age-related deficits evident. Double-vowel identification was facilitated by ΔF(0), with ΔF(0) benefit largest in UNP, reduced in EAS, and absent in VOC. Age adversely affected overall identification and ΔF(0) benefit on the double-vowel task. Some but not all older listeners derived ΔF(0) benefit in EAS hearing. This variability may partly be due to how listeners are able to draw on higher-level processing resources in extracting and integrating cues in EAS hearing.	\N	\N
20695697	In object substitution masking (OSM) a sparse, temporally trailing 4-dot mask impairs target identification, even though it has different contours from, and does not spatially overlap with the target. Here, we demonstrate a previously unknown characteristic of OSM: Observers show reduced masking at prolonged (e.g., 640 ms) relative to intermediate mask durations (e.g., 240 ms). We propose that with prolonged exposure, the mask's visual representation is consolidated, which allows processing of the lingering target icon to be reinitiated, thereby improving performance. Our findings suggest that when the visual system is confronted with 2 temporally contiguous stimuli, although one may initially gain access to consciousness above the other, the "losing" stimulus is not irreversibly lost to awareness.	\N	\N
20810622	Multisensory events in our natural environment unfold at multiple temporal scales over extended periods of time. This functional magnetic resonance imaging study investigated whether the brain uses transient (onset, offset) or sustained temporal codes to effectively integrate incoming visual and auditory signals within the cortical hierarchy. Subjects were presented with 1) velocity-modulated radial motion, 2) amplitude-modulated sound, or 3) an in phase combination of both in blocks of variable durations to dissociate transient and sustained blood oxygen level-dependent responses. Audiovisual interactions emerged primarily for transient onset and offset responses highlighting the importance of rapid stimulus transitions for multisensory integration. Strikingly, audiovisual interactions for onset and offset transients were dissociable at the functional and anatomical level. Low-level sensory areas integrated audiovisual inputs at stimulus onset in a superadditive fashion to enhance stimulus salience. In contrast, higher order association areas showed subadditive integration profiles at stimulus offset possibly reflecting the formation of higher order representations. In conclusion, multisensory integration emerges at multiple levels of the cortical hierarchy using different temporal codes and integration profiles. From a methodological perspective, these results highlight the limitations of conventional event related or block designs that cannot characterize these rich dynamics of audiovisual integration.	\N	\N
20814962	Auditory functional magnetic resonance imaging (fMRI) was used to assess neural activation in the human auditory brainstem (AB) and cortex (AC) as a function of bandwidth (BW). We recorded brain activation of 22 normal hearing listeners induced by band pass filtered pink noise stimuli with equal sound pressure level of 70 dB SPL. Tested bandwidths were 50, 500, 1,500, 3,000, 6,000, and 8,000 Hz. The center frequency was 4,000 Hz. Categorical loudness scaling had been performed in a silent booth with all of these stimuli. Loudness as a function of bandwidth followed a concave-shaped curve which reflected the influence of spectral loudness summation (SLS) for higher BW and the influence of large amplitude fluctuations for very low BW, which itself could be explained by peak-listening. While neural activation of the AB, as measured by the percent signal change from baseline (PSC), was tuned to the physical BW of the stimuli in a straight linear fashion, the trend of perceived loudness as a function of BW was reflected in several aspects by corresponding neural activation in the primary auditory cortex (PAC). Finally, from the absolute differences of the PSC between PAC and AB, gains in perceived loudness associated with SLS and the effect of large amplitude fluctuations could be predicted with an accuracy of 1-2 dB for the whole group of participants.	\N	\N
20829245	Several perisylvian brain regions show preferential activation for spoken language above and beyond other complex sounds. These "speech-selective" effects might be driven by regions' intrinsic biases for processing the acoustical or informational properties of speech. Alternatively, such speech selectivity might emerge through extensive experience in perceiving and producing speech sounds. This functional magnetic resonance imaging (fMRI) study disambiguated such audiomotor expertise from speech selectivity by comparing activation for listening to speech and music in female professional violinists and actors. Audiomotor expertise effects were identified in several right and left superior temporal regions that responded to speech in all participants and music in violinists more than actresses. Regions associated with the acoustic/information content of speech were identified along the entire length of the superior temporal sulci bilaterally where activation was greater for speech than music in all participants. Finally, an effect of performing arts training was identified in bilateral premotor regions commonly activated by finger and mouth movements as well as in right hemisphere "language regions." These results distinguish the seemingly speech-specific neural responses that can be abolished and even reversed by long-term audiomotor experience.	\N	\N
20838845	We examined horizontal directional hearing in patients with acquired severe unilateral conductive hearing loss (UCHL). All patients (n = 12) had been fitted with a bone conduction device (BCD) to restore bilateral hearing. The patients were tested in the unaided (monaural) and aided (binaural) hearing condition. Five listeners without hearing loss were tested as a control group while listening with a monaural plug and earmuff, or with both ears (binaural). We randomly varied stimulus presentation levels to assess whether listeners relied on the acoustic head-shadow effect (HSE) for horizontal (azimuth) localization. Moreover, to prevent sound localization on the basis of monaural spectral shape cues from head and pinna, subjects were exposed to narrow band (1/3 octave) noises. We demonstrate that the BCD significantly improved sound localization in 8/12 of the UCHL patients. Interestingly, under monaural hearing (BCD off), we observed fairly good unaided azimuth localization performance in 4/12 of the patients. Our multiple regression analysis shows that all patients relied on the ambiguous HSE for localization. In contrast, acutely plugged control listeners did not employ the HSE. Our data confirm and further extend results of recent studies on the use of sound localization cues in chronic and acute monaural listening.	\N	\N
20858647	There have been few reports showing a correlation between hearing levels and life style in young people. In this study, we succeeded in sensitively evaluating hearing levels in 51 young male adults of 21-23 years in age by 12 k Hz extra-high-frequency auditory thresholds, which cannot be measured by usual audiometry devices for clinical use. Noise exposure, alcohol consumption and sleeping time did not affect hearing levels in young adults. Auditory thresholds of 12 kHz frequency in smokers were significantly (p < 0.05) higher than those in non-smokers, while there were no differences in 1 kHz, 4 kHz and 8 kHz frequencies of hearing levels between smokers and non-smokers. Since the Brinkman Index (BI; cigarettes/day multiplied by number of years) of smokers in this study was from 12 to 60, our results suggest that even light smoking of less than 20 cigarettes/day for 3 years can result in the development of hearing loss of 12 kHz frequency in young adults. Binary logistic regression analysis again showed a correlation between hearing loss (≥ 40 dB of auditory thresholds in 12 kHz frequency) and light smoking (12 ≤ BI ≤ 60). Thus, this study showed that auditory threshold at 12 kHz frequency could be a sensitive marker for hearing in young adults. More importantly, we for the first time provided epidemiological evidence that light smoking might affect hearing level at 12 kHz frequency and revealed a new risk of light smoking.	\N	\N
20862531	In this paper we use information theory to quantify the information in the output spike trains of modeled cochlear nucleus globular bushy cells (GBCs). GBCs are part of the sound localization pathway. They are known for their precise temporal processing, and they code amplitude modulations with high fidelity. Here we investigated the information transmission for a natural sound, a recorded vowel. We conclude that the maximum information transmission rate for a single neuron was close to 1,050 bits/s, which corresponds to a value of approximately 5.8 bits per spike. For quasi-periodic signals like voiced speech, the transmitted information saturated as word duration increased. In general, approximately 80% of the available information from the spike trains was transmitted within about 20 ms. Transmitted information for speech signals concentrated around formant frequency regions. The efficiency of neural coding was above 60% up to the highest temporal resolution we investigated (20 μs). The increase in transmitted information to that precision indicates that these neurons are able to code information with extremely high fidelity, which is required for sound localization. On the other hand, only 20% of the information was captured when the temporal resolution was reduced to 4 ms. As the temporal resolution of most speech recognition systems is limited to less than 10 ms, this massive information loss might be one of the reasons which are responsible for the lack of noise robustness of these systems.	\N	\N
20869305	The present study examined the differential effects of voice auditory feedback perturbation direction and magnitude on voice fundamental frequency (F(0)) responses and event-related potentials (ERPs) from EEG electrodes on the scalp. The voice F(0) responses and N1 and P2 components of ERPs were examined from 12 right-handed speakers when they sustained a vowel phonation and their mid-utterance voice pitch feedback was shifted ±100, ±200, and ±500 cents with 200 ms duration. Downward voice pitch feedback perturbations led to larger voice F(0) responses than upward perturbations. The amplitudes of N1 and P2 components were larger for downward compared with upward pitch-shifts for 200 and 500 cents stimulus magnitudes. Shorter N1 and P2 latencies were also associated with larger magnitudes of pitch feedback perturbations. Corresponding changes in vocal and neural responses to upward and downward voice pitch feedback perturbations suggest that the N1 and P2 components of ERPs reflect neural concomitants of the vocal responses. The findings of interactive effects between the magnitude and direction of voice feedback pitch perturbation on N1 and P2 ERP components indicate that the neural mechanisms underlying error detection and correction in voice pitch auditory feedback are differentially sensitive to both the magnitude and direction of pitch perturbations.	\N	\N
20878201	Practice can lead to dramatic improvements in the discrimination of auditory stimuli. In this study, we investigated changes of the frequency-following response (FFR), a subcortical component of the auditory evoked potentials, after a period of pitch discrimination training. Twenty-seven adult listeners were trained for 10 h on a pitch discrimination task using one of three different complex tone stimuli. One had a static pitch contour, one had a rising pitch contour, and one had a falling pitch contour. Behavioral measures of pitch discrimination and FFRs for all the stimuli were measured before and after the training phase for these participants, as well as for an untrained control group (n = 12). Trained participants showed significant improvements in pitch discrimination compared to the control group for all three trained stimuli. These improvements were partly specific for stimuli with the same pitch modulation (dynamic vs. static) and with the same pitch trajectory (rising vs. falling) as the trained stimulus. Also, the robustness of FFR neural phase locking to the sound envelope increased significantly more in trained participants compared to the control group for the static and rising contour, but not for the falling contour. Changes in FFR strength were partly specific for stimuli with the same pitch modulation (dynamic vs. static) of the trained stimulus. Changes in FFR strength, however, were not specific for stimuli with the same pitch trajectory (rising vs. falling) as the trained stimulus. These findings indicate that even relatively low-level processes in the mature auditory system are subject to experience-related change.	\N	\N
20883593	This study aimed to evaluate the effect of lengthening the transition duration of selected speech segments upon the perception of those segments in individuals with auditory dys-synchrony. Thirty individuals with auditory dys-synchrony participated in the study, along with 30 age-matched normal hearing listeners. Eight consonant-vowel syllables were used as auditory stimuli. Two experiments were conducted. Experiment one measured the 'just noticeable difference' time: the smallest prolongation of the speech sound transition duration which was noticeable by the subject. In experiment two, speech sounds were modified by lengthening the transition duration by multiples of the just noticeable difference time, and subjects' speech identification scores for the modified speech sounds were assessed. Subjects with auditory dys-synchrony demonstrated poor processing of temporal auditory information. Lengthening of speech sound transition duration improved these subjects' perception of both the placement and voicing features of the speech syllables used. These results suggest that innovative speech processing strategies which enhance temporal cues may benefit individuals with auditory dys-synchrony.	\N	\N
20884355	Developmental differences in phonological and orthographic processing of Chinese spoken words were examined in 9-year-olds, 11-year-olds and adults using functional magnetic resonance imaging (fMRI). Rhyming and spelling judgments were made to two-character words presented sequentially in the auditory modality. Developmental comparisons between adults and both groups of children combined showed that age-related changes in activation in visuo-orthographic regions depended on a task. There were developmental increases in the left inferior temporal gyrus and the right inferior occipital gyrus in the spelling task, suggesting more extensive visuo-orthographic processing in a task that required access to these representations. Conversely, there were developmental decreases in activation in the left fusiform gyrus and left middle occipital gyrus in the rhyming task, suggesting that the development of reading is marked by reduced involvement of orthography in a spoken language task that does not require access to these orthographic representations. Developmental decreases may arise from the existence of extensive homophony (auditory words that have multiple spellings) in Chinese. In addition, we found that 11-year-olds and adults showed similar activation in the left superior temporal gyrus across tasks, with both groups showing greater activation than 9-year-olds. This pattern suggests early development of perceptual representations of phonology. In contrast, 11-year-olds and 9-year-olds showed similar activation in the left inferior frontal gyrus across tasks, with both groups showing weaker activation than adults. This pattern suggests late development of controlled retrieval and selection of lexical representations. Altogether, this study suggests differential effects of character acquisition on development of components of the language network in Chinese as compared to previous reports on alphabetic languages.	\N	\N
20888628	Mechanisms of cortical reorganization underlying the enhancement of speech processing have been poorly investigated. In the present study, we addressed changes in functional and effective connectivity induced in subjects who learned to deliberately increase activation in the right inferior frontal gyrus (rIFG), and improved their ability to identify emotional intonations by using a real-time fMRI Brain-Computer Interface. At the beginning of their training process, we observed a massive connectivity of the rIFG to a widespread network of frontal and temporal areas, which decreased and lateralized to the right hemisphere with practice. Volitional control of activation strengthened connectivity of this brain region to the right prefrontal cortex, whereas training increased its connectivity to bilateral precentral gyri. These findings suggest that changes of connectivity in a functionally specific manner play an important role in the enhancement of speech processing. Also, these findings support previous accounts suggesting that motor circuits play a role in the comprehension of speech.	\N	\N
20933093	The reproducibility of three different aspects of fMRI activations-namely binary activation maps, effect size and spatial distribution of local maxima-was evaluated for an auditory sentence comprehension task with high attention demand on a group of 17 subjects that were scanned on five different occasions. While in the scanner subjects were asked to listen to a series of six short everyday sentences from the CUNY sentence test. Comprehension and attention to the stimuli were monitored after each listen condition epoch by having subjects answer a series of multiple-choice questions. Statistical maps of activation for the listen condition were computed at three different levels: overall results for all imaging sessions, group-level/single-session results for each of the five imaging occasions, and single-subject/single-session results computed for each subject and each scanning occasion independently. The experimental task recruited a distributed bilateral network with processing nodes located in the lateral temporal cortex, inferior frontal cortex, medial BA6, medial occipital cortex and subcortical structures such as the putamen and the thalamus. Reproducibility of these activations at the group level was high (83.95% of the imaged volume was consistently classified as active/inactive across all five imaging sessions), indicating that sites of neuronal activity associated with auditory comprehension can reliably be detected with fMRI in healthy subjects, across repeated measures after group averaging. At the single-subject level reproducibility ranged from moderate to high, although no significant differences were found on behavioral measures across subjects or sessions. This result suggests that contextual differences-i.e., those specific to each imaging session, can modulate our ability to detect fMRI activations associated with speech comprehension in individual subjects.	\N	\N
20951812	Auditory event-related potentials (ERPs) have been used to understand how the brain processes auditory input, and to track developmental change in sensory systems. Localizing ERP generators can provide invaluable insights into how and where auditory information is processed. However, age-appropriate infant brain templates have not been available to aid such developmental mapping. In this study, auditory change detection responses of brain ERPs were examined in 6-month-old infants using discrete and distributed source localization methods mapped onto age-appropriate magnetic resonance images. Infants received a passive oddball paradigm using fast-rate non-linguistic auditory stimuli (tone doublets) with the deviant incorporating a pitch change for the second tone. Data was processed using two different high-pass filters. When a 0.5 Hz filter was used, the response to the pitch change was a large frontocentral positive component. When a 3 Hz filter was applied, two temporally consecutive components associated with change detection were seen: one with negative voltage, and another with positive voltage over frontocentral areas. Both components were localized close to the auditory cortex with an additional source near to the anterior cingulate cortex. The sources for the negative response had a more tangential orientation relative to the supratemporal plane compared to the positive response, which showed a more lateral, oblique orientation. The results described here suggest that at 6 months of age infants generate similar response patterns and use analogous cortical areas to that of adults to detect changes in the auditory environment. Moreover, the source locations and orientations, together with waveform topography and morphology provide evidence in infants for feature-specific change detection followed by involuntary switching of attention.	\N	\N
20961171	The present study addresses the question whether accentuation and prosodic phrasing can have a similar function, namely, to group words in a sentence together. Participants listened to locally ambiguous sentences containing object- and subject-control verbs while ERPs were measured. In Experiment 1, these sentences contained a prosodic break, which can create a certain syntactic grouping of words, or no prosodic break. At the disambiguation, an N400 effect occurred when the disambiguation was in conflict with the syntactic grouping created by the break. We found a similar N400 effect without the break, indicating that the break did not strengthen an already existing preference. This pattern held for both object- and subject-control items. In Experiment 2, the same sentences contained a break and a pitch accent on the noun following the break. We argue that the pitch accent indicates a broad focus covering two words [see Gussenhoven, C. On the limits of focus projection in English. In P. Bosch & R. van der Sandt (Eds.), Focus: Linguistic, cognitive, and computational perspectives. Cambridge: University Press, 1999], thus grouping these words together. For object-control items, this was semantically possible, which led to a "good-enough" interpretation of the sentence. Therefore, both sentences were interpreted equally well and the N400 effect found in Experiment 1 was absent. In contrast, for subject-control items, a corresponding grouping of the words was impossible, both semantically and syntactically, leading to processing difficulty in the form of an N400 effect and a late positivity. In conclusion, accentuation can group words together on the level of information structure, leading to either a semantically "good-enough" interpretation or a processing problem when such a semantic interpretation is not possible.	\N	\N
20966383	Delayed auditory feedback (DAF) of a speaker's voice disturbs normal speech production. Various traditional theories assume that the content of the delayed feedback signal interferes with the actual production of a particular speech unit (phonemic content hypothesis). The displaced rhythm hypothesis as an alternative explanation suggests that speech disturbances arise from a disruptive rhythm that is produced by the delayed speech signal. The present experimental study directly contrasted the role of rhythm and speech content in a DAF task using speech units as stimuli. One hundred fifty-one participants read aloud 4 different sequences of double syllables that varied in phonemic content and rhythm while auditory feedback was either nondelayed or delayed by 200 or 400 ms. In line with previous studies, the authors found a peak of disturbances at a delay of about 200 ms, independent of speech rate. More important, the present results clearly support the displaced rhythm hypothesis. A speech rate dependency of this effect was also found. Rhythm seems to be a significant criterion of speech monitoring, and hence a mismatch between spoken words and auditory feedback realized by DAF induces obvious speech problems on rhythmic level regardless of phonemic discrepancy at the same time.	\N	\N
21054432	Performance improvement during an hour of auditory perceptual training is accompanied by rapid physiological changes. These changes may reflect learning or simply task repetition independent of learning. We assessed the contribution of learning and task repetition to changes in auditory evoked potentials during a difficult speech identification task and an easy tone identification task. We posited that only task repetition effects would occur in the tone task but that task repetition and learning would interact in the speech task. Speech identification improved with practice (increased sensitivity d' with a constant response bias β). This behavioral improvement coincided with a decrease in the amplitude of sensory evoked responses (N1, P2) and a decrease in the amplitude of a slow wave (peak=320 ms after onset) over the left frontal and parietal sites. Results show rapid physiological changes associated with learning, distinct from changes related to task repetition.	\N	\N
21060139	Improved speech recognition in binaurally combined acoustic-electric stimulation (otherwise known as bimodal hearing) could arise when listeners integrate speech cues from the acoustic and electric hearing. The aims of this study were (a) to identify speech cues extracted in electric hearing and residual acoustic hearing in the low-frequency region and (b) to investigate cochlear implant (CI) users' ability to integrate speech cues across frequencies. Normal-hearing (NH) and CI subjects participated in consonant and vowel identification tasks. Each subject was tested in 3 listening conditions: CI alone (vocoder speech for NH), hearing aid (HA) alone (low-pass filtered speech for NH), and both. Integration ability for each subject was evaluated using a model of optimal integration--the PreLabeling integration model (Braida, 1991). Only a few CI listeners demonstrated bimodal benefit for phoneme identification in quiet. Speech cues extracted from the CI and the HA were highly redundant for consonants but were complementary for vowels. CI listeners also exhibited reduced integration ability for both consonant and vowel identification compared with their NH counterparts. These findings suggest that reduced bimodal benefits in CI listeners are due to insufficient complementary speech cues across ears, a decrease in integration ability, or both.	\N	\N
21068039	Noise-vocoded (NV) speech is often regarded as conveying phonetic information primarily through temporal-envelope cues rather than spectral cues. However, listeners may infer the formant frequencies in the vocal-tract output-a key source of phonetic detail-from across-band differences in amplitude when speech is processed through a small number of channels. The potential utility of this spectral information was assessed for NV speech created by filtering sentences into six frequency bands, and using the amplitude envelope of each band (≤30 Hz) to modulate a matched noise-band carrier (N). Bands were paired, corresponding to F1 (≈N1 + N2), F2 (≈N3 + N4) and the higher formants (F3' ≈ N5 + N6), such that the frequency contour of each formant was implied by variations in relative amplitude between bands within the corresponding pair. Three-formant analogues (F0 = 150 Hz) of the NV stimuli were synthesized using frame-by-frame reconstruction of the frequency and amplitude of each formant. These analogues were less intelligible than the NV stimuli or analogues created using contours extracted from spectrograms of the original sentences, but more intelligible than when the frequency contours were replaced with constant (mean) values. Across-band comparisons of amplitude envelopes in NV speech can provide phonetically important information about the frequency contours of the underlying formants.	\N	\N
21086218	Two experiments investigated the role that different face regions play in a variety of social judgements that are commonly made from facial appearance (sex, age, distinctiveness, attractiveness, approachability, trustworthiness, and intelligence). These judgements lie along a continuum from those with a clear physical basis and high consequent accuracy (sex, age) to judgements that can achieve a degree of consensus between observers despite having little known validity (intelligence, trustworthiness). Results from Experiment 1 indicated that the face's internal features (eyes, nose, and mouth) provide information that is more useful for social inferences than the external features (hair, face shape, ears, and chin), especially when judging traits such as approachability and trustworthiness. Experiment 2 investigated how judgement agreement was affected when the upper head, eye, nose, or mouth regions were presented in isolation or when these regions were obscured. A different pattern of results emerged for different characteristics, indicating that different types of facial information are used in the various judgements. Moreover, the informativeness of a particular region/feature depends on whether it is presented alone or in the context of the whole face. These findings provide evidence for the importance of holistic processing in making social attributions from facial appearance.	\N	\N
21092939	The ratio of scalp-recorded brain responses occurring 50 msec after paired clicks (S2-evoked P50/S1-evoked P50) serves as a measure of sensory gating. An abnormally large ratio is commonly found in schizophrenia and is considered as a sign of reduced sensory gating or otherwise dysfunctional organization of the auditory/verbal system as a factor contributing to psychopathology and cognitive dysfunction in schizophrenia. This initial randomized clinical trial compared the efficacy of two 4-week, computer-based cognitive training methods that emphasize either auditory discrimination and verbal memory or a broader range of cognitive functions in schizophrenia. Thirty-nine schizophrenia patients (ICD-F20.0 diagnosis) were assigned to Cognitive Exercises (CE) or Cognitive Package (Cogpack). The M50, the magnetoencephalographic analogue of electroencephalographic P50, and performance on verbal learning and memory tests were used to evaluate training effects. As expected, patients exhibited higher pretreatment gating ratios than 28 age-matched healthy comparison participants. Gating ratios decreased after CE but not after Cogpack. Cognitive test performance improved more after CE than after Cogpack. Appropriately specific psychological training changes the neural performance in schizophrenia, normalizing sensory and cognitive function.	\N	\N
21105829	The problem of multimodal clustering arises whenever the data are gathered with several physically different sensors. Observations from different modalities are not necessarily aligned in the sense there there is no obvious way to associate or compare them in some common space. A solution may consist in considering multiple clustering tasks independently for each modality. The main difficulty with such an approach is to guarantee that the unimodal clusterings are mutually consistent. In this letter, we show that multimodal clustering can be addressed within a novel framework: conjugate mixture models. These models exploit the explicit transformations that are often available between an unobserved parameter space (objects) and each of the observation spaces (sensors). We formulate the problem as a likelihood maximization task and derive the associated conjugate expectation-maximization algorithm. The convergence properties of the proposed algorithm are thoroughly investigated. Several local and global optimization techniques are proposed in order to increase its convergence speed. Two initialization strategies are proposed and compared. A consistent model selection criterion is proposed. The algorithm and its variants are tested and evaluated within the task of 3D localization of several speakers using both auditory and visual data.	\N	\N
21106695	To examine resource allocation and sentence processing, this study examined the effects of auditory distraction on grammaticality judgment (GJ) of sentences varied by semantics (reversibility) and short-term memory requirements. Experiment 1: Typical young adult females (N = 60) completed a whole-sentence GJ task in distraction (Quiet, Noise, or Talk). Participants judged grammaticality of Passive sentences varied by sentence (length), grammaticality, and reversibility. Reaction time (RT) data were analyzed using a mixed analysis of variance. Experiment 2: A similar group completed a self-paced reading GJ task using the similar materials. Experiment 1: Participants responded faster to Bad and to Nonreversible sentences, and in the Talk distraction. The slowest RTs were noted for Good-Reversible-Padded sentences in the Quiet condition. Experiment 2: Distraction did not differentially affect RTs for sentence components. Verb RTs were slower for Reversible sentences. Results suggest that narrative distraction affected GJ, but by speeding responses, not slowing them. Sentence variables of memory and reversibility slowed RTs, but narrative distraction resulted in faster processing times regardless of individual sentence variables. More explicit, deliberate tasks (self-paced reading) resulted in less effect from distraction. Results are discussed in terms of recent theories about auditory distraction.	\N	\N
21112404	Visual dominance refers to the observation that in bimodal environments vision often has an advantage over other senses in human. Therefore, a better memory performance for visual compared to, e.g., auditory material is assumed. However, the reason for this preferential processing and the relation to the memory formation is largely unknown. In this fMRI experiment, we manipulated cross-modal competition and attention, two factors that both modulate bimodal stimulus processing and can affect memory formation. Pictures and sounds of objects were presented simultaneously in two levels of recognisability, thus manipulating the amount of cross-modal competition. Attention was manipulated via task instruction and directed either to the visual or the auditory modality. The factorial design allowed a direct comparison of the effects between both modalities. The resulting memory performance showed that visual dominance was limited to a distinct task setting. Visual was superior to auditory object memory only when allocating attention towards the competing modality. During encoding, cross-modal competition and attention towards the opponent domain reduced fMRI signals in both neural systems, but cross-modal competition was more pronounced in the auditory system and only in auditory cortex this competition was further modulated by attention. Furthermore, neural activity reduction in auditory cortex during encoding was closely related to the behavioural auditory memory impairment. These results indicate that visual dominance emerges from a less pronounced vulnerability of the visual system against competition from the auditory domain.	\N	\N
21133642	Tonsillar hypertrophy is common in young children and affects several aspects of the speech such as distortions of the dento-alveolar consonants. The study objective was to assess /s/-articulation, perceptually and acoustically, in children with tonsillar hypertrophy and compare effects of two types of surgery, total tonsillectomy and tonsillotomy. Sixty-seven children, aged 50-65 months, on the waiting list for surgery, were randomized to tonsillectomy or tonsillotomy. The speech material was collected preoperatively and 6 months postoperatively. Two groups of age-matched children were controls. /S/-articulation was affected acoustically with lower spectral peak locations and perceptually with less distinct /s/-production before surgery, in comparison to controls. After surgery /s/-articulation was normalized perceptually, but acoustic differences remained. No significant differences between surgical methods were found.	\N	\N
21145901	The allocation of visual processing capacity is a key topic in studies and theories of visual attention. The load theory of Lavie (1995) proposes that allocation happens in two steps where processing resources are first allocated to task-relevant stimuli and secondly remaining capacity 'spills over' to task-irrelevant distractors. In contrast, the Theory of Visual Attention (TVA) proposed by Bundesen (1990) assumes that allocation happens in a single step where processing capacity is allocated to all stimuli, both task-relevant and task-irrelevant, in proportion to their relative attentional weight. Here we present data from two partial report experiments where we varied the number and discriminability of the task-irrelevant stimuli (Experiment 1) and perceptual load (Experiment 2). The TVA fitted the data of the two experiments well thus favoring the simple explanation with a single step of capacity allocation. We also show that the effects of varying perceptual load can only be explained by a combined effect of allocation of processing capacity as well as limits in visual working memory. Finally, we link the results to processing capacity understood at the neural level based on the neural theory of visual attention by Bundesen et al. (2005).	\N	\N
21147178	We investigated the effects of non-native language (English) exposure on event-related potentials (ERPs) in first- and second-year (four- and five-year-old) preschool Japanese native speakers while they listened to semantically congruent and incongruent Japanese sentences. The children were divided into a non-native language exposed group (exposed group) and a group without such experiences (control group) on the basis of their exposure to non-native language. We compared the ERPs recorded from the two groups in each of the two preschool years. N400 was observed both in the first- and second-year preschoolers. Differences owing to exposure to non-native language appeared in the second-year preschoolers but not in the first-year preschoolers. In the second-year preschoolers, the N400 onset in the exposed group was shorter than that in the control group, but there was no difference in the N400 offset between the exposed and control groups. Furthermore, the scalp distribution of the N400 in the exposed group was broader than that in the control group. These results indicate that the time course and scalp distribution of semantic processing for native language sentences in young children fluctuated depending on exposure to non-native language.	\N	\N
21148089	Numerous studies have demonstrated effects of spatial attention within single sensory modalities (within-modal spatial attention) and the effect of directing attention to one sense compared with the other senses (intermodal attention) on cortical neuronal activity. Furthermore, recent studies have been revealing that the effects of spatial attention directed to a certain location in a certain sense spread to the other senses at the same location in space (cross-modal spatial attention). The present study used magnetoencephalography to examine the temporal dynamics of the effects of within-modal and cross-modal spatial and intermodal attention on cortical processes responsive to visual stimuli. Visual or tactile stimuli were randomly presented on the left or right side at a random interstimulus interval and subjects directed attention to the left or right when vision or touch was a task-relevant modality. Sensor-space analysis showed that a response around the occipitotemporal region at around 150 ms after visual stimulation was significantly enhanced by within-modal, cross-modal spatial, and intermodal attention. A later response over the right frontal region at around 200 ms was enhanced by within-modal spatial and intermodal attention, but not by cross-modal spatial attention. These effects were estimated to originate from the occipitotemporal and lateral frontal areas, respectively. Thus the results suggest different spatiotemporal dynamics of neural representations of cross-modal attention and intermodal or within-modal attention.	\N	\N
21185855	External noise paradigms have been widely used to probe different levels of visual processing (Pelli & Farell, 1999). A basic assumption of this paradigm is that the processing strategy is noise-invariant, remaining the same in low and high external noise. We tested this assumption by examining crowding in a detection task where traditionally crowding has no effect. In the first experiment, we measured detection thresholds for a vertically oriented sine wave grating (target) surrounded by four sine wave gratings (flankers) that were either vertically or horizontally oriented. At low noise levels, the detection threshold for the target was unaffected by the orientation of the flankers--there was no crowding. Surprisingly, however, there was crowding for detection at high noise levels: the threshold increased for the similarly-oriented flankers. This suggests that high noise triggered a change in processing strategy, increasing the range of space or features over which the visual signal was sampled. In a second experiment, we evaluated the impact of the spatial and temporal window of the noise on this crowding effect. Although crowding was observed for detection when the spatial and/or temporal window of the noise was localized (i.e. identical to the signal window), no crowding was observed when the noise was spatially and temporally extended (i.e. continuously displayed, full screen dynamic noise). Our results show that certain spatiotemporal distributions of external noise can elicit a change in processing strategy, invalidating the noise-invariant assumption that underlies external noise paradigms. In contrast, spatiotemporally extended noise maintains the required noise-indifference, perhaps because it matches the characteristics of the internal noise that determines the contrast threshold in low noise.	\N	\N
21187749	Sentence stress is a vital attribute of speech since it indicates the importance of specific words within an utterance. Basic acoustic correlates of stress are syllable duration, intensity, and fundamental frequency (F0). Objectives of the study were to determine cochlear implant (CI) users' perception of the acoustic correlates and to uncover which cues are used for stress identification. Several experiments addressed the discrimination of changes in syllable duration, intensity, and F0 as well as stress identification based on these cues. Moreover, the discrimination of combined cues and identification of stress in conversational speech was examined. Both natural utterances and artificial manipulations of the acoustic cues were used as stimuli. Discrimination of syllable duration did not differ significantly between CI recipients and a control group of normal-hearing listeners. In contrast, CI users performed significantly worse on tasks of discrimination and stress identification based on F0 as well as on intensity. Results from these measurements were significantly correlated with the ability to identify stress in conversational speech. Discrimination performance for covarying F0 and intensity changes was more strongly correlated to identification performance than was found for discrimination of either F0 or intensity alone. Syllable duration was not related to stress identification in natural utterances. The outcome emphasizes the importance of both F0 and intensity for CI users' identification of sentence-based stress. Both cues were used separately for stress perception, but combining the cues provided extra benefit for most of the subjects.	\N	\N
21187751	The current study was designed to see how hearing-impaired individuals judge level differences between speech sounds with and without hearing amplification. It was hypothesized that hearing aid compression should adversely affect the user's ability to judge level differences. Thirty-eight hearing-impaired participants performed an adaptive tracking procedure to determine their level-discrimination thresholds for different word and sentence tokens, as well as speech-spectrum noise, with and without their hearing aids. Eight normal-hearing participants performed the same task for comparison. Level discrimination for different word and sentence tokens was more difficult than the discrimination of stationary noises. Word level discrimination was significantly more difficult than sentence level discrimination. There were no significant differences, however, between mean performance with and without hearing aids and no correlations between performance and various hearing aid measurements. There is a clear difficulty in judging the level differences between words or sentences relative to differences between broadband noises, but this difficulty was found for both hearing-impaired and normal-hearing individuals and had no relation to hearing aid compression measures. The lack of a clear adverse effect of hearing aid compression on level discrimination is suggested to be due to the low effective compression ratios of currently fit hearing aids.	\N	\N
21190394	The purpose of the present study was to test the hypothesis that cochlear implant (CI) users' music perception is correlated with their lexical tone perception, and the two types of perception share similar mechanisms in electric hearing. A lexical tone perception test and a pitch interval discrimination test were administered to a group of CI users and a group of normal-hearing (NH) listeners. SAMPLE STUDY: Nineteen adult CI users and 10 NH listeners who are native-Mandarin-Chinese speakers participated in the study. Tone-perception performance of the CI group was, on average, 58.3% correct (± 19.78% correct), and performance of the NH group was near perfect. The CI group had a mean threshold of 5.66 semitones (± 5.57 semitones) in pitch discrimination as compared to the threshold of 0.44 semitone from the NH group. There was a strong correlation between the CI users' tone-perception performance and their pitch discrimination threshold (r = -0.75, p < 0.001). Musical and lexical pitch perceptions are strongly correlated with each other and they might share similar mechanisms in electric hearing.	\N	\N
21206391	The round window application of the Vibrant Sound bridge, the so-called round window vibroplasty, is gaining increasing popularity for hearing rehabilitation of patients with mixed hearing loss or conductive hearing loss. In these patients, conventional hearing amplification and/or surgical restoration is either not possible or has failed because of chronic ear disease, extensive otosclerosis, or malformations. The exact mechanisms of direct cochlear stimulation via the round window membrane are not yet completely understood. It is unclear what kind and what degree of contact is required between the floating mass transducer (FMT) and the round window membrane (RWM) to elicit a functional hearing perception with the implant. We investigated the coupling efficiency between the FMT and the RWM and how the efficiency is altered by the FMT position, the degree of FMT-RWM contact, and the use of a soft tissue coupler. Prospective cohort study. Tertiary referral center in Western Australia. Patients undergoing round window vibroplasty for a mixed or conductive hearing loss otherwise not aidable. Patients underwent round window vibroplasty and received audiological and coupling analysis in the follow-up. These data were then correlated with FMT positioning and the extent of FMT-RWM interface as determined by postoperative high-resolution temporal bone computed tomography. Coupling and hearing levels in relation to FMT positioning and degree of FMT-RWM contact. Of 10 patients, 8 were available for vibroplasty behavioral threshold testing. In 2 patients, testing could not be done because of wound breakdown requiring device explantation in 1 case, and in the other case, the bone conduction thresholds dropped 2 months after implantation, thus falling out of the performance range of the device. Postoperative FMT migration occurred in 50% of the patients (3/6) with recurrent chronic ear disease and status after multiple previous ear operations. All patients, including the 3 patients requiring surgical repositioning of the FMT, attained significantly improved speech in quiet and speech in noise when compared with the preoperatively best aided performance. All patients showed significantly improved average Abbreviated Profile of Hearing Benefit scores with the use of the FMT. Direct (partial or complete) contact with the RWM resulted in good coupling efficiency; soft tissue coupling resulted in a reduced coupling efficiency.	\N	\N
21258612	This study had three goals: (1) to document the literacy skills of deaf adolescents who received cochlear implants (CIs) as preschoolers; (2) to examine reading growth from elementary grades to high school; (3) to assess the contribution of early literacy levels and phonological processing skills, among other factors, to literacy levels in high school. A battery of reading, spelling, expository writing, and phonological processing assessments were administered to 112 high school (CI-HS) students, ages 15.5 to 18.5 yrs, who had participated in a reading assessment battery in early elementary grades (CI-E), ages 8.0 to 9.9 yrs. The CI-HS students' performance was compared with either a control group of hearing peers (N = 46) or hearing norms provided by the assessment developer. Many of the CI-HS students (47 to 66%) performed within or above the average range for hearing peers on reading tests. When compared with their CI-E performance, good early readers were also good readers in high school. Importantly, the majority of CI-HS students maintained their reading levels over time compared with hearing peers, indicating that the gap in performance was, at the very least, not widening for most students. Written expression and phonological processing tasks posed a great deal of difficulty for the CI-HS students. They were poorer spellers, poorer expository writers, and displayed poorer phonological knowledge than hearing age-mates. Phonological processing skills were a critical predictor of high school literacy skills (reading, spelling, and expository writing), accounting for 39% of variance remaining after controlling for child, family, and implant characteristics. Many children who receive CIs as preschoolers achieve age-appropriate literacy levels as adolescents. However, significant delays in spelling and written expression are evident compared with hearing peers. For children with CIs, the development of phonological processing skills is not just important for early reading skills, such as decoding, but is critical for later literacy success as well.	\N	\N
21261633	Humans must often focus attention onto relevant sensory signals in the presence of simultaneous irrelevant signals. This type of attention has been explored in vision with the N2pc component, and the present study sought to find an analogous auditory effect. In Experiment 1, two 750-ms sounds were presented simultaneously, one from each of two lateral speakers. On each trial, participants indicated whether one of the two sounds was a pre-defined target. We found that targets elicited an N2ac component: a negativity in the N2 latency range at anterior contralateral electrodes. We also observed a later and more posterior contralateral positivity. Experiment 2 replicated these effects and demonstrated that they arose from competition between attended and unattended tones rather than reflecting lateralized effects of attention for individual tones. The N2ac component may provide a useful tool for studying selective attention within auditory scenes.	\N	\N
21264649	In two experiments, each including a simple reaction time (RT) task, a localization task, and a passive oddball paradigm, the physical similarity between two dichotically presented auditory stimuli was manipulated. In both experiments, a redundant signals effect (RSE), high localization performance, and a reliable mismatch negativity (MMN) was observed for largely differing stimuli, suggesting that these are coded separately in auditory memory. In contrast, no RSE and a localization rate close to chance level (experiment 1) or at chance (experiment 2) were observed for stimuli differing to a lesser degree. Crucially, for such stimuli a small (experiment 1) or no (experiment 2) MMN were observed. These MMN results indicate that such stimuli tend to fuse into a single percept and that this fusion occurs rather early within information processing.	\N	\N
21264730	Fundamental limitations in performing multiple tasks concurrently are well illustrated by the attentional blink (AB) deficit, which refers to the difficulty in reporting a second target (T2) when it is presented shortly after a first target (T1). Surprisingly, recent studies have shown that the AB, which is often thought of as a manifestation of capacity limitations in central processing, can be reduced when the AB task is performed simultaneously with concurrent distracting activities. In the present study, we sought to investigate whether such concurrency benefits would also be observed when the AB task was performed concurrently with a central demanding timing task. The AB was reduced under concurrent-task conditions, as compared with single-AB-task conditions, even though T1 performance was unaffected by the concurrent task. Moreover, shifts in decision criteria were found to be associated with the concurrency benefit effect.	\N	\N
21277208	Crowding by nearby features causes identification failures in the peripheral visual field. However, prominent visual features can sometimes fail to reach awareness, causing scenes to be incorrectly interpreted. Here we examine whether awareness of the flanking features is necessary for crowding to occur. Flankers that were physically present were rendered perceptually absent with adaptation-induced blindness. In a letter identification task, targets were presented unflanked or with up to four flanker letters. On each trial, observers reported both the number of letters they perceived and the identity of a target letter. This paradigm allowed trial-by-trial assessment of awareness and crowding and ensured that both targets and flankers were attended. Target-letter identification performance was correlated with the number of flanking letters that were perceived on a given trial, regardless of the number that were physically present. Our data demonstrate that crowding can be released when flanking elements at attended locations are suppressed from visual awareness.	\N	\N
21299272	We argue that 4 fundamental gestalt phenomena in perception apply to the control of motor action. First, a motor gestalt, like a perceptual gestalt, is holistic in the sense that it is processed as a single unit. This notion is consistent with reaction time results indicating that all gestures for a brief unit of action must be programmed prior to initiation of any part of the movement. Additional reaction time results related to initiation of longer responses are consistent with processing in terms of a sequence of indivisible motor gestalts. Some actions (e.g., many involving coordination of the hands) can be carried out effectively only if represented as a unitary gestalt. Second, a perceptual gestalt is independent of specific sensory receptors, as evidenced by perceptual constancy. In a similar manner a motor gestalt can be represented independently of specific muscular effectors, thereby allowing motor constancy. Third, just as a perceptual pattern (e.g., a Necker cube) is exclusively structured into only 1 of its possible configurations at any moment in time, processing prior to action is limited to 1 motor gestalt. Fourth, grouping in apparent motion leads to stream segregation in visual and auditory perception; this segregation is present in motor action and is dependent on the temporal rate. We discuss congruence of gestalt phenomena across perception and motor action (a) in relation to a unitary perceptual-motor code, (b) with respect to differences in the role of awareness, and (c) in conjunction with separate neural pathways for conscious perception and motor control.	\N	\N
21300112	Children's foreign-language (FL) learning is a matter of much social as well as scientific debate. Previous behavioral research indicates that starting language learning late in life can lead to problems in phonological processing. Inadequate phonological capacity may impede lexical learning and semantic processing (phonological bottleneck hypothesis). Using both behavioral and neuroimaging data, here we examine the effects of age of first exposure (AOFE) and total hours of exposure (HOE) to English, on 350 Japanese primary-school children's semantic processing of spoken English. Children's English proficiency scores and N400 event-related brain potentials (ERPs) were analyzed in multiple regression analyses. The results showed (1) that later, rather than earlier, AOFE led to higher English proficiency and larger N400 amplitudes, when HOE was controlled for; and (2) that longer HOE led to higher English proficiency and larger N400 amplitudes, whether AOFE was controlled for or not. These data highlight the important role of amount of exposure in FL learning, and cast doubt on the view that starting FL learning earlier always produces better results.	\N	\N
21308886	Anxiety Sensitivity (AS), the tendency to fear the thoughts, symptoms, and social consequences associated with the experience of anxiety, is associated with increased risk for developing anxiety disorders. Some evidence suggests that higher scores on the Anxiety Sensitivity Index (ASI), a measure of the AS construct, are associated with activation of the anterior insular cortex during overt emotion perception. Although the ASI provides subscale scores measuring Physical, Mental Incapacitation, and Social Concerns of AS, no study has examined the relationship between these factors and regional brain activation during affect processing. We hypothesized that insular responses to fear-related stimuli would be primarily related to the Physical Concerns subscale of the ASI, particularly for a sample of subjects with specific phobias. Adult healthy controls (HC; n = 22) and individuals with specific phobia, small animal subtype (SAP; n = 17), completed the ASI and underwent functional magnetic resonance imaging while engaged in a backward-masked affect perception task that presents emotional facial stimuli below the threshold of conscious perception. Groups did not differ in ASI, state or trait anxiety scores, or insula activation. Total ASI scores were positively correlated with activation in the right middle/anterior insula for the combined sample and for the HC and SAP groups separately. Multiple regression analysis revealed that the relationship between AS and insular activation was primarily accounted for by Physical Concerns only. Findings support the hypothesized role of the right anterior insula in the visceral/interoceptive aspects of AS, even in response to masked affective stimuli.	\N	\N
21315438	Using the mismatch negativity (MMN) response, we examined how Standard French and Southern French speakers access the meaning of words ending in /e/ or /ε/ vowels which are contrastive in Standard French but not in Southern French. In Standard French speakers, there was a significant difference in the amplitude of the brain response after the deviant-minus-standard subtraction between the frontocentral (FC) and right lateral (RL) recording sites for the final-/ε/ word but not the final-/e/ word. In contrast, the difference in the amplitude of the brain response between the FC and RL recording sites did not significantly vary as a function of the word's final vowel in Southern French speakers. Our findings provide evidence that access to lexical meaning in spoken word recognition depends on the speaker's native regional accent.	\N	\N
21315875	The present study examined the occurrence and content of auditory hallucinatory experiences in 41 non-clinical participants scoring high or low on the Oxford-Liverpool Inventory of Feelings and Experiences (brief version; OLIFE-B) measure of schizotypy. Participants listened to 10 1-min recordings of white noise, some of which contained embedded concrete or abstract words, and were asked to record the words that they had heard. High scorers on the unusual experiences (UE) scale of the OLIFE-B reported hearing more words, not actually present, relative to low scorers on that measure. In addition, high UE scorers showed a bias toward making hallucinatory reports of an abstract type over a concrete type. These results suggest a bias toward more auditory hallucinatory reports in high scorers in schizotypy, and particularly to those of an abstract type.	\N	\N
21319937	A Danish version of the hearing in noise test (HINT) has been developed and evaluated in normal-hearing (NH) and hearing-impaired (HI) listeners. The speech material originated from Nielsen & Dau (2009) where a sentence-based intelligibility equalization method was presented. In the present study, the speech material was evaluated for naturalness and a subset of sentences selected. The new sentence lists were validated, and after three weeks retested. An additional experiment investigated how recollection of sentences affected the listeners' performance. 16 NH and 16 HI listeners participated in the validation and retest. Twelve HI listeners participated in the experiment on recollection. The average speech recognition threshold in noise (SRT(N)) for the NH listeners was -2.52 dB, with an overall standard deviation of 0.87 dB. The within-subject standard deviation was similar for the NH and the HI listeners. In the retest, the SRT(N) decreased by 0.4 dB in both groups. The Danish HINT consists of 10 test lists and three practice lists each containing 20 sentences. The validation results are comparable to those of other versions of HINT. The test seems equally reliable for NH and HI listeners. After three weeks, reliable results can be obtained when sentence lists are reused with the same listeners.	\N	\N
21324531	In recent years, new speech coding strategies have been developed with the aim of improving the transmission of temporal fine structure to cochlear implant recipients. This study reports on the implementation of one such strategy (fine structure processing, FSP) in children. This was a prospective study investigating the upgrade to a new speech processor. The upgrade used a repeated measures design with an alternating order of conditions (A-B-A-B design). Twelve pre- and perilingually deaf children with MED-EL C40+ cochlear implants were enrolled in the study. Patients were upgraded from their Tempo+ speech processor, which used continuous interleaved sampling (CIS) in combination with a frequency spectrum of 200-8500 Hz, to an Opus speech processor, which used FSP with an extended frequency spectrum of 70-8500 Hz. The primary means of testing was an HSM (Hochmair, Schulz and Moser) sentence test at 65 and 80 dB in quiet. In addition, the "Mainzer Kindersprachtest" (Mainz audiometric speech test for children) was applied at 65 and 70 dB. When the new FSP speech processor was used together with the extended low frequency range, HSM sentence tests at 65 and 80 dB resulted in scores indicating statistically significant improvements of 7.1 and 9.9 percentage points, respectively. Scores in the "Mainzer Kindersprachtest" at 65 and 70 dB indicated statistically significant improvements of 9.3 and 6.1 percentage points, respectively. The present study clearly shows that children benefit from the fine structure speech coding strategy in combination with an extended frequency spectrum in the low frequencies, as is offered by the Opus speech processors. This should be taken into consideration when fitting pre- and perilingually deaf children implanted almost a decade previously.	\N	\N
21329941	Children with speech sound disorder (SSD) and reading disability (RD) have poor phonological awareness, a problem believed to arise largely from deficits in processing the sensory information in speech, specifically individual acoustic cues. However, such cues are details of acoustic structure. Recent theories suggest that listeners also need to be able to integrate those details to perceive linguistically relevant form. This study examined abilities of children with SSD, RD, and SSD+RD not only to process acoustic cues but also to recover linguistically relevant form from the speech signal. Ten- to 11-year-olds with SSD (n=17), RD (n=16), SSD+RD (n=17), and Controls (n=16) were tested to examine their sensitivity to (1) voice onset times (VOT); (2) spectral structure in fricative-vowel syllables; and (3) vocoded sentences. Children in all groups performed similarly with VOT stimuli, but children with disorders showed delays on other tasks, although the specifics of their performance varied. Children with poor phonemic awareness not only lack sensitivity to acoustic details, but are also less able to recover linguistically relevant forms. This is contrary to one of the main current theories of the relation between spoken and written language development. Readers will be able to (1) understand the role speech perception plays in phonological awareness, (2) distinguish between segmental and global structure analysis of speech perception, (3) describe differences and similarities in speech perception among children with speech sound disorder and/or reading disability, and (4) recognize the importance of broadening clinical interventions to focus on recognizing structure at all levels of speech analysis.	\N	\N
21330649	English proficiency must be considered when a bilingual individual is to be evaluated clinically with English speech material. This study describes the minimum level of self-reported English proficiency that identifies bilingual individuals who may perform on par with monolingual listeners on an English word recognition test. A total of 125 normal hearing bilingual listeners rated their English proficiency in listening, speaking, and reading on an 11-point scale. Other related linguistic variables were also obtained. A randomly selected Northwestern University Auditory Test No. 6 (NU-6) list (50 English monosyllabic words) was presented to all participants at 45 dB HL in quiet. Over 90% of the listeners self-rated to have at least "good" proficiency in English listening, speaking, or reading. Of these participants, more than 30% did not achieve a monolingual normative level in English as delimited by binomial distribution. Composite proficiency ratings across language domains better predicted word recognition performance than self-ratings for listening proficiency only. Combining language dominance and age of English acquisition with proficiency ratings further improved prediction specificity. Self-rated English proficiency can predict bilingual listeners' performance on the NU-6 test. For desirable sensitivity and specificity in predicting monolingual-like performance, a minimum rating of 8 out of 10 across all language domains is recommended.	\N	\N
21331781	Data are limited on the role of psychotherapy in the treatment of Ménière disease. We sought to document the effect of a psychotherapeutic technique known as autogenic training on clinical outcome in Ménière disease. Six patients with Ménière disease were studied. Retrospective chart review was conducted. All patients were refractory to conventional therapy and completed a course of autogenic training, which was offered as a complementary treatment. Autogenic training with initial psychological counseling was conducted by a clinical psychologist during 45-min sessions. Outcome measures assessed were the frequency of vertigo and functional levels 2 years after initiation of autogenic training. Functional levels were evaluated according to the 1995 guidelines of the American Academy of Otolaryngology-Head Neck Surgery (AAO-HNS). As a personality measure, we used the Maudsley Personality Inventory (MPI), devised by Eysenck, which measures neuroticism (N), extraversion (E), and propensity to lie (L). Five of six patients showed improved functional level after three to eight sessions of psychotherapy; hearing level did not change. The score of the N scale of the MPI was closely related to the number of psychotherapy sessions. Prognosis was evaluated based on the AAO-HNS reporting guidelines, as follows: A = 3, B = 1, C = 1, F = 1. The value of N in MPI was closely related to the number of psychological counseling sessions (R = 0.97, P < 0.05). In conclusion, autogenic training may enhance the mental well-being of patients with Ménière disease and improve clinical outcome.	\N	\N
21332488	Although a deficit perceiving phonemes, as indexed by the mismatch negativity (MMN), is apparent in developmental dyslexia (DD), studies have not yet addressed whether this deficit might be a result of deficient native language speech representations. The present study examines how a native-vowel prototype and an atypical vowel are discriminated by 9-year-old children with (n = 14) and without (n = 12) DD. MMN was elicited in all conditions in both groups. The control group revealed enhanced MMN to the native-vowel prototype in comparison to the atypical vowel. Children with DD did not show enhanced MMN amplitude to the native-vowel prototype, suggesting impaired tuning to native language speech representations. Furthermore, higher MMN amplitudes to the native-vowel prototype correlated with more advanced reading (r = - .47) and spelling skills (r = - .52).	\N	\N
21336137	Werner and Bargones (1991) observed that a 4-10-kHz noise band can mask a 1-kHz signal during infancy. The purpose of this study was to examine whether remote-noise masking extends into the school-aged years. Listeners were 4-6-yr-olds, 7-9-yr-olds, and adults. Detection thresholds were measured for the 1-kHz signal in quiet and in the presence of the remote-frequency noise. In separate conditions, masker level was either 40 or 60 dB SPL. On average, thresholds for the 1-kHz signal were elevated in the presence of the remote-frequency noise for 4-6-yr-olds, but not for 7-9-yr-olds or adults. Group average thresholds were similar across masker levels, indicating nonperipheral effects. Susceptibility to remote-frequency masking in children extends to 4-6 yrs of age for some children.	\N	\N
21340665	The songbird model is widely established in a number of laboratories for the investigation of the neurobiology and development of vocal learning. While vocal learning is rare in the animal kingdom, it is a trait that songbirds share with humans. The neuroanatomical and physiological organization of the brain circuitry that controls learned vocalizations has been extensively characterized, particularly in zebra finches (Taeniopygia guttata). Recently, several powerful molecular and genomic tools have become available in this organism, making it an attractive choice for neurobiologists interested in the neural and genetic basis of a complex learned behavior. Here, we briefly review some of the main features of vocal learning and associated brain structures in zebra finches and comment on some examples that illustrate how themes related to nutrition and addiction can be explored using this model organism.	\N	\N
21346208	Research on the control of visually guided limb movements indicates that the brain learns and continuously updates an internal model that maps the relationship between motor commands and sensory feedback. A growing body of work suggests that an internal model that relates motor commands to sensory feedback also supports vocal control. There is evidence from arm-reaching studies that shows that when provided with a contextual cue, the motor system can acquire multiple internal models, which allows an animal to adapt to different perturbations in diverse contexts. In this study we show that trained singers can rapidly acquire multiple internal models regarding voice fundamental frequency (F(0)). These models accommodate different perturbations to ongoing auditory feedback. Participants heard three musical notes and reproduced each one in succession. The musical targets could serve as a contextual cue to indicate which direction (up or down) feedback would be altered on each trial; however, participants were not explicitly instructed to use this strategy. When participants were gradually exposed to altered feedback adaptation was observed immediately following vocal onset. Aftereffects were target specific and did not influence vocal productions on subsequent trials. When target notes were no longer a contextual cue, adaptation occurred during altered feedback trials and evidence for trial-by-trial adaptation was found. These findings indicate that the brain is exceptionally sensitive to the deviations between auditory feedback and the predicted consequence of a motor command during vocalization. Moreover, these results indicate that, with contextual cues, the vocal control system may maintain multiple internal models that are capable of independent modification during different tasks or environments.	\N	\N
21354285	This study investigates behavioural and objective measures of temporal auditory processing and their relation to the ability to understand speech in noise. The experiments were carried out on a homogeneous group of seven hearing-impaired listeners with normal sensitivity at low frequencies (up to 1 kHz) and steeply sloping hearing losses above 1 kHz. For comparison, data were also collected for five normal-hearing listeners. Temporal processing was addressed at low frequencies by means of psychoacoustical frequency discrimination, binaural masked detection and amplitude modulation (AM) detection. In addition, auditory brainstem responses (ABRs) to clicks and broadband rising chirps were recorded. Furthermore, speech reception thresholds (SRTs) were determined for Danish sentences in speech-shaped noise. The main findings were: (1) SRTs were neither correlated with hearing sensitivity as reflected in the audiogram nor with the AM detection thresholds which represent an envelope-based measure of temporal resolution; (2) SRTs were correlated with frequency discrimination and binaural masked detection which are associated with temporal fine-structure coding; (3) The wave-V thresholds for the chirp-evoked ABRs indicated a relation to SRTs and the ability to process temporal fine structure. Overall, the results demonstrate the importance of low-frequency temporal processing for speech reception which can be affected even if pure-tone sensitivity is close to normal.	\N	\N
21355809	This study examined listeners' endorsement of cognitive, linguistic, segmental, and suprasegmental strategies employed when listening to speakers with dysarthria. The study also examined whether strategy endorsement differed between listeners who earned the highest and lowest intelligibility scores. Speakers were eight individuals with dysarthria and cerebral palsy. Listeners were 80 individuals who transcribed speech stimuli and rated their use of each of 24 listening strategies on a 4-point scale. Results showed that cognitive and linguistic strategies were most highly endorsed. Use of listening strategies did not differ between listeners with the highest and lowest intelligibility scores. Results suggest that there may be a core of strategies common to listeners of speakers with dysarthria that may be supplemented by additional strategies, based on characteristics of the speaker and speech signal.	\N	\N
21368051	Certain features of objects or events can be represented by more than a single sensory system, such as roughness of a surface (sight, sound, and touch), the location of a speaker (audition and sight), and the rhythm or duration of an event (by all three major sensory systems). Thus, these properties can be said to be sensory-independent or amodal. A key question is whether common multisensory cortical regions process these amodal features, or does each sensory system contain its own specialized region(s) for processing common features? We tackled this issue by investigating simple duration-detection mechanisms across audition and touch; these systems were chosen because fine duration discriminations are possible in both. The mismatch negativity (MMN) component of the human event-related potential provides a sensitive metric of duration processing and has been elicited independently during both auditory and somatosensory investigations. Employing high-density electroencephalographic recordings in conjunction with intracranial subdural recordings, we asked whether fine duration discriminations, represented by the MMN, were generated in the same cortical regions regardless of the sensory modality being probed. Scalp recordings pointed to statistically distinct MMN topographies across senses, implying differential underlying cortical generator configurations. Intracranial recordings confirmed these noninvasive findings, showing generators of the auditory MMN along the superior temporal gyrus with no evidence of a somatosensory MMN in this region, whereas a robust somatosensory MMN was recorded from postcentral gyrus in the absence of an auditory MMN. The current data clearly argue against a common circuitry account for amodal duration processing.	\N	\N
21375597	The neural processing of auditory motion information shows a pronounced interhemispheric asymmetry. In previous electrophysiological studies, the so-called motion-onset response (MOR), a prominent auditory-evoked potential to the onset of sound motion, was stronger over the hemisphere contralateral to the side of motion. Here, effects of lateral-onset position and direction of motion on MOR contralaterality were investigated. Eighteen listeners were presented with free-field sound stimuli that, after an initial stationary phase at a lateral spatial position within the left or right hemifield, started to move either left- or rightward. The early part of the MOR, the so-called change-N1, exhibited contralaterality that depended on the lateral motion-onset position with stronger activations over the hemisphere contralateral to the side of motion onset, whereas the contralaterality of the later part of the MOR, the so-called change-P2, merely depended on the direction of motion. Cortical source localization indicated that this pattern of contralaterality primarily resulted from asymmetric activation in primary auditory cortex and insula. These findings suggest that the early and late parts of the MOR reflect different phases in auditory motion perception, supporting the notion of a modular organization of discrete processing stages.	\N	\N
21382389	Evidence from event-related potential (ERP) analyses of English spoken words suggests that the time course of English word recognition in monosyllables is cumulative. Different types of phonological competitors (i.e., rhymes and cohorts) modulate the temporal grain of ERP components differentially (Desroches, Newman, & Joanisse, 2009). The time course of Chinese monosyllabic spoken word recognition could be different from that of English due to the differences in syllable structure between the two languages (e.g., lexical tones). The present study investigated the time course of Chinese monosyllabic spoken word recognition using ERPs to record brain responses online while subjects listened to spoken words. During the experiment, participants were asked to compare a target picture with a subsequent picture by judging whether or not these two pictures belonged to the same semantic category. The spoken word was presented between the two pictures, and participants were not required to respond during its presentation. We manipulated phonological competition by presenting spoken words that either matched or mismatched the target picture in one of the following four ways: onset mismatch, rime mismatch, tone mismatch, or syllable mismatch. In contrast to the English findings, our findings showed that the three partial mismatches (onset, rime, and tone mismatches) equally modulated the amplitudes and time courses of the N400 (a negative component that peaks about 400ms after the spoken word), whereas, the syllable mismatched words elicited an earlier and stronger N400 than the three partial mismatched words. The results shed light on the important role of syllable-level awareness in Chinese spoken word recognition and also imply that the recognition of Chinese monosyllabic words might rely more on global similarity of the whole syllable structure or syllable-based holistic processing rather than phonemic segment-based processing. We interpret the differences in spoken word processing between Chinese and English listeners as being due to morphosyllabic structural differences between the two languages.	\N	\N
21382438	Emotions signal the particular relevance of situations, threatening or rewarding, and influence perception and behaviour accordingly. Research to date has predominantly investigated the impact of negative emotional stimuli. However, rapid reactions to positive emotional stimuli are similarly adaptive. Here, we tested the influence of positive emotional stimuli on attentional control, which enables reacting to conflicting stimulation. We therefore presented positive emotional and neutral words in an auditory Simon task. Reaction times revealed faster resolution of conflict when target stimuli were positive compared to neutral words. Also, emotion modulated the first conflict-sensitive event-related brain potential, a negativity at 420 ms, indicating an influence on early stages of conflict processing. These results complement recent data on negative stimuli and suggest that positive stimuli are equally salient. The rapid impact on attentional control is evolutionary highly adaptive as it reduces the time that conflict yields an organism incapable of responding to reward-signalling stimuli.	\N	\N
21385014	The objective of this study was to describe the auditory evoked response to silent gaps for a group of older adults using stimulus conditions identical to those used in psychophysical studies of gap detection. The P1-N1-P2 response to the onsets of stimuli (markers) defining a silent gap for within-channel (spectrally identical markers) and across-channel (spectrally different markers) conditions was examined using four perceptually-equated gap durations. A group of 24 older adults (mean age = 63 years) with normal hearing or minimal hearing loss participated. Older adults exhibited neural activation patterns that were qualitatively different and more frontally oriented than those observed in a previous study (Lister et al., 2007) of younger listeners. Older adults showed longer P2 latencies and larger P1 amplitudes than younger adults, suggesting relatively slower neural travel time and altered auditory inhibition/arousal by irrelevant stimuli. Older adults appeared to recruit later-occurring T-complex-like generators for gap processing, compared to earlier-occurring T-complex-like generators by the younger group. Early and continued processing of channel cues with later processing of gap cues may represent the inefficiency of the aging auditory system and may contribute to poor speech understanding in noisy, real-world listening environments.	\N	\N
21387016	Important sounds can be easily missed or misidentified in the presence of extraneous noise. We describe an auditory illusion in which a continuous ongoing tone becomes inaudible during a brief, non-masking noise burst more than one octave away, which is unexpected given the frequency resolution of human hearing. Participants strongly susceptible to this illusory discontinuity did not perceive illusory auditory continuity (in which a sound subjectively continues during a burst of masking noise) when the noises were short, yet did so at longer noise durations. Participants who were not prone to illusory discontinuity showed robust early electroencephalographic responses at 40-66 ms after noise burst onset, whereas those prone to the illusion lacked these early responses. These data suggest that short-latency neural responses to auditory scene components reflect subsequent individual differences in the parsing of auditory scenes.	\N	\N
21391255	Semantic knowledge is supported by a widely distributed neuronal network, with differential patterns of activation depending upon experimental stimulus or task demands. Despite a wide body of knowledge on semantic object processing from the visual modality, the response of this semantic network to environmental sounds remains relatively unknown. Here, we used fMRI to investigate how access to different conceptual attributes from environmental sound input modulates this semantic network. Using a range of living and manmade sounds, we scanned participants whilst they carried out an object attribute verification task. Specifically, we tested visual perceptual, encyclopedic, and categorical attributes about living and manmade objects relative to a high-level auditory perceptual baseline to investigate the differential patterns of response to these contrasting types of object-related attributes, whilst keeping stimulus input constant across conditions. Within the bilateral distributed network engaged for processing environmental sounds across all conditions, we report here a highly significant dissociation within the left hemisphere between the processing of visual perceptual and encyclopedic attributes of objects.	\N	\N
21401449	There is no significant difference in speech recognition scores obtained with the Vibrant Soundbridge and the open-fit hearing aid. However, the Vibrant Soundbridge may be superior to open-fit hearing aids in improving hearing at high frequencies (4-8 kHz). To assess whether an improvement in speech recognition conferred by Vibrant Soundbridge is more marked than that afforded by open-fit hearing aids in patients with sloping high frequency sensorineural hearing loss (SNHL). This study had a self-control prospective design. Seven patients aged 21-62 years with sloping high frequency SNHL were recruited into the study. Each patient received a Vibrant Soundbridge middle ear implant (Vibrant MED-EL) and wore an open-fit hearing aid (Danavox, DOT 10). Speech recognition tests were performed according to protocols suggested by árpád Götze's speech definition test in Hungarian language. In the first session, conventional hearing thresholds (unaided pure tone thresholds) were measured. In the second session, the aided sound-field threshold, speech understanding score and functional gain obtained using middle ear implants and open-fit hearing aids were determined after programming of the devices. Regarding speech recognition scores, there were no significant differences between data obtained with the middle ear implant and those with the open-fit hearing aid.	\N	\N
21417673	The effects of asymmetric directional microphone fittings (i.e., an omnidirectional microphone on one ear and a directional microphone on the other) on speech understanding in noise and acceptance of background noise were investigated in 15 full-time hearing aid users. Subjects were fitted binaurally with four directional microphone conditions (i.e., binaural omnidirectional, right asymmetric directional, left asymmetric directional and binaural directional microphones) using Siemens Intuis Directional behind-the-ear hearing aids. Speech understanding in noise was assessed using the Hearing in Noise Test, and acceptance of background noise was assessed using the Acceptable Noise Level procedure. Speech was presented from 0° while noise was presented from 180° azimuth. The results revealed that speech understanding in noise improved when using asymmetric directional microphones compared to binaural omnidirectional microphone fittings and was not significantly hindered compared to binaural directional microphone fittings. The results also revealed that listeners accepted more background noise when fitted with asymmetric directional microphones as compared to binaural omnidirectional microphones. Lastly, the results revealed that the acceptance of noise was further increased for the binaural directional microphones when compared to the asymmetric directional microphones, maximizing listeners' willingness to accept background noise in the presence of noise. Clinical implications will be discussed.	\N	\N
21425399	Multisensory integration assists us to identify objects by providing multiple cues with respect to object category and spatial location. We used a semantic audiovisual object matching task to determine the effect of spatial congruency on response behavior and fMRI brain activation. Fifteen subjects responded in a four-alternative response paradigm, which visual quadrant contained the object best matched to the sound presented. Realistic sounds based on head-related transfer functions were presented binaurally with the simulated sound source corresponding to one of the four quadrants. Following a random sequence, the location of the sound corresponded to the quadrant containing the semantically congruent target on half the trials, whereas on other trials the sound arose from an incongruent location. We examined the effects of spatial congruency on response latencies, hit-rates and fMRI responses. Preliminary behavioral results revealed a significant effect of spatial congruency on response latency or performance for stimuli with noise added. In the fMRI experiment, spatial congruency had a significant effect on the BOLD response. A cluster in the right middle and superior temporal gyrus was more activated when the auditory sound sources were spatially congruent with the semantically matching visual stimulus. In an exploratory post-hoc analysis, in which we correlated the BOLD signal with the subjects' ability to locate the sound sources, we found a significant cluster in the left inferior frontal cortex, where the BOLD response increased with sound-source localization performance. Thus spatial congruency appears to enhance the semantic integration of audiovisual object information in these brain regions.	\N	\N
21425900	Absolute pitch is a rare pitch-naming ability with unknown etiology. Some scientists maintain that its manifestation depends solely on environmental factors, while others suggest that genetic factors contribute to it. We sought to further investigate the hypothesis that genetic factors support the acquisition of absolute pitch and to better elucidate the inheritance pattern of this trait. To this end, we conducted a twin study and a segregation analysis using data collected from a large population of absolute pitch possessors. The casewise concordance rate of 14 monozygotic twin pairs, 78.6%, was significantly different from that of 31 dizygotic twin pairs, 45.2%, assuming single ascertainment (x(2) = 5.57, 1 df, p = .018), supporting a role for genetics in the development of absolute pitch. Segregation analysis of 1463 families, assuming single ascertainment, produced a segregation ratio p(D) = .089 with SEp(D) = 0.006. Unlike an earlier segregation analysis on a small number of absolute pitch probands from musically educated families, our study indicates that absolute pitch is not inherited in a simple Mendelian fashion. Based on these data, absolute pitch is likely genetically heterogeneous, with environmental, epigenetic, and stochastic factors also perhaps contributing to its genesis. These findings are in agreement with the results of our recent linkage analysis.	\N	\N
21425948	Acute migraine could be associated with neurophysiological and cognitive changes. This study evaluates the neurophysiological changes in auditory information processing in adolescents with acute migraine by means of magnetoencephalography. The multifeature sound mismatch negativity (MMN) paradigm was used to study nine adolescents with an acute migraine and nine age- and gender-matched healthy controls. Latencies and amplitudes of M100, M150, M200, and MMNm responses were evaluated. Migraine subjects had smaller M150 amplitudes than healthy subjects. The latencies of MMNm response for the frequency change were delayed in both hemispheres in migraine subjects, as compared with healthy controls. Our results indicate that the function of neural substrates, responsible for different stages of auditory information processing, is impaired during the acute migraine. The identification of underlying cortical dysfunction during an acute migraine can lead to future identification of neurophysiological biomarkers for studying acute migraine and response to treatment.	\N	\N
21426312	To examine the social cognitive vulnerabilities mediating delusion formation in children presenting with hallucinatory experiences. A sample of 259 12- and 13-year-old children, from a baseline case-control sample of children with and without auditory hallucinations (AH), were re-assessed after 5 years for presence of AH. Presence of delusions and theory of mind (ToM) were also assessed, to examine the hypothesized moderating role of ToM in delusion formation in children hearing voices. In children with AH at age 7-8 and/or 12-13 years, the risk of delusion formation was significantly higher (P interaction = 0.027) in those with lower ToM skills (OR = 4.3, 95% CI 1.9-9.9, P = 0.000), compared to those with higher ToM skills (OR 1.6, 95% CI 0.7-3.7, P = 0.26), independently from secondary school level. The results suggest that better mentalizing abilities confer protection against delusion formation in children experiencing perceptual anomalies, not reducible to general cognitive ability.	\N	\N
21429648	Dichotic listening (DL) techniques have been used extensively as a non-invasive procedure to assess language lateralization among children with and without learning disabilities (LD), and with individuals who have other auditory system related brain disorders. Results of studies using DL have indicated that language is lateralized in children with LD and that the lateralized language asymmetries do not develop after age 6 nor are they affected by gender. Observed differences in lateralized language processes between control children and those with LD were found not due to delayed cerebral dominance, but rather to deficits in selective attention. In addition, attention factors have a greater influence on auditory processing of verbal than nonverbal stimuli for children with LD, and children with LD exhibit a general processing bias to the same hemisphere unlike control children. Furthermore, employing directed attention conditions in DL experiments has played an important role in explaining learning disabled children's performance on DL tasks. We conclude that auditory perceptual asymmetries as assessed by DL with children who experience LD are the result of the interaction of hemispheric capability and attention factors.	\N	\N
21439268	Studies using event related potentials have shown that men are more likely than women to rely on semantic cues when understanding emotional speech. In a previous functional Magnetic Resonance Imaging (fMRI) study, using an affective sentence classification task, we were able to separate areas involved in semantic processing and areas involved in the processing of affective prosody (Beaucousin et al., 2007). Here we searched for sex-related differences in the neural networks active during emotional speech processing in groups of men and women. The ortholinguistic abilities of the participants did not differ when evaluated with a large battery of tests. Although the neural networks engaged by men and women during emotional sentence classification were largely overlapping, sex-dependent modulations were detected during emotional sentence classification, but not during grammatical sentence classification. Greater activity was observed in men, compared with women, in inferior frontal cortical areas involved in emotional labeling and in attentional areas. In conclusion, at equivalent linguistic abilities and performances, men activate semantic and attentional cortical areas to a larger extent than women during emotional speech processing.	\N	\N
21439350	Bone-conducted ultrasound (BCU) modulated by speech sound is recognized as speech sound and activates the auditory cortex similar to audible sound. To investigate the mechanisms of perception, the effects of stimulus duration on N1m were compared among air-conducted audible speech sound (AC speech), AC speech with carrier BCU and speech-modulated BCU in eight native Japanese with normal hearing. The Japanese vowel sound /a/ was used as a stimulus with durations of 10, 15, 20, 30, 40 and 60 ms. Comparison between AC speech with and without carrier showed that the presentation of carrier had no effect on N1m evoked by AC speech. Comparison among the three conditions showed that N1m amplitude for speech-modulated BCU differed from that for the two AC speeches. Moreover, N1m amplitude growth saturated at 40 ms for speech-modulated BCU, and at 20 ms for two AC speeches. These results suggest a difference in temporal integration of N1m between speech-modulated BCU and AC speech. Considering these results, it is reasonable to conclude that N1m evoked by speech-modulated BCU is influenced mainly by the ultrasonic component rather than demodulated audible sound. Given this finding, the notion needs to be considered that the mechanisms underlying perception and recognition of speech-modulated BCU depend on the ultrasonic component to some extent.	\N	\N
21441013	Many reports have described that individuals with Alzheimer's disease show neural breakdown in the brainstem nuclei, hippocampus and auditory cortex in the temporal lobe of the brain. However, it is still unclear whether auditory skills mediated by these areas differ across individuals with and without Alzheimer's disease and how these auditory skills are further confounded by reduction in cognitive function in individuals with AD. The aim of this study is to discover the hidden and nonlinear associations among higher-order auditory and cognitive processes in individuals with and without Alzheimer's disease through artificial neural network analysis. The analyses were based on auditory test data obtained from nine clinically confirmed Alzheimer's disease cases and nine age-matched controls. Hearing threshold sensitivity was equivalent across groups, indicating similar peripheral auditory function. Auditory function was evaluated by standardized tests of auditory closure, auditory attention, and auditory figure ground in listeners with and without Alzheimer's disease. The inputs used for analyses were cognitive status and auditory function. The dependent variables were RAU scores computed from scores of auditory tests. Artificial neural networks showed a complex relationship between the input variables (cognitive status and auditory function) that cannot be predicted simply on the basis of cognition differences between individuals with and without Alzheimer's disease. The results of this study suggest that central auditory function declines with age, regardless of changes in cognitive function.	\N	\N
21452943	In this work, we show that electrophysiological responses during pitch perception are best explained by distributed activity in a hierarchy of cortical sources and, crucially, that the effective connectivity between these sources is modulated with pitch strength. Local field potentials were recorded in two subjects from primary auditory cortex and adjacent auditory cortical areas along the axis of Heschl's gyrus (HG) while they listened to stimuli of varying pitch strength. Dynamic causal modeling was used to compare system architectures that might explain the recorded activity. The data show that representation of pitch requires an interaction between nonprimary and primary auditory cortex along HG that is consistent with the principle of predictive coding.	\N	\N
21455973	The loudness dependence of auditory evoked potentials (LDAEP) has been described as a measure of central serotonergic activity. Single-electrode estimation and dipole source analysis (DSA) are the most utilized methods for the estimation of LDAEP. To date, it is assumed that both methods are equally reliable. Nevertheless, according to our knowledge, the advantage of either method has not yet been shown directly. The aim of our study was to compare single-electrode estimation and dipole source analysis in the determination of the LDAEP. Tones of five different intensities were presented binaurally to 10 healthy volunteers. Amplitudes of N1/P2 and LDAEP were determined at the central electrode site referenced to average and to linked mastoids and with DSA in the left and the right hemispheres. Scores were normalized (z-scores), compared, and correlated. Contrary to our expectations, we found a significant difference between scores obtained with single-electrode estimation and with DSA. The difference may be caused by confounding activation of a frontal source in the single-electrode method. The single-electrode approach cannot be equated with DSA in the determination of the LDAEP. This should be considered when comparing the results of different LDAEP studies using only one of these methods.	\N	\N
21458862	The purposes of the present study were to establish the Standard-Chinese version of Lexical Neighborhood Test (LNT) and to examine the lexical and age effects on spoken-word recognition in normal-hearing children. Six lists of monosyllabic and six lists of disyllabic words (20 words/list) were selected from the database of daily speech materials for normal-hearing (NH) children of ages 3-5 years. The lists were further divided into "easy" and "hard" halves according to the word frequency and neighborhood density in the database based on the theory of Neighborhood Activation Model (NAM). Ninety-six NH children (age ranged between 4.0 and 7.0 years) were divided into three different age groups of 1-year intervals. Speech-perception tests were conducted using the Standard-Chinese monosyllabic and disyllabic LNT. The inter-list performance was found to be equivalent and inter-rater reliability was high with 92.5-95% consistency. Results of word-recognition scores showed that the lexical effects were all significant. Children scored higher with disyllabic words than with monosyllabic words. "Easy" words scored higher than "hard" words. The word-recognition performance also increased with age in each lexical category. A multiple linear regression analysis showed that neighborhood density, age, and word frequency appeared to have increasingly more contributions to Chinese word recognition. The results of the present study indicated that performances of Chinese word recognition were influenced by word frequency, age, and neighborhood density, with word frequency playing a major role. These results were consistent with those in other languages, supporting the application of NAM in the Chinese language. The development of Standard-Chinese version of LNT and the establishment of a database of children of 4-6 years old can provide a reliable means for spoken-word recognition test in children with hearing impairment.	\N	\N
21461784	Four eyetracking experiments examined whether semantic and visual-shape representations are routinely retrieved from printed word displays and used during language-mediated visual search. Participants listened to sentences containing target words that were similar semantically or in shape to concepts invoked by concurrently displayed printed words. In Experiment 1, the displays contained semantic and shape competitors of the targets along with two unrelated words. There were significant shifts in eye gaze as targets were heard toward semantic but not toward shape competitors. In Experiments 2-4, semantic competitors were replaced with unrelated words, semantically richer sentences were presented to encourage visual imagery, or participants rated the shape similarity of the stimuli before doing the eyetracking task. In all cases, there were no immediate shifts in eye gaze to shape competitors, even though, in response to the Experiment 1 spoken materials, participants looked to these competitors when they were presented as pictures (Huettig & McQueen, 2007). There was a late shape-competitor bias (more than 2,500 ms after target onset) in all experiments. These data show that shape information is not used in online search of printed word displays (whereas it is used with picture displays). The nature of the visual environment appears to induce implicit biases toward particular modes of processing during language-mediated visual search.	\N	\N
21467806	Vital-sign checks and physical assessment have been performed by physicians and nurses among medical staff in particular. However, pharmacists must also have basic skills of vital-sign checking and physical assessment to evaluate the patient condition/drug efficacy or prevent adverse reactions to drugs. To promote the acquisition of these skills, we prepared simulation programs with an emergency-care simulator, which facilitate the reproduction of excess-dose drug administration/condition changes. We used an emergency-care simulator equipped with a personal computer. General condition was established using the blinking velocity, cardiac/respiratory sounds and blood pH as parameters. As a results, concerning drug administration, the simulation programs facilitated the reproduction of symptoms related to the excess-dose insulin administration. With respect to changes in the condition, it facilitated the reproduction of asthma, hyperglycemia, and hemorrhage. This facilitated the palpation-, visual perception-, and auditory perception-mediated understanding of changes in the patient condition through fingertips and warnings/alarms on the monitor. Evaluation of the student for these program contents increased significantly (p<0.01). These programs can be downloaded via the Internet. Experience regarding excess-dose drug administration/condition changes with an emergency-care simulator is useful for checking patients' vital signs, evaluating the drug efficacy, and confirming adverse reactions to drugs. By the practice of these programs, we can teach pharmacy students how to check for vital signs (pulse palpation, auscultation, blood pressure measurement, and electrocardiography) in a school setting, not a hospital setting. Mastering these techniques may allow pharmacy students to determine the efficacy of a drug and adverse reactions.	\N	\N
21476651	Recently, it has been suggested that the annoyance of residents at a given aircraft noise exposure level increases over the years. The objective of the present study was to verify the hypothesized trend and to identify its possible causes. To this end, the large database used to establish earlier exposure-response relationships on aircraft noise was updated with original data from several recent surveys, yielding a database with data from 34 separate airports. Multilevel grouped regression was used to determine the annoyance response per airport, after which meta-regression was used to investigate whether study characteristics could explain the heterogeneity in annoyance response between airports. A significant increase over the years was observed in annoyance at a given level of aircraft noise exposure. Furthermore, the type of annoyance scale, the type of contact, and the response percentage were found to be sources of heterogeneity. Of these, only the scale factor could statistically account for the trend, although other findings rule it out as a satisfactory explanation. No evidence was found for increased self-reported noise sensitivity. The results are of importance to the applicability of current exposure-annoyance relationships for aircraft noise and provide a basis for decisions on whether these need to be updated.	\N	\N
21476675	Key features of the voice--fundamental frequency (F(0)) and formant frequencies (Fn)--can vary extensively among individuals. Some of this variation might cue fitness-related, biosocial dimensions of speakers. Three experiments tested the independent, joint and relative effects of F(0) and Fn on listeners' assessments of the body size, masculinity (or femininity), and attractiveness of male and female speakers. Experiment 1 replicated previous findings concerning the joint and independent effects of F(0) and Fn on these assessments. Experiment 2 established frequency discrimination thresholds (or just-noticeable differences, JND's) for both vocal features to use in subsequent tests of their relative salience. JND's for F(0) and Fn were consistent in the range of 5%-6% for each sex. Experiment 3 put the two voice features in conflict by equally discriminable amounts and found that listeners consistently tracked Fn over F(0) in rating all three dimensions. Several non-exclusive possibilities for this outcome are considered, including that voice Fn provides more reliable cues to one or more dimensions and that listeners' assessments of the different dimensions are partially interdependent. Results highlight the value of first establishing JND's for discrimination of specific features of natural voices in future work examining their effects on voice-based social judgments.	\N	\N
21477130	Evaluation of clinical characteristics, bacteriology and hearing in paediatric patients with and without chronic suppurative otitis media (CSOM) in Luanda, Angola. Interview, clinical examination, ear-discharge culture, open air pure-tone audiometry and brainstem auditory-evoked potentials of 23 outpatients with CSOM and 23 controls in a paediatric hospital. Of the CSOM vs. control children, 35% vs. 26% had running water, 70% vs. 70% electricity, 64% vs. 0% HIV (p<0.0001) and 36% vs. 0% tuberculosis in history (p=0.002). Ten (43%) children had bilateral CSOM. The major ear-discharge pathogens were Proteus spp. (44%) and Pseudomonas (22%). Hearing impairment of >25 dB was present in 52% of CSOM-affected ears and bilateral hearing loss in 7 (30%) CSOM children vs. zero control child (p=0.009). Only one hearing-impaired child's family had previously detected the handicap. CSOM occurred in children with high co-morbidity. Persistent otorrhoea was usually caused by Proteus spp. or Pseudomonas, and often suggestive of either HIV or hearing impairment. In the developing countries, prompt diagnosis and treatment of CSOM would enhance the children's linguistic and academic development.	\N	\N
21477198	To investigate the interaction between segmental and supra-segmental stress-related information in early word learning, two experiments were conducted with 20- to 24-month-old English-learning children. In an adaptation of the object categorization study designed by Nazzi and Gopnik (2001), children were presented with pairs of novel objects whose labels differed by their initial consonant (Experiment 1) or their medial consonant (Experiment 2). Words were produced with a stress initial (trochaic) or a stress final (iambic) pattern. In both experiments successful word learning was established when the to-be-remembered contrast was embedded in a stressed syllable, but not when embedded in unstressed syllables. This was independent of the overall word pattern, trochaic or iambic, or the location of the phonemic contrast, word-initial or -medial. Results are discussed in light of the use of phonetic information in early lexical acquisition, highlighting the role of lexical stress and ambisyllabicity in early word processing.	\N	\N
21479656	It is well established that sounds can enhance visual-target detection, but the mechanisms that govern these cross-sensory effects, as well as the neural pathways involved, are largely unknown. Here, we tested behavioral predictions stemming from the neurophysiologic and neuroanatomic literature. Participants detected near-threshold visual targets presented either at central fixation or peripheral to central fixation that were sometimes paired with sounds that originated from widely misaligned locations (up to 104° from the visual target). Our results demonstrate that co-occurring sounds improve the likelihood of visual-target detection (1) regardless of retinal eccentricity and (2) despite wide audiovisual misalignments. With regard to the first point, these findings suggest that auditory facilitation of visual-target detection is unlikely to operate through previously described corticocortical pathways from auditory cortex that predominantly terminate in regions of visual cortex that process peripheral visual space. With regard to the second point, auditory facilitation of visual-target detection seems to operate through a spatially non-specific modulation of visual processing.	\N	\N
21483666	Acute stress is a stereotypical, but multimodal response to a present or imminent challenge overcharging an organism. Among the different branches of this multimodal response, the consequences of glucocorticoid secretion have been extensively investigated, mostly in connection with long-term memory (LTM). However, stress responses comprise other endocrine signaling and altered neuronal activity wholly independent of pituitary regulation. To date, knowledge of the impact of such "paracorticoidal" stress responses on higher cognitive functions is scarce. We investigated the impact of an ecological stressor on the ability to direct selective attention using event-related potentials in humans. Based on research in rodents, we assumed that a stress-induced imbalance of catecholaminergic transmission would impair this ability. The stressor consisted of a single cold pressor test. Auditory negative difference (Nd) and mismatch negativity (MMN) were recorded in a tonal dichotic listening task. A time series of such tasks confirmed an increased distractibility occurring 4-7 minutes after onset of the stressor as reflected by an attenuated Nd. Salivary cortisol began to rise 8-11 minutes after onset when no further modulations in the event-related potentials (ERP) occurred, thus precluding a causal relationship. This effect may be attributed to a stress-induced activation of mesofrontal dopaminergic projections. It may also be attributed to an activation of noradrenergic projections. Known characteristics of the modulation of ERP by different stress-related ligands were used for further disambiguation of causality. The conjuncture of an attenuated Nd and an increased MMN might be interpreted as indicating a dopaminergic influence. The selective effect on the late portion of the Nd provides another tentative clue for this. Prior studies have deliberately tracked the adrenocortical influence on cognition, as it has proven most influential with respect to LTM. However, current cortisol-optimized study designs would have failed to detect the present findings regarding attention.	\N	\N
21487700	Anxious individuals have been shown to interpret others' emotional states negatively. Since most studies have used facial expressions as emotional cues, we examined whether trait anxiety affects the recognition of emotion in a dynamic face and voice that were presented in synchrony. The face and voice cues conveyed either matched (e.g., happy face and voice) or mismatched emotions (e.g., happy face and angry voice). Participants with high or low trait anxiety were to indicate the perceived emotion using one of the cues while ignoring the other. The results showed that individuals with high trait anxiety were more likely to interpret others' emotions in a negative manner, putting more weight on the to-be-ignored angry cues. This interpretation bias was found regardless of the cue modality (i.e., face or voice). Since trait anxiety did not affect recognition of the face or voice cues presented in isolation, this interpretation bias appears to reflect an altered integration of the face and voice cues among anxious individuals.	\N	\N
21491276	In order to determine how the interior of a car should sound, automotive manufacturers often rely on obtaining data from individual evaluations of vehicle sounds. Company identity could play a role in these appraisals, particularly when individuals are comparing cars from opposite ends of the performance spectrum. This research addressed the question: does company identity influence the evaluation of automotive sounds belonging to cars of a similar performance level and from the same market segment? Participants listened to car sounds from two competing manufacturers, together with control sounds. Before listening to each sound, participants were presented with the correct company identity for that sound, the incorrect identity or were given no information about the identity of the sound. The results showed that company identity did not influence appraisals of high performance cars belonging to different manufacturers. These results have positive implications for methodologies employed to capture the perceptions of individuals. STATEMENT OF RELEVANCE: A challenge in automotive design is to set appropriate targets for vehicle sounds, relying on understanding subjective reactions of individuals to such sounds. This paper assesses the role of company identity in influencing these subjective reactions and will guide sound evaluation studies, in which the manufacturer is often apparent.	\N	\N
21493243	To determine whether patterns of functional connectivity of cortical regions responsible for auditory processing and executive functions differ in children with unilateral hearing loss (UHL) versus their normal-hearing (NH) siblings. Prospective observational study. Academic medical center. Children with severe-to-profound UHL (9 right UHL, 7 left UHL) and 10 NH sibling controls were imaged using resting state functional connectivity magnetic resonance imaging (rs-fcMRI). All MRI images were transformed to a single common atlas; regions of interest (ROI) were chosen based on previous literature and unpublished results. Mean regionwise correlations and conjunction analyses were performed across 34 seed ROIs to identify temporally synchronized, low-frequency spontaneous fluctuations in the resting state blood oxygenation level-dependent signal that reveal functionally related regions. Mean regionwise Student t tests found a left posterior opercular region with more correlated resting state activity with the inferior parietal lobule seed in the children with both left and right UHL than NH. In conjunction analysis, 4 regions showed different resting-state functional interactions between the NH and both UHL groups. These differences were in left medial globus pallidus, left middle temporal gyrus, right parahippocampal gyrus, and mid-cingulate cortex. These regions include areas associated with auditory processing, executive function, and memory formation. Resting state fcMRI identified differences in brain network interconnections between children with UHL and NH and may inform further investigation into the educational and behavioral difficulties experienced by children with UHL.	\N	\N
21495790	To assess factors that contribute to Tinnitus Handicap Inventory (THI) scores in Japan. Case series with chart review. Two hundred and eighty-five tinnitus patients at tertiary referral center, who completed the Japanese version of the THI, the Self-rating Depression Scale (SDS), and the State Trait Anxiety Inventory (STAI). In multiple regression analysis, the SDS score contributed the most to the THI score. The state section of the STAI score and pure tone average (PTA) at four high frequencies also contributed significantly, but to lesser degrees. The other following factors were not statistically significant: age, gender, time from the onset of tinnitus to the first clinical visit, PTA at three mid frequencies, and trait section of the STAI score. This model may account for approximately 45% of THI score variability. The THI scores may be influenced by depressive symptoms, state anxiety, and pure tone thresholds in Japan.	\N	\N
21502927	Mismatch negativity (MMN) is an event-related potential that is elicited by deviant sounds that are presented along with frequent sounds in the absence of attention. Auditory MMN is generated by the comparison process between sensory memory trace of a frequent auditory event and a deviant event. It is well known that frequent sounds are encoded in memory trace and processed as a single unit within 160-170 ms. This study examined whether deviant sound would be similarly processed as a temporal unit. Twelve healthy men were presented with relatively short standard sounds and relatively long deviant sounds that contained an omitted (i.e. silent) part. Three types of deviant sounds were designed to vary in duration. The MMN amplitude was gradually enhanced from the short to long duration deviant events that contained an omitted part. In contrast, MMN latency showed no significant differences among the deviants. These findings show that deviant sounds are also processed as a unitary event.	\N	\N
21503649	Primate multisensory object perception involves distributed brain regions. To investigate the network character of these regions of the human brain, we applied data-driven group spatial independent component analysis (ICA) to a functional magnetic resonance imaging (fMRI) data set acquired during a passive audio-visual (AV) experiment with common object stimuli. We labeled three group-level independent component (IC) maps as auditory (A), visual (V), and AV, based on their spatial layouts and activation time courses. The overlap between these IC maps served as definition of a distributed network of multisensory candidate regions including superior temporal, ventral occipito-temporal, posterior parietal and prefrontal regions. During an independent second fMRI experiment, we explicitly tested their involvement in AV integration. Activations in nine out of these twelve regions met the max-criterion (A < AV > V) for multisensory integration. Comparison of this approach with a general linear model-based region-of-interest definition revealed its complementary value for multisensory neuroimaging. In conclusion, we estimated functional networks of uni- and multisensory functional connectivity from one dataset and validated their functional roles in an independent dataset. These findings demonstrate the particular value of ICA for multisensory neuroimaging research and using independent datasets to test hypotheses generated from a data-driven analysis.	\N	\N
21507543	Dichotic listening originally was a means of studying attention. Half a century ago Doreen Kimura parlayed the dichotic method into a noninvasive indicator of lateralized cerebral language representation. The ubiquitous right-ear advantage (REA) for verbal material was accepted as a concomitant of left-sided language lateralization and preferential conduction of right-ear messages to the left hemisphere. As evidence has accumulated over the past 50years showing the REA to be dynamic and modifiable, the concept of attention has become essential for interpreting the findings. Progress in understanding the role of attention has been manifested as a transition from efforts to document attention effects to efforts to characterize their mechanisms. We summarize the relevant evidence, trace the evolution of explanatory models, and outline contemporary accounts of the role of attention in dichotic listening.	\N	\N
21508086	Recent evidence demonstrates that perceptual rivalry rate can be modulated by perturbation of the serotonergic system. Specifically, pharmacologically lowering the availability of serotonin results in slower rivalry rates. As it has been suggested that brain serotonin is low during the interictal phase of migraine, we hypothesized that perceptual rivalry rates would be reduced in individuals with migraine. Visual and auditory perceptual rivalry measures were obtained for a group of 30 participants with migraine (15 migraine with aura, 15 migraine without aura) and 20 non-headache control individuals. Our experiments reveal fewer perceptual rivalry switches within both visual and auditory domains for our migraine without aura group, while the with-aura group performed similarly to non-headache controls. Dividing the data by headache frequency rather than headache subtype classification revealed fewer perceptual switches in those with more frequent headaches. Our data provides further support for interictal differences in brain sensory reactivity in migraine, with the observed effects being in the same direction as those caused by pharmacologically reducing brain availability of serotonin in normal observers.	\N	\N
21509624	Elderly persons frequently complain about problems with speech understanding especially in complex acoustic situations. Besides hearing impairment the decline of cognitive functions might explain these problems. In 12 normal hearing young subjects and 14 elderly listeners with extraordinarily good hearing speech perception was measured in a broad range of different acoustic situations. Cognitive functioning was evaluated with different neuropsychological tests. Despite comparable pure tone thresholds the elderly listeners revealed worse speech discrimination than the young subjects in almost all test situations. Largest differences were found in situations with fluctuating maskers and competing talkers. Most of the speech perception results revealed significant correlations with the outcome from a neuropsychological test addressing declarative verbal memory. In complex listening situations elderly persons reveal worse speech understanding than younger subjects. Differences in speech perception can partly be attributed to cognitive abilities. In particular, working memory seems to be an important factor.	\N	\N
21512805	The purpose of this study was to investigate whether multi-stimulus auditory steady-state responses were capable of estimating hearing thresholds in high-risk infants. A retrospective chart review study. Three tertiary referral centers. Infants born between January 2004 and December 2006 who met the criteria for risk factors of congenital hearing loss were enrolled in the study. While under sedation, the multi-stimulus auditory steady-state response was used to determine multi-channel auditory steady-state response thresholds for high-risk infants younger than 13 months. Conditioned play audiometry was then applied to these children at 23-48 months of age to obtain pure tone audiograms. Auditory steady-state response thresholds and pure tone thresholds were then compared. A total of 249 high-risk infants were enrolled in the study. 39 infants were lost during follow-up. The remaining 216 infants completed both examinations. The Pearson correlation coefficients (r) between the ASSR levels and pure tone thresholds were 0.88, 0.94, 0.94 and 0.97 at 500, 1,000, 2,000 and 4,000 Hz, respectively. The strength of the relationship between the auditory steady-state responses and pure tone thresholds increased with more severe degrees of hearing loss and higher frequencies. We conclude that initial multichannel ASSR thresholds measured under sedation are highly correlated with pure tone thresholds obtained 2 or 3 years later. ASSR can be used to predict the frequency-specific hearing thresholds of high-risk infants and can provide information for early hearing intervention.	\N	\N
21524014	Recent research provides evidence that individuals shift in their perception of variants depending on social characteristics attributed to the speaker.This paper reports on a speech perception experiment designed to test the degree to which the age attributed to a speaker influences the perception of vowels undergoing a chain shift. As a result of the shift, speakers from different generations produce different variants from one another. Results from the experiment indicate that a speaker's perceived age can influence vowel categorization in the expected direction. However, only older participants are influenced by perceived speaker age.This suggests that social characteristics attributed to a speaker affect speech perception differently depending on the salience of the relationship between the variant and the characteristic.The results also provide evidence of an unexpected interaction between the sex of the participant and the sex of the stimulus.The interaction is interpreted as an effect of the participants' previous exposure with male and female speakers.The results are analyzed under an exemplar model of speech production and perception where social information is indexed to acoustic information and the weight of the connection varies depending on the perceived salience of sociophonetic trends.	\N	\N
21526589	In a sample of 18 European nations, suicide rates were positively associated with the proportion of low notes in the national anthems and, albeit less strongly, with students' ratings of how gloomy and how sad the anthems sounded, supporting a hypothesis proposed by Rihmer.	\N	\N
21534716	We suggest that cochlear implantation (CI) should be a good therapeutic modality for hearing restoration in patients with common cavity malformed ears. To analyze hearing improvement from CI performed in common cavity malformed cochleae. A total of 11 patients (5 male and 6 female, mean age 4.5 ± 2.8 years) and 12 ears were enrolled in this study. During the insertion of electrodes, we used C-arm fluoroscopy to avoid intrameatal placement. We evaluated hearing improvement every 6 months and the mean follow-up period was 80.5 ± 24.1 months (53-125 months). During the operation, there were only four cases with fully inserted electrodes. Cerebrospinal fluid gushed out in two cases during the cochleostomy and postoperative meningitis occurred in two patients. One patient had to undergo reimplantation 4 years later due to device failure and recurrent meningitis. During the 48 months follow-up hearing evaluation, the ability of hearing increased along with the age. The final average MAIS, CAP, SIR, and open set one- and two-syllable word scores were 90.3 ± 18.1%, 4.9 ± 1.6, 3.1 ± 0.9, 24.1 ± 25.9%, and 48.6 ± 38.7%, respectively.	\N	\N
21537615	Profound hearing loss is a disability that affects personality and when it involves teenagers before language acquisition, these bio-psychosocial conflicts can be exacerbated, requiring careful evaluation and choice of them for cochlear implant. To evaluate speech perception by adolescents with profound hearing loss, users of cochlear implants. Prospective. Twenty-five individuals with severe or profound pre-lingual hearing loss who underwent cochlear implantation during adolescence, between 10 to 17 years and 11 months, who went through speech perception tests before the implant and 2 years after device activation. For comparison and analysis we used the results from tests of four choice, recognition of vowels and recognition of sentences in a closed setting and the open environment. The average percentage of correct answers in the four choice test before the implant was 46.9% and after 24 months of device use, this value went up to 86.1% in the vowels recognition test, the average difference was 45.13% to 83.13% and the sentences recognition test together in closed and open settings was 19.3% to 60.6% and 1.08% to 20.47% respectively. All patients, although with mixed results, achieved statistical improvement in all speech tests that were employed.	\N	\N
21545766	This paper presents longitudinal case studies of children who received (cochlear implants) CIs and a controlled sample of children with normal hearing (NH). Phoneme discrimination (i.e., /sa-ma/, /a-i/, /a-u/, /u-i/, /ta-da/, /pa-ka/) was assessed prior to receiving CIs and monthly for 3 mo following CI activation. Case studies. Three cochlear implant recipients and seven NH control participants were recruited through the University of Colorado Hospital and the University of Colorado, Boulder. The study utilized the visual reinforcement audiometry and interactive play assessment of speech pattern contrasts (VRASPAC) algorithm. A comparison of scoring was conducted using Cohen's kappa to determine interrater reliability. Findings from this study revealed that CI recipients could discriminate at least three out of five phoneme contrasts at mastery level (≥90%) by 2 mo of device use. None of the CI recipients reached mastery prior to implantation. Following 3 mo of CI use there was no difference in contrast discrimination performance between the CI users and their NH age-matched peers (with the exception of /pa-ka/ for one CI user. The CI users in this case study, who were implanted between 12 and 16 mo of age, were able to master the phoneme contrasts regardless of bilateral or unilateral CI, socioeconomic status, or language spoken at home.	\N	\N
21552274	Responses of neurons that integrate multiple sensory inputs are traditionally characterized in terms of a set of empirical principles. However, a simple computational framework that accounts for these empirical features of multisensory integration has not been established. We propose that divisive normalization, acting at the stage of multisensory integration, can account for many of the empirical principles of multisensory integration shown by single neurons, such as the principle of inverse effectiveness and the spatial principle. This model, which uses a simple functional operation (normalization) for which there is considerable experimental support, also accounts for the recent observation that the mathematical rule by which multisensory neurons combine their inputs changes with cue reliability. The normalization model, which makes a strong testable prediction regarding cross-modal suppression, may therefore provide a simple unifying computational account of the important features of multisensory integration by neurons.	\N	\N
21553997	Using a novel variant of dichotic selective listening, we examined the control of auditory selective attention. In our task, subjects had to respond selectively to one of two simultaneously presented auditory stimuli (number words), always spoken by a female and a male speaker, by performing a numerical size categorization. The gender of the task-relevant speaker could change, as indicated by a visual cue prior to auditory stimulus onset. Three experiments show clear performance costs with instructed attention switches. Experiment 2 varied the cuing interval to examine advance preparation for an attention switch. Experiment 3 additionally isolated auditory switch costs from visual cue priming by using two cues for each gender, so that gender repetition could be indicated by a changed cue. Experiment 2 showed that switch costs decreased with prolonged cuing intervals, but Experiment 3 revealed that preparation did not affect auditory switch costs but only visual cue priming. Moreover, incongruent numerical categories in competing auditory stimuli produced interference and substantially increased error rates, suggesting continued processing of task-relevant information that often leads to responding to the incorrect auditory source. Together, the data show clear limitations in advance preparation of auditory attention switches and suggest a considerable degree of inertia in intentional control of auditory selection criteria.	\N	\N
21559468	In humans, emotions from music serve important communicative roles. Despite a growing interest in the neural basis of music perception, action and emotion, the majority of previous studies in this area have focused on the auditory aspects of music performances. Here we investigate how the brain processes the emotions elicited by audiovisual music performances. We used event-related functional magnetic resonance imaging, and in Experiment 1 we defined the areas responding to audiovisual (musician's movements with music), visual (musician's movements only), and auditory emotional (music only) displays. Subsequently a region of interest analysis was performed to examine if any of the areas detected in Experiment 1 showed greater activation for emotionally mismatching performances (combining the musician's movements with mismatching emotional sound) than for emotionally matching music performances (combining the musician's movements with matching emotional sound) as presented in Experiment 2 to the same participants. The insula and the left thalamus were found to respond consistently to visual, auditory and audiovisual emotional information and to have increased activation for emotionally mismatching displays in comparison with emotionally matching displays. In contrast, the right thalamus was found to respond to audiovisual emotional displays and to have similar activation for emotionally matching and mismatching displays. These results suggest that the insula and left thalamus have an active role in detecting emotional correspondence between auditory and visual information during music performances, whereas the right thalamus has a different role.	\N	\N
21564122	We studied whether a multifeature mismatch negativity (MMN) paradigm using naturally produced speech stimuli is feasible for studies of auditory discrimination accuracy of adult participants. A naturally produced trisyllabic pseudoword was used in the paradigm, and MMNs were recorded to changes that were acoustic (changes in fundamental frequency or intensity) or potentially phonological (changes in vowel identity or vowel duration). All the different changes were presented in three different word segments (initial, middle, or final syllable). All changes elicited an MMN response, but the vowel duration change elicited a different response pattern than the other deviant types. Changes in vowel duration and identity also had an effect on MMN lateralization. Our results show that assessing speech sound discrimination of several features in word context is possible in a short recording time (30 min) with the multifeature paradigm.	\N	\N
21568161	Although receptive priming has long been used as a way to examine lexical access in adults, few studies have applied this method to children and rarely in an auditory modality. We compared auditory associative priming in children and adults. A testing battery and a Lexical Decision (LD) task was administered to 42 adults and 27 children (8;1-10; 11 years-old) from Spain. They listened to Spanish word pairs (semantically related/unrelated word pairs and word-pseudoword pairs), and tone pairs. Then participants pressed one key for word pairs, and another for pairs with a word and a pseudoword. They also had to press the two keys alternatively for tone pairs as a basic auditory control. Both groups of participants, children and adults, exhibited semantic priming, with significantly faster Reaction Times (RTs) to semantically related word pairs than to unrelated pairs and to the two word-pseudoword sets. The priming effect was twice as large in the adults compared to children, and the children (not the adults) were significantly slower in their response to word-pseudoword pairs than to the unrelated word pairs. Moreover, accuracy was somewhat higher in adults than children for each word pair type, but especially in the word-pseudoword pairs. As expected, children were significantly slower than adults in the RTs for all stimulus types, and their RTs decreased significantly from 8 to 10 years of age and they also decreased in relation to some of their language abilities development (e.g., relative clauses comprehension). In both age groups, the Reaction Time average for tone pairs was lower than for speech pairs, but only all adults obtained 100% accuracy (which was slightly lower in children). Auditory processing and semantic networks are still developing in 8-10 year old children.	\N	\N
21568376	The corruption of intonation contours has detrimental effects on sentence-based speech recognition in normal-hearing listeners Binns and Culling [(2007). J. Acoust. Soc. Am. 122, 1765-1776]. This paper examines whether this finding also applies to cochlear implant (CI) recipients. The subjects' F0-discrimination and speech perception in the presence of noise were measured, using sentences with regular and inverted F0-contours. The results revealed that speech recognition for regular contours was significantly better than for inverted contours. This difference was related to the subjects' F0-discrimination providing further evidence that the perception of intonation patterns is important for the CI-mediated speech recognition in noise.	\N	\N
21568411	This study examined the time course of cochlear suppression using a tone-burst suppressor to measure decrement of distortion-product otoacoustic emissions (DPOAEs). Seven normal-hearing subjects with ages ranging from 19 to 28 yr participated in the study. Each subject had audiometric thresholds ≤ 15 dB HL [re ANSI (2004) Specifications for Audiometers] for standard octave and inter-octave frequencies from 0.25 to 8 kHz. DPOAEs were elicited by primary tones with f(2) = 4.0 kHz and f(1) = 3.333 kHz (f(2)/f(1) = 1.2). For the f(2), L(2) combination, suppression was measured for three suppressor frequencies: One suppressor below f(2) (3.834 kHz) and two above f(2) (4.166 and 4.282 kHz) at three levels (55, 60, and 65 dB SPL). DPOAE decrement as a function of L(3) for the tone-burst suppressor was similar to decrements obtained with longer duration suppressors. Onset- and setoff- latencies were ≤ 4 ms, in agreement with previous physiological findings in auditory-nerve fiber studies that suggest suppression results from a nearly instantaneous compression of the waveform. Persistence of suppression was absent for the below-frequency suppressor (f(3) = 3.834 kHz) and was ≤ 3 ms for the two above-frequency suppressors (f(3) = 4.166 and 4.282 kHz).	\N	\N
21568423	The octave or Deutsch illusion occurs when two tones, separated by about one octave, are presented simultaneously but alternating between ears, such that when the low tone is presented to the left ear the high tone is presented to the right ear and vice versa. Most subjects hear a single tone that alternates both between ears and in pitch; i.e., they hear a low pitched tone in one ear alternating with a high pitched tone in the other ear. The present study examined whether the illusion can be elicited by aperiodic signals consisting of low-frequency band-pass filtered noises with overlapping spectra. The amount of spectral overlap was held constant, but the high- and low-frequency content of the signals was systematically varied. The majority of subjects perceived an auditory illusion in terms of a dominant ear for pitch and lateralization by frequency, as proposed by Deutsch [(1975a) Sci. Am. 233, 92-104]. Furthermore, the salience of the illusion increased as the high frequency of the content in the signal increased. Since no harmonics were present in the stimuli, it is highly unlikely that this illusion is perceived on the basis of binaural diplacusis or harmonic binaural fusion.	\N	\N
21569617	After a prolonged exposure to a paired presentation of different types of signals (e.g., color and motion), one of the signals (color) becomes a driver for the other signal (motion). This phenomenon, which is known as contingent motion aftereffect, indicates that the brain can establish new neural representations even in the adult's brain. However, contingent motion aftereffect has been reported only in visual or auditory domain. Here, we demonstrate that a visual motion aftereffect can be contingent on a specific sound. Dynamic random dots moving in an alternating right or left direction were presented to the participants. Each direction of motion was accompanied by an auditory tone of a unique and specific frequency. After a 3-minutes exposure, the tones began to exert marked influence on the visual motion perception, and the percentage of dots required to trigger motion perception systematically changed depending on the tones. Furthermore, this effect lasted for at least 2 days. These results indicate that a new neural representation can be rapidly established between auditory and visual modalities.	\N	\N
21598839	This study examined the relationship between proactive learning in hypnosis, post-hypnotic suggestion, and academic performance. Participants (N = 56) were randomly assigned to a control group or a treatment group. The treatment group was hypnotized and read a passage while in hypnosis. Concurrently, they were given a post-hypnotic suggestion, which attempted to aid recognition and performance on a test immediately following the hypnosis session. Both groups completed a multiple-choice test based on the aforementioned passage. An analysis of covariance discerned the effect of proactive learning and post-hypnotic suggestion on test performance, while controlling for the variance introduced by scholastic aptitude as measured by the ACT. Results indicated that the hypnosis sessions predicted significantly impaired test performance.	\N	\N
21599613	To develop and evaluate the Mandarin speech signal content on the acceptable noise level (ANL) test in listeners with normal hearing in mainland China. The Mandarin ANL tests were conducted using three different sets of Mandarin running speech materials which were chosen from textbooks for primary school, secondary school, and high school, respectively. For each discourse, two ANL measurements were obtained and averaged for each experimental condition using ANL test procedures. Thirty-one normal-hearing listeners participated in this study. There were significant differences for ANLs among the normal-hearing listeners, but no differences were found for MCLs and ANLs for the three sets of test materials. The Pearson correlations suggested significant correlations between MCL and ANL among the three test materials; also the results showed that the correlation coefficient between MCL-ANL of the primary material was much better than other two materials. (1) The contents of different Mandarin running speeches may not affect the acceptable noise level in Mandarin normal-hearing listeners; (2) The running speech selected from the primary school ought to be used as the Mandarin acceptable noise level test material to evaluate the outcomes of hearing aid fitting.	\N	\N
21604474	To enhance speech recognition in noise, as well as tone recognition, we presented a new kind of speech coding strategy, called one-octave wavelet transform zero-crossing stimulation (WTZS), for cochlear implants based on amplitude and frequency modulation. We selected 15 volunteers with normal hearing ability to carry out hearing simulation experiments by picking up the amplitude (amplitude modulation, AM), zero-crossings (frequency modulation, FM) and gradient parameters from processed speech signal in the domain of one-octave wavelet transform to synthesize the stimulating pulstile series. The experimental results demonstrated that the phonetic recognition in quiet surroundings with amplitude modulation only strategy (CIS) is similar to that of amplitude and frequency modulations strategies (FAME and WTZS), while the tone perception of CIS is inferior to that of FAME and WTZS strategies. However, in noisy environment, the phonetic recognition, tone perception, as well as sentence recognition of WTZS strategy are better than those of CIS and FAME strategies. WTZS strategy, utilizing amplitude (AM), zero-crossings (FM) and gradient parameters to synthesize stimulus, can enhance the phonetic and tonal language recognition in noise environment effectively, and could be used in cochlear implant system for speech processor design after arithmetic optimization.	\N	\N
21613467	There is an increasing interest to integrate electrophysiological and hemodynamic measures for characterizing spatial and temporal aspects of cortical processing. However, an informative combination of responses that have markedly different sensitivities to the underlying neural activity is not straightforward, especially in complex cognitive tasks. Here, we used parametric stimulus manipulation in magnetoencephalography (MEG) and functional magnetic resonance imaging (fMRI) recordings on the same subjects, to study effects of noise on processing of spoken words and environmental sounds. The added noise influenced MEG response strengths in the bilateral supratemporal auditory cortex, at different times for the different stimulus types. Specifically for spoken words, the effect of noise on the electrophysiological response was remarkably nonlinear. Therefore, we used the single-subject MEG responses to construct parametrization for fMRI data analysis and obtained notably higher sensitivity than with conventional stimulus-based parametrization. fMRI results showed that partly different temporal areas were involved in noise-sensitive processing of words and environmental sounds. These results indicate that cortical processing of sounds in background noise is stimulus specific in both timing and location and provide a new functionally meaningful platform for combining information obtained with electrophysiological and hemodynamic measures of brain function.	\N	\N
21613485	Growing evidence from electrophysiological data in animal and human studies suggests that multisensory interaction is not exclusively a higher-order process, but also takes place in primary sensory cortices. Such early multisensory interaction is thought to be mediated by means of phase resetting. The presentation of a stimulus to one sensory modality resets the phase of ongoing oscillations in another modality such that processing in the latter modality is modulated. In humans, evidence for such a mechanism is still sparse. In the current study, the influence of an auditory stimulus on visual processing was investigated by measuring the electroencephalogram (EEG) and behavioral responses of humans to visual, auditory, and audiovisual stimulation with varying stimulus-onset asynchrony (SOA). We observed three distinct oscillatory EEG responses in our data. An initial gamma-band response around 50 Hz was followed by a beta-band response around 25 Hz, and a theta response around 6 Hz. The latter was enhanced in response to cross-modal stimuli as compared to either unimodal stimuli. Interestingly, the beta response to unimodal auditory stimuli was dominant in electrodes over visual areas. The SOA between auditory and visual stimuli--albeit not consciously perceived--had a modulatory impact on the multisensory evoked beta-band responses; i.e., the amplitude depended on SOA in a sinusoidal fashion, suggesting a phase reset. These findings further support the notion that parameters of brain oscillations such as amplitude and phase are essential predictors of subsequent brain responses and might be one of the mechanisms underlying multisensory integration.	\N	\N
21615286	Research into speech perception by nonhuman animals can be crucially informative in assessing whether specific perceptual phenomena in humans have evolved to decode speech, or reflect more general traits. Birds share with humans not only the capacity to use complex vocalizations for communication but also many characteristics of its underlying developmental and mechanistic processes; thus, birds are a particularly interesting group for comparative study. This review first discusses commonalities between birds and humans in perception of speech sounds. Several psychoacoustic studies have shown striking parallels in seemingly speech-specific perceptual phenomena, such as categorical perception of voice-onset-time variation, categorization of consonants that lack phonetic invariance, and compensation for coarticulation. Such findings are often regarded as evidence for the idea that the objects of human speech perception are auditory or acoustic events rather than articulations. Next, I highlight recent research on the production side of avian communication that has revealed the existence of vocal tract filtering and articulation in bird species-specific vocalization, which has traditionally been considered a hallmark of human speech production. Together, findings in birds show that many of characteristics of human speech perception are not uniquely human but also that a comparative approach to the question of what are the objects of perception--articulatory or auditory events--requires careful consideration of species-specific vocal production mechanisms.	\N	\N
21616132	Presbycusis, or age-related hearing loss is a growing problem as the general population ages. In this longitudinal study, the influence of noise or styrene exposure on presbycusis was investigated in Brown Norway rats. Animals were exposed at 6 months of age, either to a band noise centered at 8 kHz at a Lex,8h = 85 dB (86.2 dB SPL for 6 h), or to 300 ppm of styrene for 6 h per day, five days per week, for four weeks. Cubic distortion product otoacoustic emissions (2f1-f2 DPOAEs) were used to test the capacity of the auditory receptor over the lifespan of the animals. 2f1-f2DPOAE measurements are easy to implement and efficiently track the age-related deterioration of mid- and high-frequencies. They are good indicators of temporary auditory threshold shift, especially with a level of primaries close to 60 dB SPL. Post-exposure hearing defects are best identified using moderate, rather than high, levels of primaries. Like many aging humans, aging rats lose sensitivity to high-frequencies faster than to medium-frequencies. Although the results obtained with the styrene exposure were not entirely conclusive, histopathological data showed the presbycusis process to be enhanced. Noise-exposed rats exhibit a loss of spiral ganglion cells from 12 months and a 7 dB drop in 2f1-f2DPOAEs at 24 months, indicating that even moderate-intensity noise can accelerate the presbycusis process. Even though the results obtained with the styrene exposure are less conclusive, the histopathological data show an enhancement of the presbycusis process.	\N	\N
21630061	Since air-conducted (AC) and clinical (mastoid) bone-conducted (BC) sounds interact in the cochlea (e.g. pitch, cancellation, masking, beats), it has been thought that both AC and BC stimulations lead to a mechanical wave in the cochlea. However, there are also "non-osseous" forms of BC, i.e. auditory sensation produced when the clinical bone vibrator is applied to "non-osseous" soft tissue sites. In the present study, such "non-osseous" sites were identified (e.g. eye, cheek, neck) and they interacted with AC and osseous BC (pitch matching, beats, masking), indicating that all of these forms of auditory stimulation converge in the cochlea, producing the same pattern of mechanical activity, leading to their interactions.	\N	\N
21632920	The integration of multisensory information has been shown to be guided by spatial and temporal proximity, as well as to be influenced by attention. Here we used neural measures of the multisensory spread of attention to investigate the spatial and temporal linking of synchronous versus near-synchronous auditory and visual events. Human participants attended selectively to one of two lateralized visual-stimulus streams while task-irrelevant tones were presented centrally. Electrophysiological measures of brain activity showed that tones occurring simultaneously or delayed by 100 ms were temporally linked to an attended visual stimulus, as reflected by robust cross-modal spreading-of-attention activity, but not when delayed by 300 ms. The neural data also indicated a ventriloquist-like spatial linking of the auditory to the attended visual stimuli, but only when occurring simultaneously. These neurophysiological results thus provide unique insight into the temporal and spatial principles of multisensory feature integration and the fundamental role attention plays in such integration.	\N	\N
21632945	Contemporary models of the neural system that supports reading propose that activity in a ventral occipitotemporal area (vOT) drives activity in higher-order language areas, for example, those in the posterior superior temporal sulcus (pSTS) and anterior superior temporal sulcus (aSTS). We used fMRI with dynamic causal modeling (DCM) to investigate evidence for other routes from visual cortex to the left temporal lobe language areas. First we identified activations in posterior inferior occipital (iO) and vOT areas that were more activated for silent reading than listening to words and sentences; and in pSTS and aSTS areas that were commonly activated for reading relative to false-fonts and listening to words relative to reversed words. Second, in three different DCM analyses, we tested whether visual processing of words modulates activity from the following: (1) iO→vOT, iO→pSTS, both, or neither; (2) vOT→pSTS, iO→pSTS, both or neither; and (3) pSTS→aSTS, vOT→aSTS, both, or neither. We found that reading words increased connectivity (1) from iO to both pSTS and vOT; (2) to pSTS from both iO and vOT; and (3) to aSTS from both vOT and pSTS. These results highlight three potential processing streams in the occipitotemporal cortex: iO→pSTS→aSTS; iO→vOT→aSTS; and iO→vOT→pSTS→aSTS. We discuss these results in terms of cognitive models of reading and propose that efficient reading relies on the integrity of all these pathways.	\N	\N
21637344	Previous cue integration studies have examined continuous perceptual dimensions (e.g., size) and have shown that human cue integration is well described by a normative model in which cues are weighted in proportion to their sensory reliability, as estimated from single-cue performance. However, this normative model may not be applicable to categorical perceptual dimensions (e.g., phonemes). In tasks defined over categorical perceptual dimensions, optimal cue weights should depend not only on the sensory variance affecting the perception of each cue but also on the environmental variance inherent in each task-relevant category. Here, we present a computational and experimental investigation of cue integration in a categorical audio-visual (articulatory) speech perception task. Our results show that human performance during audio-visual phonemic labeling is qualitatively consistent with the behavior of a Bayes-optimal observer. Specifically, we show that the participants in our task are sensitive, on a trial-by-trial basis, to the sensory uncertainty associated with the auditory and visual cues, during phonemic categorization. In addition, we show that while sensory uncertainty is a significant factor in determining cue weights, it is not the only one and participants' performance is consistent with an optimal model in which environmental, within category variability also plays a role in determining cue weights. Furthermore, we show that in our task, the sensory variability affecting the visual modality during cue-combination is not well estimated from single-cue performance, but can be estimated from multi-cue performance. The findings and computational principles described here represent a principled first step towards characterizing the mechanisms underlying human cue integration in categorical tasks.	\N	\N
21638105	In two experiments, we examined the impact of the degree of match between sequential auditory perceptual organization processes and the demands of a short-term memory task (memory for order vs. item information). When a spoken sequence of digits was presented so as to promote its perceptual partitioning into two distinct streams by conveying it in alternating female (F) and male (M) voices (FMFMFMFM)--thereby disturbing the perception of true temporal order--recall of item order was greatly impaired (as compared to recall of item identity). Moreover, an order error type consistent with the formation of voice-based streams was committed more quickly in the alternating-voice condition (Exp. 1). In contrast, when the perceptual organization of the sequence mapped well onto an optimal two-group serial rehearsal strategy--by presenting the two voices in discrete clusters (FFFFMMMM)--order, but not item, recall was enhanced (Exp. 2). The results are consistent with the view that the degree of compatibility between perceptual and deliberate sequencing processes is a key determinant of serial short-term memory performance. Alternative accounts of talker variability effects in short-term memory, based on the concept of a dedicated phonological short-term store and a capacity-limited focus of attention, are also reviewed.	\N	\N
21646423	To determine the rate of word learning for children with hearing loss (HL) in quiet and in noise compared to normal-hearing (NH) peers. The effects of digital noise reduction (DNR) were examined for children with HL. Forty-one children with NH and 26 children with HL were grouped by age (8-9 years and 11-12 years). The children learned novel words associated with novel objects through a process of trial and error. Functions relating performance across trials were calculated for each child in each listening condition and were compared. Significant effects were observed for age (older > younger) in the children with NH and listening condition (quiet > noise) in the children with HL. Significant effects of hearing status were also observed across groups (NH > HL), indicating that the children with HL required more trials to learn the new words. However, word learning improved significantly in noise with the use of DNR for the older but not for the younger children with HL. Hearing aid history and signal-to-noise ratio did not contribute to performance. Word learning was significantly reduced in younger children, in noise, and in the presence of hearing loss. Age-related benefits of DNR were apparent for children over 10 years of age.	\N	\N
21646931	The perception of pitch has recently gained attention. At present, clinical audiologic tests to assess this are hardly available. This article reports on the development of a clinical test using harmonic intonation (HI) and disharmonic intonation (DI). Prospective collection of normative data and pilot study in hearing-impaired subjects. Tertiary referral center. Normative data were collected from 90 normal-hearing subjects recruited from 3 different language backgrounds. The pilot study was conducted on 18 hearing-impaired individuals who were selected into 3 pathologic groups: high-frequency hearing loss (HF), low-frequency hearing loss (LF), and cochlear implant users (CI). Normative data collection and exploratory diagnostics by means of the newly constructed HI/DI tests using intonation patterns to find the just noticeable difference (JND) for pitch discrimination in low-frequency harmonic complex sounds presented in a same-different task. JND for pitch discrimination using HI/DI tests in the hearing population and pathologic groups. Normative data are presented in 5 parameter statistics and box-and-whisker plots showing median JNDs of 2 (HI) and 3 Hz (DI). The results on both tests are statistically abnormal in LF and CI subjects, whereas they are not significantly abnormal in the HF group. The HI and DI tests allow the clinical assessment of low-frequency pitch perception. The data obtained in this study define the normal zone for both tests. Preliminary results indicate possible abnormal TFS perception in some hearing-impaired subjects.	\N	\N
21664147	Homonyms, i.e. ambiguous words like 'score', have different meanings in different contexts. Previous research indicates that all potential meanings of a homonym are first accessed in parallel before one of the meanings is selected in a competitive race. If these processes are automatic, these processes of selection should even be observed when homonyms are shown subliminally. This study measured the time course of subliminal and supraliminal priming by homonyms with a frequent (dominant) and a rare (subordinate) meaning in a neutral context, using a lexical decision task. In the subliminal condition, priming across prime-target asynchronies ranging from 100 ms to 1.5 s indicated that the dominant meaning of homonyms was facilitated and the subordinate meaning was inhibited. This indicates that selection of meaning was much faster with subliminal presentation than with supraliminal presentation. Awareness of a prime might decelerate an otherwise rapid selection process.	\N	\N
21666515	The cortical processing of musical sounds is influenced by listeners' sensitivity to the structural regularities of music, and particularly by sensitivity to harmonic relationships. As subcortical and cortical processing dynamically interact to shape auditory perception in an experience-dependent manner, we asked whether subcortical processing of musical sounds would be sensitive to harmonic relationships. We examined auditory brainstem responses to a chord that was preceded either by a harmonically related chord, by an unrelated chord, or was repeated. We observed higher spectral response magnitudes in the related than in the unrelated or repeated conditions, for both musician and nonmusician listeners. Our results suggest that listeners' implicit knowledge of musical regularities influences subcortical auditory processing.	\N	\N
21669238	The fast detection of novel or deviant stimuli is a striking property of the auditory processing which reflects basic organizational principles of the auditory system and at the same time is of high practical significance. In human electrophysiology, deviance detection has been related to the occurrence of the mismatch negativity (MMN)--a component of the event-related potential (ERP) evoked 100 to 250 ms after the occurrence of a rare irregular sound. Recently, it has been shown in animal studies that a considerable portion of neurons in the auditory pathway exhibits a property called stimulus-specific adaptation enabling them to encode inter-sound relationships and to discharge at higher rates to rare changes in the acoustic stimulation. These neural responses have been linked to the deviant-evoked potential measured at the human scalp, but such responses occur at lower levels anatomically (e.g. the primary auditory cortex as well as the inferior colliculi) and are elicited earlier (20-30 ms after sound onset) in comparison to MMN. Further, they are not considerable enough in size to be interpreted as a direct neural correlate of the MMN. We review here a series of recent findings that provides a first step toward filling this gap between animal and human recordings by showing that comparably early modulations due to a sound's deviancy can be observed in humans, particularly in the middle-latency portion of the ERP within the first 50 ms after sound onset. The existence of those early indices of deviance detection preceding the well-studied MMN component strongly supports the idea that the encoding of regularities and the detection of violations is a basic principle of human auditory processing acting on multiple levels. This sustains the notion of a hierarchically organized novelty and deviance detection system in the human auditory system.	\N	\N
21680846	The attentional effects triggered by emotional stimuli in humans have been substantially investigated, but little is known about the impact of affective valence on the processing of meaning. Here, we used a cross-modal priming paradigm involving visually presented adjective-noun dyads and environmental sounds of controlled affective valence to test the contributions of conceptual relatedness and emotional congruence to priming. Participants undergoing event-related potential recording indicated whether target environmental sounds were related in meaning to adjective-noun dyads presented as primes. We tested spontaneous emotional priming by manipulating the congruence between the affective valence of the adjective in the prime and that of the sound. While the N400 was significantly reduced in amplitude by both conceptual relatedness and emotional congruence, there was no interaction between the 2 factors. The same pattern of results was found when participants judged the emotional congruence between environmental sounds and adjective-noun dyads. These results support the hypothesis that conceptual and emotional processes are functionally independent regardless of the specific cognitive focus of the comprehender.	\N	\N
21682421	Cross-channel envelope correlations are hypothesized to influence speech intelligibility, particularly in adverse conditions. Acoustic analyses suggest speech envelope correlations differ for syllabic and phonemic ranges of modulation frequency. The influence of cochlear filtering was examined here by predicting cross-channel envelope correlations in different speech modulation ranges for normal and impaired auditory-nerve (AN) responses. Neural cross-correlation coefficients quantified across-fiber envelope coding in syllabic (0-5 Hz), phonemic (5-64 Hz), and periodicity (64-300 Hz) modulation ranges. Spike trains were generated from a physiologically based AN model. Correlations were also computed using the model with selective hair-cell damage. Neural predictions revealed that envelope cross-correlation decreased with increased characteristic-frequency separation for all modulation ranges (with greater syllabic-envelope correlation than phonemic or periodicity). Syllabic envelope was highly correlated across many spectral channels, whereas phonemic and periodicity envelopes were correlated mainly between adjacent channels. Outer-hair-cell impairment increased the degree of cross-channel correlation for phonemic and periodicity ranges for speech in quiet and in noise, thereby reducing the number of independent neural information channels for envelope coding. In contrast, outer-hair-cell impairment was predicted to decrease cross-channel correlation for syllabic envelopes in noise, which may partially account for the reduced ability of hearing-impaired listeners to segregate speech in complex backgrounds.	\N	\N
21683500	Responses to threat occur via two known independent processing routes. We propose that early, reflexive processing is predominantly tuned to the detection of congruent combinations of facial cues that signal threat, whereas later, reflective processing is predominantly tuned to incongruent combinations of threat. To test this prediction, we examined responses to threat-gaze expression pairs (anger versus fear expression by direct versus averted gaze). We report on two functional magnetic resonance imaging (fMRI) studies, one employing prolonged presentations (2s) of threat-gaze pairs to allow for reflective processing (Study 1), and one employing severely restricted (33 ms), backward masked presentations of threat-gaze pairs to isolate reflexive neural responding (Study 2). Our findings offer initial support for the conclusion that early, reflexive responses to threat are predominantly tuned to congruent threat-gaze pairings, whereas later reflective responses are predominantly tuned to ambiguous threat-gaze pairings. These findings highlight a distinct dual function in threat perception.	\N	\N
21683995	Electrophysiological studies investigating similarities between music and language perception have relied exclusively on the signal averaging technique, which does not adequately represent oscillatory aspects of electrical brain activity that are relevant for higher cognition. The current study investigated the patterns of brain oscillations during simultaneous processing of music and language using visually presented sentences and auditorily presented chord sequences. Music-syntactically regular or irregular chord functions were presented in sync with syntactically or semantically correct or incorrect words. Irregular chord functions (presented simultaneously with a syntactically correct word) produced an early (150-250 ms) spectral power decrease over anterior frontal regions in the theta band (5-7 Hz) and a late (350-700 ms) power increase in both the delta and the theta band (2-7 Hz) over parietal regions. Syntactically incorrect words (presented simultaneously with a regular chord) elicited a similar late power increase in delta-theta band over parietal sites, but no early effect. Interestingly, the late effect was significantly diminished when the language-syntactic and music-syntactic irregularities occurred at the same time. Further, the presence of a semantic violation occurring simultaneously with regular chords produced a significant increase in later delta-theta power at posterior regions; this effect was marginally decreased when the identical semantic violation occurred simultaneously with a music syntactical violation. Altogether, these results show that low frequency oscillatory networks get activated during the syntactic processing of both music and language, and further, these networks may possibly be shared.	\N	\N
21689048	The purpose of this study was to develop a music quality rating test battery (MQRTB) and pilot test it by comparing appraisal ratings from cochlear implant (CI) recipients using the fine-structure processing (FSP) and high-definition continuous interleaved sampling (HDCIS) speech processing strategies. The development of the MQRTB involved three stages: (1) Selection of test items for the MQRTB; (2) Verification of its length and complexity with normally-hearing individuals; and (3) Pilot testing with CI recipients. Part 1 involved 65 adult listeners, Part 2 involved 10 normally-hearing adults, and Part 3 involved five adult MED-EL CI recipients. The MQRTB consisted of ten songs, with ratings made on scales assessing pleasantness, naturalness, richness, fullness, sharpness, and roughness. Results of the pilot study, which compared FSP and HDCIS for music, indicated that acclimatization to a strategy had a significant effect on ratings (p < 0.05). When acclimatized to FSP, the group rated FSP as closer to 'exactly as I want it to sound' than HDCIS (p < 0.05), and that HDCIS sounded significantly sharper and rougher than FSP. However when acclimatized to HDCIS, there were no significant differences between ratings. There was no effect of song familiarity or genre on ratings. Overall the results suggest that the use of FSP as the default strategy for MED-EL recipients would have a positive effect on music appreciation, and that the MQRTB is an effective tool for assessing music sound quality.	\N	\N
21692141	The aim of this functional magnetic resonance imaging (fMRI) study was to identify human brain areas that are sensitive to the direction of auditory motion. Such directional sensitivity was assessed in a hypothesis-free manner by analyzing fMRI response patterns across the entire brain volume using a spherical-searchlight approach. In addition, we assessed directional sensitivity in three predefined brain areas that have been associated with auditory motion perception in previous neuroimaging studies. These were the primary auditory cortex, the planum temporale and the visual motion complex (hMT/V5+). Our whole-brain analysis revealed that the direction of sound-source movement could be decoded from fMRI response patterns in the right auditory cortex and in a high-level visual area located in the right lateral occipital cortex. Our region-of-interest-based analysis showed that the decoding of the direction of auditory motion was most reliable with activation patterns of the left and right planum temporale. Auditory motion direction could not be decoded from activation patterns in hMT/V5+. These findings provide further evidence for the planum temporale playing a central role in supporting auditory motion perception. In addition, our findings suggest a cross-modal transfer of directional information to high-level visual cortex in healthy humans.	\N	\N
21701947	Phenomena in a variety of verbal tasks--for example, masked priming, lexical decision, and word naming--are typically explained in terms of similarity between word-forms. Despite the apparent commonalities between these sets of phenomena, the representations and similarity measures used to account for them are not often related. To show how this gap might be bridged, we build on the work of Hannagan, Dupoux, and Christophe, Cognitive Science 35:79-118, (2011) to explore several methods of representing visual word-forms using holographic reduced representations and to evaluate them on their ability to account for a wide range of effects in masked form priming, as well as data from lexical decision and word naming. A representation that assumes that word-internal letter groups are encoded relative to word-terminal letter groups is found to predict qualitative patterns in masked priming, as well as lexical decision and naming latencies. We then show how this representation can be integrated with the BEAGLE model of lexical semantics (Jones & Mewhort, Psychological Review 114:1-37, 2007) to enable the model to encompass a wider range of verbal tasks.	\N	\N
21707205	In reaction time research, there has been an increasing appreciation that response-initiation processes are sensitive to recent experience and, in particular, the difficulty of previous trials. From this perspective, the authors propose an explanation for a perplexing property of masked priming: Although primes are not consciously identified, facilitation of target processing by a related prime is magnified in a block containing a high proportion of related primes and a low proportion of unrelated primes relative to a block containing the opposite mix (Bodner & Masson, 2001). In the present study, this phenomenon is explored with a parity (even/odd) decision task in which a prime (e.g., 2) precedes a target that can be either congruent (e.g., 4) or incongruent (e.g., 3). It is shown that the effect of congruence proportion with masked primes cannot be explained in terms of the blockwise prime-target contingency. Specifically, with masked primes, there is no congruency disadvantage in a block containing a high proportion of incongruent primes, but there is a congruency advantage when the block contains an equal proportion of congruent and incongruent primes. In qualitative contrast, visible primes are sensitive to the blockwise prime-target contingency. The authors explain the relatedness proportion effect found with masked primes in terms of a model according to which response-initiation processes adapt to the statistical structure of the environment, specifically the difficulty of recent trials. This account is supported with an analysis at the level of individual trials using the linear mixed effects model.	\N	\N
21707266	We report a single case study of a synesthete (PS) who has complex visual experiences from sounds, including human voices. Different vowel sounds from different speakers and modified to be of different pitch (f0) were presented to PS and controls who were asked to draw an (abstract) visual image of the sound noting colors, sizes, and locations. PS tended to be more consistent over time than controls. For both PS and controls, the pitch of the vowel influenced the choice of luminance (higher pitch being lighter) and vertical position (higher pitch being higher in space). However, the gender of the speaker influenced the size of the 'image' independently of pitch (vowels from males being larger).	\N	\N
21710713	To investigate the contralateral suppressions of transient evoked otoacoustic emissions (TEOAE) in diabetes mellitus patients with normal hearing. The pure tone audiometry, acoustic immittance and TEOAE tests were performed in 30 diabetes mellitus patients with normal hearing and 30 healthy controls. The efferent system functions were evaluated by contralateral suppression of TEOAE. There were no significant differences of pure tone thresholds and amplitudes of TEOAE between the two groups. The contralateral suppressions of TEOAE in diabetes mellitus patients were significantly lower than that in controls (P<0.05 at 2000 and 4000 Hz respectively). The nerve functions of central nerve system can be damaged in diabetes mellitus patients with normal hearing.	\N	\N
21714708	We investigated if linguistic complexity contributes to the variation of the speech reception threshold in noise (SRTN) and thus should be employed as an additional design criterion in sentence tests used for audiometry. Three test lists were established with sentences from the Göttingen sentence test ( Kollmeier & Wesselkamp, 1997 ). One list contained linguistically simple sentences, the other two lists contained sentences with two types of linguistic complexity. For each listener the SRTN was determined for each list. Younger and older listeners with normal hearing and older listeners with hearing impairment were tested. Younger listeners with normal hearing showed significantly worse SRTNs on the complex lists than on the simple list. This difference could not be found for either of the older groups. The effect of linguistic complexity on speech recognition seems to depend on age and/or hearing status. Hence, pending further research, linguistic complexity seems less relevant as a sentence test design criterion for clinical-audiological purposes, but we argue that a test with larger variation in linguistic complexity across sentences might show a relation between linguistic complexity and speech recognition even in a clinical population.	\N	\N
21719027	Web based speech training for dysarthric speakers, such as E-learning based Speech Therapy (EST), puts considerable demands on auditory discrimination abilities. To discuss the development and the evaluation of an auditory discrimination test (ADT) for the assessment of auditory speech discrimination skills in Dutch adult dysarthric speakers as a prelude to EST. Five ADT subtests were developed, each addressing a vital speech dimension in speech therapy: articulation (segmental elements), intensity, overall pitch, speech rate and intonation. A healthy control group of 36 participants performed a 'same-different task' in each subtest. ADT items yielding scores of at least 80% but below 100% correctly responding healthy controls were considered sensitive to diminished auditory discrimination. Subsequently, the ADT was carried out by 14 neurological patients with dysarthric speech and 14 matched healthy controls. Score percentages, sensitivity indices and reaction times (ms) on only sensitive items were compared. The majority of the ADT items met the 'minimal 80% to below 100% criterion' in the healthy control group. The neurological participants performed lower on all outcome measures across all subtests than the healthy controls, although not all of these differences achieved statistical significance. The results of the healthy control group show that the majority of the ADT items meet our criterion for sensitivity to diminished auditory discrimination. The poorer performance of dysarthric patients across all subtests supports the sensitivity of the ADT. However, further research involving larger and more homogeneous groups of neurological patients is required. Readers will be encouraged to (1) identify potential factors that may hinder web based speech training and (2) estimate the value of assessing auditory discrimination skills as a vital condition for (web based) speech training in dysarthric patients.	\N	\N
21723130	Human voices play a fundamental role in social communication, and areas of the adult "social brain" show specialization for processing voices and their emotional content (superior temporal sulcus, inferior prefrontal cortex, premotor cortical regions, amygdala, and insula). However, it is unclear when this specialization develops. Functional magnetic resonance (fMRI) studies suggest that the infant temporal cortex does not differentiate speech from music or backward speech, but a prior study with functional near-infrared spectroscopy revealed preferential activation for human voices in 7-month-olds, in a more posterior location of the temporal cortex than in adults. However, the brain networks involved in processing nonspeech human vocalizations in early development are still unknown. To address this issue, in the present fMRI study, 3- to 7-month-olds were presented with adult nonspeech vocalizations (emotionally neutral, emotionally positive, and emotionally negative) and nonvocal environmental sounds. Infants displayed significant differential activation in the anterior portion of the temporal cortex, similarly to adults. Moreover, sad vocalizations modulated the activity of brain regions involved in processing affective stimuli such as the orbitofrontal cortex and insula. These results suggest remarkably early functional specialization for processing human voice and negative emotions.	\N	\N
21723376	Older human listeners demonstrate perceptual deficits in temporal processing even when audibility has been controlled. These age-related auditory deficits in temporal processing are thought to originate in the central auditory pathway. Precise temporal processing is necessary to detect and discriminate auditory cues such as modulation frequency, modulation depth and envelope shape which are critical for perception of speech and environmental sounds. This study aims to further understanding of temporal processing in aging using non-invasive electrophysiological measurements. Amplitude modulation following responses (AMFRs) and frequency modulation following responses (FMFRs) were recorded from aged (92-95-weeks old) and young (9-12-weeks old) Fischer-344 (F-344) rats for sinusoidally amplitude modulated (sAM) tones, sinusoidally frequency modulated (sFM) tones and ramped and damped amplitude modulation (AM) stimuli which differ in their envelope shapes. The modulation depth for the sAM and sFM stimuli and envelope shape for the ramped and damped stimuli were systematically varied. There was a monotonic decrease in AMFR and FMFR amplitudes with decreases in modulation depth across age for sAM and sFM stimuli. There was no significant difference between the response amplitudes of the young and aged animals for the largest modulation depths. However, a reduction in modulation depth resulted in a significant decrease in the response amplitudes and higher modulation detection thresholds for sAM and sFM stimuli with age. The aged animals showed significantly lower response amplitudes for ramped stimuli but not for damped stimuli. Cross correlating the responses with the ramped, symmetric, or damped stimulus envelopes revealed a decreased fidelity in encoding envelope shapes with age. These results indicate that age related temporal processing deficits become apparent only with reduced modulation depths or when discriminating envelope shapes. This has implications for psychophysical or diagnostic testing as well as for constraining potential cellular and network mechanisms responsible for these deficits.	\N	\N
21724244	In a neuroimaging study focusing on young bilinguals, we explored the brains of bilingual and monolingual babies across two age groups (younger 4-6 months, older 10-12 months), using fNIRS in a new event-related design, as babies processed linguistic phonetic (Native English, Non-Native Hindi) and non-linguistic Tone stimuli. We found that phonetic processing in bilingual and monolingual babies is accomplished with the same language-specific brain areas classically observed in adults, including the left superior temporal gyrus (associated with phonetic processing) and the left inferior frontal cortex (associated with the search and retrieval of information about meanings, and syntactic and phonological patterning), with intriguing developmental timing differences: left superior temporal gyrus activation was observed early and remained stably active over time, while left inferior frontal cortex showed greater increase in neural activation in older babies notably at the precise age when babies' enter the universal first-word milestone, thus revealing a first-time focal brain correlate that may mediate a universal behavioral milestone in early human language acquisition. A difference was observed in the older bilingual babies' resilient neural and behavioral sensitivity to Non-Native phonetic contrasts at a time when monolingual babies can no longer make such discriminations. We advance the "Perceptual Wedge Hypothesis" as one possible explanation for how exposure to greater than one language may alter neural and language processing in ways that we suggest are advantageous to language users. The brains of bilinguals and multilinguals may provide the most powerful window into the full neural "extent and variability" that our human species' language processing brain areas could potentially achieve.	\N	\N
21728463	Gestalt phenomena are often so powerful that mere demonstrations can confirm their existence, but Gestalts have proven hard to define and measure. Here we outline a theory of basic Gestalts (TBG) that defines Gestalts as emergent features (EFs). The logic relies on discovering wholes that are more discriminable than are the parts from which they are built. These wholes contain EFs that can act as basic features in human vision. As context is added to a visual stimulus, a hierarchy of EFs appears. Starting with a single dot and adding a second yields the first two potential EFs: the proximity (distance) and orientation (angle) between the two dots. A third dot introduces two more potential EFs: symmetry and linearity; a fourth dot produces surroundedness. This hierarchy may extend to collinearity, parallelism, closure, and more. We use the magnitude of Configural Superiority Effects to measure the salience of EFs on a common scale, potentially letting us compare the strengths of various grouping principles. TBG appears promising, with our initial experiments establishing and quantifying at least three basic EFs in human vision.	\N	\N
21730860	Auditory temporal processing frequently appears more affected in old subjects than would be predicted by the degree of peripheral hearing loss, pointing to an age-dependent central processing deficit. In parallel, an age-dependent decline of inhibitory function has been demonstrated in the auditory pathway, suggesting a causal relationship between temporal processing and inhibition. Gabapentin has been specifically synthesized as a potential gamma-amino-butyric-acid (GABA) mimetic with the capability to cross the blood-brain barrier. Gabapentin treatment ameliorated tinnitus in a rat model and improved tinnitus annoyance in humans with acoustic trauma. Consequently, the present study evaluated the effect of gabapentin on auditory temporal processing in the gerbil model. Psychometric functions were collected for different test paradigms. (A) "Gap detection": The detection of a gap in the middle of a 800 msec broadband noise pulse was determined either at 15 or at 30 dB SL. (B) "Forward masking": The detection of a 20 msec probe stimulus following 2.5 msec after a 400 msec 40 dB SPL masker was determined with masker and probe frequency at 2.85 kHz. The effect of gabapentin was evaluated by collecting gap detection and forward masking functions before, during, and after treating gerbils with gabapentin doses of 115 or 350 mg/kg/day administered via drinking water. Data under different experimental conditions were collected for groups of 3 to 5 young (<2 years) and 6 to 10 old (>2 years) gerbils. Two-way analyses of variance for the factors age groups and treatment groups with subsequent pairwise comparisons for significant effects were used for the statistical evaluation of the data. For gap detection, mean thresholds were significantly increased in the group of old as compared with the young gerbils at 30 dB SL (young 2.0 msec; old 3.2 msec) and at 15 dB SL (young 2.9 msec; old 9.1 msec). Gabapentin had no significant effect on gap detection, and there was no significant interaction between age group and gabapentin treatment. Mean thresholds in the forward masking paradigm were significantly elevated in old (45.5 dB SPL) as compared with young (35.0 dB SPL) gerbils. Overall, gabapentin had no significant effect on masked thresholds; however, there was a significant interaction between treatment and age. Subsequent pairwise comparisons revealed no significant effect on masked thresholds in old gerbils but showed significantly elevated thresholds of young gerbils during 350 mg/kg gabapentin (38.3 dB SPL) compared with thresholds obtained in young gerbils before (32.3 dB SPL) and after (33.5 dB SPL) treatment. Gabapentin did not exert a therapeutic effect on impaired gap detection and forward masking in old gerbils. The lack of an effect of gabapentin on impaired auditory temporal processing in old gerbils and the finding of elevated masked thresholds in young gerbils can be reconciled with reports of only moderate GABAergic effects compared with other drugs (e.g., comparing elevation of GABA levels in the brain by gabapentin and vigabatrin) and effects due to binding of gabapentin to alpha-2-delta units of voltage-gated calcium channels.	\N	\N
21732223	Increasing the target-field luminance aids detection for a simultaneously presented black target disc and a black masking annulus. At an intermediate interval separating the onset of the target from the mask, increasing the target-field luminance reduces target detection. This decrease in performance occurs with both temporal and spatial forced choice tasks. With a spatial forced choice, an observer's performance can fall below chance. We associate below-chance performance with a brightness reversal of the black target disc, such that the target disc appears brighter than its surround. The occurrence of brightness reversals follows from our model of the Broca-Sulzer effect, and nonmonotone masking functions result from a generalization of luminance summation.	\N	\N
21736456	The aim of this study was to examine the influence of musical expertise in 9-year-old children on passive (as reflected by MMN) and active (as reflected by discrimination accuracy) processing of speech sounds. Musician and nonmusician children were presented with a sequence of syllables that included standards and deviants in vowel frequency, vowel duration, and VOT. Both the passive and the active processing of duration and VOT deviants were enhanced in musician compared with nonmusician children. Moreover, although no effect was found on the passive processing of frequency, active frequency discrimination was enhanced in musician children. These findings are discussed in terms of common processing of acoustic features in music and speech and of positive transfer of training from music to the more abstract phonological representations of speech units (syllables).	\N	\N
21736927	We used a new virtual program in two experiments to prepare subjects to perform the Morris water task (www.nesplora.com). The subjects were Psychology students; they were trained to locate a safe platform amidst the presence of four pinpoint landmarks spaced around the edge of the pool (i.e., two landmarks relatively near the platform and two landmarks relatively distant away from it). At the end of the training phase, we administered one test trial without the platform and recorded the amount of time that the students had spent in the platform quadrant. In Experiment 1, we conducted the test trial in the presence of one or two of the distant landmarks. When only one landmark was present during testing, performance fell to chance. However, the men outperformed the women when the two distant landmarks were both present. Experiment 2 replicated the previous results and extended it by showing that no sex differences exist when the searching process is based on the near landmarks. Both the men and the women had similarly good performances when the landmarks were present both individually and together. When present together, an addition effect was found. Far landmark tests favor configural learning processes, whereas near landmark tests favor elemental learning. Our findings suggest that other factors in addition to the use of directional cues can underlie the sex differences in the spatial learning process. Thus, we expand upon previous research in the field.	\N	\N
21752361	A controversial issue in the cognitive neuroscience of language is the question whether independent lexical representations need to be included in cognitive models. Recent models claim to account for the available data without including phonological or orthographic lexicons. These models base their lexical decision ("Is it a word or not?") either on familiarity of the input string or alternatively, on semantic information. These two alternatives were evaluated in a series of experiments with an individual suffering from word-meaning deafness. This is a rare disorder of auditory word comprehension which affects mapping of a word's phonology to its meaning. The participant, BB, was unaffected by the 'word-likeness' of nonwords with comparable accuracy for plausible and abstruse nonwords. She was further able to make lexical decisions despite her severe impairment in comprehending the word's meaning. Lexical and semantic processing were assessed on an item-specific basis providing a methodological advancement over previous studies. The comprehension tasks involved word-picture matching as well as definition tasks. The results suggest that BB's lexical decisions are based neither on familiarity of the input string nor on semantic information, which was largely unavailable. The only alternative are lexical representations on which she could base her decisions.	\N	\N
21753000	Feeling the beat and meter is fundamental to the experience of music. However, how these periodicities are represented in the brain remains largely unknown. Here, we test whether this function emerges from the entrainment of neurons resonating to the beat and meter. We recorded the electroencephalogram while participants listened to a musical beat and imagined a binary or a ternary meter on this beat (i.e., a march or a waltz). We found that the beat elicits a sustained periodic EEG response tuned to the beat frequency. Most importantly, we found that meter imagery elicits an additional frequency tuned to the corresponding metric interpretation of this beat. These results provide compelling evidence that neural entrainment to beat and meter can be captured directly in the electroencephalogram. More generally, our results suggest that music constitutes a unique context to explore entrainment phenomena in dynamic cognitive processing at the level of neural networks.	\N	\N
21756455	Cochlear implant (CI) devices are the choice of treatment for individuals with severe to profound hearing loss. The CI devices provide the opportunity for children who are deaf to perceive sound by electrical stimulation of the auditory nerve, with the goal of optimizing oral communication. A natural benefit of acquiring hearing using CIs is the ability to hear, and perhaps enjoy, music. Music is a non-verbal auditory stimulus and a powerful tool for transmitting emotion. Identifying emotional cues is an important part of normal social development and communication and thus music may play an important role in establishing these skills during development. To date, it is not known whether children who use cochlear implants to hear can identify the emotional content carried in music. Our objective in the present study was to determine whether children who have been deaf from infancy and are experienced CI users have acquired the ability to identify emotion in musical phrases. Study participants were 18 CI users (ages 7-13 years) who received right unilateral CIs (mean age at CI activation of 2.9 years) and 18 age-and gender-matched controls. Participants were asked to judge 32 brief musical excerpts as happy or sad by pointing to simple graphics of a smiling or frowning face. Children using CIs were able to correctly distinguish happy versus sad music well above chance levels, but performed more poorly on this task than their peers with typical hearing. Age at CI activation and time since CI activation were both uncorrelated with outcome measures. Children with CIs show the ability to perceive emotion in music but do so less accurately than typically hearing peers.	\N	\N
21756504	To describe the rate of occurrence of unsuspected decrease in sensitivity of the sound processor microphone and to evaluate its effect on the patient's audiological performance in terms of reduction in speech recognition scores. Speech processor microphones were tested by connecting the speech processor acoustic monitor circuit to a hearing aid analyzer. The response curves were compared with those obtained from fully working microphones. During a 6-month investigation period, microphone response curves were measured from a group of cochlear implant recipients who had not reported any problems. Despite the absence of any subjective problem, some microphones were found to show a loss of sensitivity. Their users, aged between 4 and 67 years, were tested both with the defective and a working microphone in order to calculate the correlation between the degree of microphone failure and the decline in audiological performance. To quantify the effect of microphone failure, patients' speech recognition skills were measured by live voice connected discourse tracking series administered in different conditions and by recorded sentences lists. A total of 120 apparently fully functioning sound processors were tested in the investigation: 33 (27.5%) were affected by a subjectively unreported sensitivity decrease. Speech-tracking scores correlated significantly with the loss of microphone sensitivity in all test conditions (r = 0.69-0.77, P < 0.05). A high degree of correlation was also found for speech audiometry tests (r = 0.70-0.73, P < 0.05). Microphone sensitivity loss affected speech recognition skills, especially without lip reading and in the presence of background noise. The results indicate that any reduction in sound processor microphone sensitivity causes a degree of hearing decline that negatively affects the cochlear recipient's clinical performance. Microphone faults are often unreported events, and their occurrence rate is underestimated. To establish that the microphone is providing correct input to the speech processor a standard control procedure, including technical and clinical checks, is needed in clinical practice.	\N	\N
21756841	The overall goal of the current study was to examine the relationships among uncompensated admittance (Ya) at ambient pressure extracted from tympanograms, energy reflectance (ER) measures at ambient pressure from wideband acoustic transfer functions (WATF), and distortion product otoacoustic emissions (DPOAEs). If WATF measures of Ya are comparable to tympanometric measures of Ya at ambient pressure, it would be further evidence that the two systems provide comparable information at ambient pressure. Such a relationship could be used as a cross-check or validation for WATF measures and support the use of WATFs in lieu of tympanograms in some applications. Finally, if WATF measures of Ya and/or ER at DPOAE stimulus frequencies can account for some of the variability observed in DPOAE levels and/or signal-to-noise ratios (SNRs) in ears with normal hearing, the relationships could be used to improve hearing screening procedures. The hypotheses were as follows: (1) measures of Ya at ambient pressure are significantly correlated as measured with tympanometric and WATF procedures and (2) measures of Ya and ER at DPOAE stimulus frequencies are significantly correlated with DPOAE level and SNR. Repeated measures in human adults. Forty ears of 20 adults with normal hearing and middle ear function were included in the final sample. Tympanograms were obtained using probe frequencies of 226, 678, and 1000 Hz; WATFs were obtained using a click probe, and DPOAEs were elicited with f2's of 1000, 2000, and 4000 Hz. A repeated measures analysis of variance (RM-ANOVA) was completed to identify significant differences between ears and among probe frequencies for Ya measured at ambient pressure from the Tympstar and for Ya measured at the three closest frequencies on the WATFs. Lines were fit to the comparison of Ya from the Tympstar and WATF, and percent variance accounted for (r2) was calculated. Ya and ER were extracted at all stimulus frequencies that were used to elicit DPOAEs and were compared to DPOAE levels and SNRs. RM-ANOVAs were completed to identify any significant differences in DPOAE level and SNR between ears and among f2 conditions. Lines were fit to the comparison of Ya and ER measures at f1 and f2 with the DPOAE levels and SNRs. The relationship between behavioral air conduction threshold at each f2 and DPOAE level (and SNR) was examined with regression analysis. Ya was significantly correlated between the tympanometric and WATF measures at all three probe-tone frequencies. Ya and ER at f1 and f2 were significantly correlated with DPOAE level for f2 = 4000 Hz. The implications are as follows: (1) WATFs, which can be obtained with the same probe microphone system as DPOAEs, could be used as a supplement to tympanometry in a diagnostic test battery, and the relationship between Ya measured on the two systems could be used for verification, and (2) Ya and ER measures from WATFs at both DPOAE stimulus frequencies account for some of the variability observed in DPOAE levels at f2 = 4000 Hz in normal ears.	\N	\N
21760512	Good test-retest reliability of high frequency (≥ 8 kHz) pure-tone audiometry (HFPTA) is essential to detect significant changes in hearing threshold caused by ototoxicity. While the test-retest reliability of HFPTA in adults has been extensively studied, such investigations in children are scant. This study aimed to evaluate the test-retest reliability of the HFPTA in normal-hearing children with particular reference to the criteria for ototoxicity. Participants were 125 children aged between 4 and 13 yr, with normal hearing in the 0.25 to 4 kHz range and normal tympanometric findings. The participants were divided into three age groups, 4 to 6 yr (16M; 16F); 7 to 9 yr (22M; 30F); and 10 to 13 yr (24M; 17F), for investigating possible age effects in the test-retest reliability of HFPTA. The instrumentation for the HFPTA procedure was an Interacoustics AC40 audiometer with Koss R/80 high-frequency headphones, calibrated to meet Australian standards. Hearing thresholds at 8, 9, 10, 11.2, 12.5, 14, and 16 kHz were measured in a sound-treated chamber using a modified Hughson-Westlake procedure with a 5 dB step size. Testing began with an ear and test frequency selected at random; the subsequent test frequencies were randomly selected. After acquisition of hearing threshold data at all frequencies, the other ear was tested using the same procedure. After the first HFPTA test, the headphones were removed and carefully replaced. A second HFPTA test was performed with the ear order reversed. The order of testing the ear for the next participant was reversed. Good test-retest reliability of HFPTA was achieved with no significant difference in mean HFPTA thresholds across test and retest conditions for all age groups. An age effect in the test-retest reliability of HFPTA was evident with the 4- to 6-yr-old, 7- to 9-yr-old, and 10- to 13-yr-old children demonstrating normal variability of thresholds (within ±10 dB) in 89.9%, 93.0%, and 97% of ears tested, respectively. When the variability of test-retest thresholds was assessed at each frequency, the 4 to 6 yr group showed significantly lower percentage of normal variability at 14 kHz. In identifying significant deterioration of hearing thresholds across test-retest conditions in relation to the ASHA (1994) ototoxicity criteria, the three age groups (youngest to oldest) demonstrated false-positive rates of 24.6%, 11%, and 7.6%, respectively. : Overall, this study demonstrated high test-retest reliability of HFPTA in all but the 4 to 6 yr group. With a false-positive rate of 24.6% for ototoxicity for the youngest group, it is recommended that the HFPTA should not be used alone in assessing the possibility of a genuine threshold shift for this age group. If possible, the HFPTA should be supplemented with an objective test of auditory function to confirm the diagnosis. For children aged 7 yr or older, the HFPTA test is promising as a useful tool to identify hearing impairment in the extended high-frequency range (>8 kHz). However, interpretation of HFPTA findings in serial testing for monitoring hearing in a child should be made with due attention being given to the frequency of the stimulus, age of the child, and the associated nonzero false-positive rates.	\N	\N
21763342	During the last decades music neuroscience has become a rapidly growing field within the area of neuroscience. Music is particularly well suited for studying neuronal plasticity in the human brain because musical training is more complex and multimodal than most other daily life activities, and because prospective and professional musicians usually pursue the training with high and long-lasting commitment. Therefore, music has increasingly been used as a tool for the investigation of human cognition and its underlying brain mechanisms. Music relates to many brain functions like perception, action, cognition, emotion, learning and memory and therefore music is an ideal tool to investigate how the human brain is working and how different brain functions interact. Novel findings have been obtained in the field of induced cortical plasticity by musical training. The positive effects, which music in its various forms has in the healthy human brain are not only important in the framework of basic neuroscience, but they also will strongly affect the practices in neuro-rehabilitation.	\N	\N
21769535	Previous work has demonstrated that the ability to keep track of moving objects is improved when the objects have unique visual features, such as color or shape. In the present study, we investigated how orientation information is used during the tracking of objects. Orientation is an interesting feature to explore in moving objects because it is directional and is often informative of the direction of motion. Most objects move forward, in the direction they are oriented. In the present experiments, participants tracked a subset of moving isosceles triangles whose orientations were constant, related, or unrelated to the direction of motion. In the standard multiple object tracking (MOT) task, tracking performance improved when orientations were unique and remained constant, but not when orientation and direction of motion were aligned. In the target recovery task, in which MOT was interrupted by a brief blanking of the display, performance did improve when orientation and direction were aligned. In the final experiment, results showed that orientation was not used before the blank to predict future target locations, but was instead used after the blank. We concluded that people use orientation to compare a stored representation to target position for recovery of lost targets.	\N	\N
21771217	There is strong evidence that bilinguals have a deficit in speech perception for their second language compared with monolingual speakers under unfavourable listening conditions (e.g., noise or reverberation), despite performing similarly to monolingual speakers under quiet conditions. This deficit persists for speakers highly proficient in their second language and is greater in those who learned the language later in life. These findings have important educational implications because the number of multilingual children is increasing worldwide, and many of these children are being taught in their non-native language under poor classroom acoustic conditions. The performance of monolingual, bilingual and trilingual speakers on an English speech perception task was examined in both quiet and noisy conditions. Trilingual performance was compared with that of monolingual and bilingual speakers. Monolingual speakers of English and early bilingual and trilingual speakers (i.e., acquired English as a second/third language before the age of 6 years) were recruited. Their fluency in English was tested by interview and by a questionnaire assessing their knowledge and use of the language. Audiological evaluation confirmed normal hearing in all participants. English speech perception was tested in quiet and in different levels of noise (50, 55, 60, 65 and 70 dB SPL) using the Speech Perception in Noise (SPIN) Test. Bilingual and trilingual listeners performed similarly to monolingual listeners in quiet conditions, but their performance declined more rapidly in noise and was significantly poorer at 65 and 70 dB SPL. Trilingual listeners performed less well than bilinguals at these noise levels, but not significantly so. A subgroup of five bilingual speakers who learned Arabic and English simultaneously since birth were poorer at higher levels of noise than monolinguals, but not significantly so. The results replicate previous findings of poorer speech perception in noise with bilingual speakers compared with monolinguals and extend the findings to trilingual speakers.	\N	\N
21786870	The ability to obtain reliable phonetic information from a talker's face during speech perception is an important skill. However, lip-reading abilities vary considerably across individuals. There is currently a lack of normative data on lip-reading abilities in young normal-hearing listeners. This letter describes results obtained from a visual-only sentence recognition experiment using CUNY sentences and provides the mean number of words correct and the standard deviation for different sentence lengths. Additionally, the method for calculating T-scores is provided to facilitate the conversion between raw and standardized scores. This metric can be utilized by clinicians and researchers in lip-reading studies. This statistic provides a useful benchmark for determining whether an individual's lip-reading score falls within the normal range, or whether it is above or below this range.	\N	\N
21786905	Spectral ripple discrimination thresholds were measured in 15 cochlear-implant users with broadband (350-5600 Hz) and octave-band noise stimuli. The results were compared with spatial tuning curve (STC) bandwidths previously obtained from the same subjects. Spatial tuning curve bandwidths did not correlate significantly with broadband spectral ripple discrimination thresholds but did correlate significantly with ripple discrimination thresholds when the rippled noise was confined to an octave-wide passband, centered on the STC's probe electrode frequency allocation. Ripple discrimination thresholds were also measured for octave-band stimuli in four contiguous octaves, with center frequencies from 500 Hz to 4000 Hz. Substantial variations in thresholds with center frequency were found in individuals, but no general trends of increasing or decreasing resolution from apex to base were observed in the pooled data. Neither ripple nor STC measures correlated consistently with speech measures in noise and quiet in the sample of subjects in this study. Overall, the results suggest that spectral ripple discrimination measures provide a reasonable measure of spectral resolution that correlates well with more direct, but more time-consuming, measures of spectral resolution, but that such measures do not always provide a clear and robust predictor of performance in speech perception tasks.	\N	\N
21790494	Three experiments tested how the physical format and information content of forward and backward masks affected the extent of visual pattern masking. This involved using different types of forward and backward masks with target discrimination measured by percentage correct in the first experiment (with a fixed target duration) and by an adaptive threshold procedure in the last two. The rationale behind the manipulation of the content of the masks stemmed from masking theories emphasizing attentional and/or conceptual factors rather than visual ones. Experiment 1 used word masks and showed that masking was reduced (a masking reduction effect) when the forward and backward masks were the same word (although in different case) compared to when the masks were different words. Experiment 2 tested the extent to which a reduction in masking might occur due to the physical similarity between the forward and backward masks by comparing the effect of the same content of the masks in the same versus different case. The result showed a significant reduction in masking for same content masks but no significant effect of case. The last experiment examined whether the reduction in masking effect would be observed with nonword masks--that is, having no high-level representation. No reduction in masking was found from same compared to different nonword masks (Experiment 3). These results support the view that the conscious perception of a rapidly displayed target stimulus is in part determined by high-level perceptual/cognitive factors concerned with masking stimulus grouping and attention.	\N	\N
21796943	The spray drying technique was used to obtain the roxithromycin containing microcapsules with high taste masking efficiency. Eudragit L30D-55 was chosen as a barrier coating. The taste was evaluated by an electronic tongue, and taste-masking effect in water lasted at least several dozen hours.	\N	\N
21799207	We investigated training-related improvements in listening in noise and the biological mechanisms mediating these improvements. Training-related malleability was examined using a program that incorporates cognitively based listening exercises to improve speech-in-noise perception. Before and after training, auditory brainstem responses to a speech syllable were recorded in quiet and multitalker noise from adults who ranged in their speech-in-noise perceptual ability. Controls did not undergo training but were tested at intervals equivalent to the trained subjects. Trained subjects exhibited significant improvements in speech-in-noise perception that were retained 6 months later. Subcortical responses in noise demonstrated training-related enhancements in the encoding of pitch-related cues (the fundamental frequency and the second harmonic), particularly for the time-varying portion of the syllable that is most vulnerable to perceptual disruption (the formant transition region). Subjects with the largest strength of pitch encoding at pretest showed the greatest perceptual improvement. Controls exhibited neither neurophysiological nor perceptual changes. We provide the first demonstration that short-term training can improve the neural representation of cues important for speech-in-noise perception. These results implicate and delineate biological mechanisms contributing to learning success, and they provide a conceptual advance to our understanding of the kind of training experiences that can influence sensory processing in adulthood.	\N	\N
21801242	We investigated the effect of long-term musical training on the time course of development of neuronal representations within the auditory cortex by means of magnetoencephalography. In musicians but not in nonmusicians, pre-attentive encoding of a complex regularity within a tone sequence was evident by a constant increase of the pattern mismatch negativity within < 10 min. The group difference was more pronounced in the left hemisphere, indicating stronger plastic changes in its structures supporting temporal analysis and sound pattern encoding. The results suggest an effect of long-term musical training on short-term auditory learning processes. This has implications not only for cognitive neuroscience in showing how short-term and long-term neuronal plasticity can interact within the auditory cortex, but also for educational and clinical applications of implicit auditory learning where beneficial effects of (musical) experience might be exploited.	\N	\N
21805200	It has recently been shown that spatially uninformative sounds can cause a visual stimulus to pop out from an array of similar distractor stimuli when that sound is presented in temporal proximity to a feature change in the visual stimulus. Until now, this effect has predominantly been demonstrated by using stationary stimuli. Here, we extended these results by showing that auditory stimuli can also improve the sensitivity of visual motion change detection. To accomplish this, we presented moving visual stimuli (small dots) on a computer screen. At a random moment during a trial, one of these stimuli could abruptly move in an orthogonal direction. Participants' task was to indicate whether such an abrupt motion change occurred or not by making a corresponding button press. If a sound (a short 1,000 Hz tone pip) co-occurred with the abrupt motion change, participants were able to detect this motion change more frequently than when the sound was not present. Using measures derived from signal detection theory, we were able to demonstrate that the effect on accuracy was due to increased sensitivity rather than to changes in response bias.	\N	\N
21817932	The transmission of fine structure information to cochlear implant users is an expanding area of research. Previous studies comparing the fine structure processing (FSP) speech coding strategy to the envelope-based continuous interleaved sampling (CIS) strategy indicated improved speech perception when using the fine structure strategy. Those investigations were performed with an extended frequency spectrum in the low frequencies together with the fine structure strategy. The current study addresses the question whether these improvements are due to the presentation of fine structure per se or rather the extended frequency spectrum. Hence, this cross over study compares the two strategies using an identical frequency spectrum. Randomized crossover study. 31 patients were randomly assigned to two groups. One group was fitted with a CIS map for 4 weeks, tested and subsequently fitted with a FSP map for 4 weeks. The other group followed the same pattern in reverse. Test material consisted of sentence tests in noise, monosyllables in quiet and melody recognition. No statistical significance was noted between the different speech coding strategies at an identical frequency spectrum. This study shows that there is no difference in speech perception with FSP compared to CIS at an extended frequency spectrum. Therefore, the extended frequency spectrum in the low frequencies might explain a benefit of FSP observed in previous studies.	\N	\N
21818631	When a single brief flash is accompanied by two auditory beeps, participants often report perceiving two flashes. The present experiment examined whether the perception of illusory redundant flashes can result in faster responses as compared to the perception of a single flash, because previous research has shown such a redundancy gain for physical stimuli. To this end, participants were asked to respond as rapidly as possible to the onset of any flash. Following their response, they additionally indicated whether they perceived a single flash or a double flash. Most importantly, we observed significant shorter reaction times in response to redundant flashes, irrespective of whether they were physically presented or illusorily perceived. Taken together, our results suggest that an illusory percept can affect simple reaction time in much the same manner as the corresponding physical stimulation.	\N	\N
21826003	A number of clinical measures of directivity, including the front-to-back ratio (FBR) and front-to-side ratio (FSR), have been suggested to audiologists to monitor the functionality of hearing aids with directional microphones. These suggestions, however, are based on the assumption that directivity measured clinically changes monotonically when compared with changes measured using the directivity index (DI) and perceptual directional benefit. The objective of the present study was to empirically examine this assumption. In addition, the reliability of the clinical directivity measure was estimated to establish a referral threshold for defective directional microphone hearing aids. The directivity of the directional microphones of two behind-the-ear hearing aids was systematically degraded by plugging the microphone ports. The directivity was measured using four clinical measures: the FBR and FSR performed in the test chamber of a hearing aid analyzer and in sound field. Each measure was repeated four times in each directivity-degraded condition. The degraded directivity was also assessed using the DI measure in an anechoic chamber. The perceptual directional benefit in each directivity-degraded condition was obtained by testing 10 hearing-impaired adults in a sound field with diffuse noise using the Hearing in Noise Test (HINT). The results of the DI and HINT measures showed strong correlation between the two FSRs (test chamber and sound field), while the two FBRs showed no correlation. The directivity generated by the FBRs could remain unchanged even when the directional microphone had lost more than 50% of its directivity. The results further indicated that the measures performed in the sound field were more reliable than those performed in the test chamber. Based on the results of the reliability measures, a 30% change in directivity was suggested as the referral threshold signifying defective directional systems. Because the FSR predicts the DI and HINT measurements more accurately than does the FBR, it is suggested that clinicians use the FSR to monitor hearing aid directivity. By using the FSR measure and informed by the suggested referral threshold, clinicians would be able to correctly identify defective directional microphone hearing aids at an early stage, rather than at a point when the directivity has been diminished completely or even reversed.	\N	\N
21826552	Strong cross-modal interactions exist between visual and auditory processing. The relative contributions of perceptual versus decision-related processes to such interactions are only beginning to be understood. We used methodological and statistical approaches to control for potential decision-related contributions such as response interference, decisional criterion shift, and strategy selection. Participants were presented with rising-, falling-, and constant-amplitude sounds and were asked to detect change (increase or decrease) in sound amplitude while ignoring an irrelevant visual cue of a disk that grew, shrank, or stayed constant in size. Across two experiments, testing context was manipulated by varying the grouping of visual cues during testing, and cross-modal congruency showed independent perceptual and decision-related effects. Whereas a change in testing context greatly affected criterion shifts, cross-modal effects on perceptual sensitivity remained relatively consistent. In general, participants were more sensitive to increases in sound amplitude and less sensitive to sounds paired with dynamic visual cues. As compared with incongruent visual cues, congruent cues enhanced detection of amplitude decreases, but not increases. These findings suggest that the relative contributions of perceptual and decisional processing and the impacts of these processes on cross-modal interactions can vary significantly depending on asymmetries in within-modal processing, as well as consistencies in cross-modal dynamics.	\N	\N
21833562	A bone-anchored hearing aid (Baha) is used in patients with single-sided sensorineural deafness (SSD) to overcome the head shadow effect. Of all the patients with SSD, treated at our hospital, 196 patients used a Baha on trial between November 2001 and April 2010. The objective of this study is to evaluate what factors determine the decision of a SSD patient whether or not to opt for a Baha device following a Baha trial period. 196 patients with SSD were enrolled for a trial period of 2 weeks at the Antwerp University Hospital, a tertiary referral centre. 93% of these patients suffered from an acquired hearing loss. 44% of all the patients (87/196) chose to wear a Baha device after the trail period, either on an abutment or on a headband. The collected data were analysed to determine correlations between the decision of a patient following a Baha trial period on the one hand, and Fletcher Index ipsi- and contralaterally, bone conduction hearing thresholds at the better hearing ear, aetiology, age at the start of the trial period, duration of hearing loss at the start of the trial period and the type of device used during the trial period, on the other hand. Although 66% of all the patients (109/196) declined the Baha after a trial, reasons not to choose a Baha were diverse and no crucial factors could be found that determine the success of a Baha trial period. Lack of improvement concerning speech understanding in noise was the most important reason mentioned by patients who declined the Baha. The authors advocate that all patients, suffering from SSD, should be offered the opportunity to try a Baha device as no factors could be found that determine the decision of a patient following the trial period.	\N	\N
21844339	"Normal hearing" is typically defined by threshold audibility, even though everyday communication relies on extracting key features of easily audible sound, not on sound detection. Anecdotally, many normal-hearing listeners report difficulty communicating in settings where there are competing sound sources, but the reasons for such difficulties are debated: Do these difficulties originate from deficits in cognitive processing, or differences in peripheral, sensory encoding? Here we show that listeners with clinically normal thresholds exhibit very large individual differences on a task requiring them to focus spatial selective auditory attention to understand one speech stream when there are similar, competing speech streams coming from other directions. These individual differences in selective auditory attention ability are unrelated to age, reading span (a measure of cognitive function), and minor differences in absolute hearing threshold; however, selective attention ability correlates with the ability to detect simple frequency modulation in a clearly audible tone. Importantly, we also find that selective attention performance correlates with physiological measures of how well the periodic, temporal structure of sounds above the threshold of audibility are encoded in early, subcortical portions of the auditory pathway. These results suggest that the fidelity of early sensory encoding of the temporal structure in suprathreshold sounds influences the ability to communicate in challenging settings. Tests like these may help tease apart how peripheral and central deficits contribute to communication impairments, ultimately leading to new approaches to combat the social isolation that often ensues.	\N	\N
21860975	The electrical stimulation generated by the Cochlear Implant (CI) may improve the neural synchrony and hence contribute to the development of auditory skills in patients with Auditory Neuropathy/Auditory Dyssynchrony (AN/AD). Prospective cohort cross-sectional study to evaluate the auditory performance and the characteristics of the electrically evoked compound action potential (ECAP) in 18 children with AN/AD and cochlear implants. The auditory perception was evaluated by sound field thresholds and speech perception tests. To evaluate ECAP's characteristics, the threshold and amplitude of neural response were evaluated at 80 Hz and 35 Hz. No significant statistical difference was found concerning the development of auditory skills. The ECAP's characteristics differences at 80 and 35 Hz stimulation rate were also not statistically significant. The CI was seen as an efficient resource to develop auditory skills in 94% of the AN/AD patients studied. The auditory perception benefits and the possibility to measure ECAP showed that the electrical stimulation could compensate for the neural dyssynchrony caused by the AN/AD. However, a unique clinical procedure cannot be proposed at this point. Therefore, a careful and complete evaluation of each AN/AD patient before recommending a Cochlear Implant is advised. Clinical Trials: NCT01023932.	\N	\N
21860978	Hearing has an important role in human development and social adaptation in blind people. To evaluate the performance of temporal auditory processing in blind people; to characterize the temporal resolution ability; to characterize the temporal ordinance ability and to compare the performance of the study population in the applied tests. Fifteen blind adults participated in this study. A cross-sectional study was undertaken; approval was obtained from the Pernambuco Catholic University Ethics Committee, no. 003/2008. Temporal auditory processing was excellent--the average composed threshold in the original RGDT version was 4. 98 ms; it was 50 ms for all frequencies in the expanded version. PPS and DPS results ranged from 95% to 100%. There were no quantitative differences in the comparison of tests; but oral reports suggested that the original RGDT original version was more difficult. The study sample performed well in temporal auditory processing; it also performed well in temporal resolution and ordinance abilities.	\N	\N
21862680	To evaluate potential contributions of broadband spectral integration in the perception of static vowels. Specifically, can the auditory system infer formant frequency information from changes in the intensity weighting across harmonics when the formant itself is missing? Does this type of integration produce the same results in the lower (first formant [F1]) and higher (second formant [F2]) regions? Does the spacing between the spectral components affect a listener's ability to integrate the acoustic cues? Twenty young listeners with normal hearing identified synthesized vowel-like stimuli created for adjustments in the F1 region (/Λ/-/α/, /i/-/ε/) and in the F2 region (/Λ/-/æ/). There were 2 types of stimuli: (a) 2-formant tokens and (b) tokens in which 1 formant was removed and 2 pairs of sine waves were inserted below and above the missing formant; the intensities of these harmonics were modified to cause variations in their spectral center of gravity (COG). The COG effects were tested over a wide range of frequencies. Obtained patterns were consistent with calculated changes to the spectral COG, in both the F1 and F2 regions. The spacing of the sine waves did not affect listeners' responses. The auditory system may perform broadband integration as a type of auditory wideband spectral analysis.	\N	\N
21877769	This study investigated the ability to use temporal-envelope (E) cues in a consonant identification task when presented within one or two frequency bands. Syllables were split into five bands spanning the range 70-7300 Hz with each band processed to preserve E cues and degrade temporal fine-structure cues. Identification scores were measured for normal-hearing listeners in quiet for individual processed bands and for pairs of bands. Consistent patterns of results were obtained in both the single- and dual-band conditions: identification scores increased systematically with band center frequency, showing that E cues in the higher bands (1.8-7.3 kHz) convey greater information.	\N	\N
21877806	A functional simulation of hearing loss was evaluated in its ability to reproduce the temporal masking functions for eight listeners with mild to severe sensorineural hearing loss. Each audiometric loss was simulated in a group of age-matched normal-hearing listeners through a combination of spectrally-shaped masking noise and multi-band expansion. Temporal-masking functions were obtained in both groups of listeners using a forward-masking paradigm in which the level of a 110-ms masker required to just mask a 10-ms fixed-level probe (5-10 dB SL) was measured as a function of the time delay between the masker offset and probe onset. At each of four probe frequencies (500, 1000, 2000, and 4000 Hz), temporal-masking functions were obtained using maskers that were 0.55, 1.0, and 1.15 times the probe frequency. The slopes and y-intercepts of the masking functions were not significantly different for listeners with real and simulated hearing loss. The y-intercepts were positively correlated with level of hearing loss while the slopes were negatively correlated. The ratio of the slopes obtained with the low-frequency maskers relative to the on-frequency maskers was similar for both groups of listeners and indicated a smaller compressive effect than that observed in normal-hearing listeners.	\N	\N
21877812	The auditory system takes advantage of early reflections (ERs) in a room by integrating them with the direct sound (DS) and thereby increasing the effective speech level. In the present paper the benefit from realistic ERs on speech intelligibility in diffuse speech-shaped noise was investigated for normal-hearing and hearing-impaired listeners. Monaural and binaural speech intelligibility tests were performed in a virtual auditory environment where the spectral characteristics of ERs from a simulated room could be preserved. The useful ER energy was derived from the speech intelligibility results and the efficiency of the ERs was determined as the ratio of the useful ER energy to the total ER energy. Even though ER energy contributed to speech intelligibility, DS energy was always more efficient, leading to better speech intelligibility for both groups of listeners. The efficiency loss for the ERs was mainly ascribed to their altered spectrum compared to the DS and to the filtering by the torso, head, and pinna. No binaural processing other than a binaural summation effect could be observed.	\N	\N
21878379	Otoacoustic emission (OAE) amplitude can be reduced by acoustic stimulation. This effect is produced by the medial olivocochlear (MOC) reflex. Past studies have shown that the MOC reflex is related to listening in noise and attention. In the present study, the relationship between strength of the contralateral MOC reflex and masked threshold was investigated in 19 adults. Detection thresholds were determined for 1000-Hz, 300-ms tone presented simultaneously with one repetition of a 300-ms masker in an ongoing train of masker bursts. Three masking conditions were tested: 1) broadband noise 2) a fixed-frequency 4-tone complex masker and 3) a random-frequency 4-tone complex masker. Broadband noise was expected to produce energetic masking and the tonal maskers were expected to produce informational masking in some listeners. DPOAEs were recorded at fine frequency intervals from 500 to 4000 Hz, with and without contralateral acoustic stimulation. MOC reflex strength was estimated as a reduction in baseline level and a shift in frequency of DPOAE fine-structure maxima near 1000-Hz. MOC reflex and psychophysical testing were completed in separate sessions. Individuals with poorer thresholds in broadband noise and in random-frequency maskers were found to have stronger MOC reflexes.	\N	\N
21886362	Event-related potential (ERPs) provide an exquisite means to monitor the extent of processing of external stimulus input during sleep. The processing of relatively high intensity stimuli has been well documented. Sleep normally occurs in much less noisy environments. The present study therefore employed ERPs to examine the extent of processing of very low intensity (near-hearing threshold) stimuli. Brief duration 1000 Hz auditory tone bursts varying in intensity at random from -5 to +45 dB from normative hearing level (nHL) in 10 dB steps were presented every 1.5 to 2.5 s when the subject was awake and reading a book and again during all-night sleep. n = 10 healthy young adults. In the waking state, the auditory stimuli elicited a negative-going deflection, N1, peaking at about 100 ms, followed by a smaller positivity, P2, peaking at about 180 ms. N1-P2 gradually decreased in amplitude with decreases in stimulus intensity and remained visible at near-hearing threshold levels. During NREM sleep, the amplitude of N1 was at baseline level and was reduced to only 15% to 20% of its waking amplitude during REM sleep. P2 was much larger in sleep than in wakefulness. Importantly, during sleep, P2 could be reliably elicited by the auditory stimuli to within 15 dB of threshold. During NREM, a large amplitude negativity peaking at about 350 ms was elicited by the higher intensity stimuli. This N350 was much reduced in amplitude during REM sleep. A significant N350 was not, however, elicited when stimuli intensity levels were below 25 dB nHL. Auditory stimuli that are only slightly above hearing threshold appear to be processed extensively during a 200 to 400 ms interval in both NREM and REM sleep. The nature of this processing is, however, very different compared to the waking state.	\N	\N
21889805	Auditory training has been advocated as a management strategy for children with hearing, listening or language difficulties. Because poor speech-in-noise perception is commonly reported, previous research has focused on the use of complex (word/sentence) stimuli as auditory training material to improve sentence-in-noise perception. However, some evidence suggests that engagement with the training stimuli is more important than the type of stimuli used for training. The aim of this experiment was to assess if sentence-in-noise perception could be improved using simpler auditory training stimuli. We recruited 41 typically developing, normal-hearing children aged 8-10 years divided into four groups. Groups 1-3 trained over 4 weeks (12 × 30 min sessions) on either: (1) pure-tone frequency discrimination (FD), (2) FD in a modulated noise (FDN) or, (3) mono-syllabic words in a modulated noise (WN). Group 4 was an untrained Control. In the training tasks, either tone frequency (Group 1), or tone (Group 2) or speech (Group 3) level was varied adaptively. All children completed pre- and post-training tests of sentence perception in modulated (SMN) and unmodulated (SUN) noise and a probe measure of each training task. All trained groups improved significantly on the trained tasks. Transfer of training occurred between FDN training and FD, WN and SMN testing, and between WN training and SMN testing. A significant performance suppression on the SUN test resulted from FD and FDN training. The pattern of training-induced improvement, relative to Controls, suggests that transfer of training is more likely when some stimulus dimensions (tone frequency, speech, modulated noise) are shared between training tasks and outcomes. This and the finding of suppressed post-training performance, relative to Controls, between tasks not sharing a stimulus dimension both favour the use of outcome-specific material for auditory training.	\N	\N
21895071	Human listening tests were conducted to investigate if participants could distinguish between samples of target echoes and clutter obtained from a broadband active sonar experiment. For each echo, the listeners assigned a rating based on how confident they were that it was a target echo or clutter. The measure of performance was the area under the binormal receiver-operating-characteristic (ROC) curve, A(z). The mean performance was A(z)=0.95 ± 0.04 when signals were presented with their full available acoustic bandwidth of approximately 0-2 kHz. It was A(z)=0.77 ± 0.08 when the bandwidth was reduced to 0.5-2 kHz. The error bounds are stated as 95% confidence intervals. These results show that the listeners could definitely hear differences, but their performance was significantly degraded when the low-frequency signal information was removed. The performance of an automatic aural classifier was compared against this human-performance baseline. Results of statistical tests showed that it outperformed 2 of 13 listeners and 5 of 9 human listeners in the full-bandwidth and reduced-bandwidth tests, respectively, and performed similarly to the other listeners. Given its performance, the automatic aural classifier may prove beneficial to Navy sonar systems.	\N	\N
21895094	In cochlear implants (CIs), simultaneous or sequential stimulation of adjacent electrodes can produce intermediate pitch percepts between those of the component electrodes. However, it is unclear whether simultaneous and sequential virtual channels (VCs) can be discriminated. In this study, CI users were asked to discriminate simultaneous and sequential VCs; discrimination was measured for monopolar (MP) and bipolar + 1 stimulation (BP + 1), i.e., relatively broad and focused stimulation modes. For sequential VCs, the interpulse interval (IPI) varied between 0.0 and 1.8 ms. All stimuli were presented at comfortably loud, loudness-balanced levels at a 250 pulse per second per electrode (ppse) stimulation rate. On average, CI subjects were able to reliably discriminate between sequential and simultaneous VCs. While there was no significant effect of IPI or stimulation mode on VC discrimination, some subjects exhibited better VC discrimination with BP + 1 stimulation. Subjects' discrimination between sequential and simultaneous VCs was correlated with electrode discrimination, suggesting that spatial selectivity may influence perception of sequential VCs. To maintain equal loudness, sequential VC amplitudes were nearly double those of simultaneous VCs, presumably resulting in a broader spread of excitation. These results suggest that perceptual differences between simultaneous and sequential VCs might be explained by differences in the spread of excitation.	\N	\N
21895095	Three experiments were designed to examine temporal envelope processing by cochlear implant (CI) listeners. In experiment 1, the hypothesis that listeners' modulation sensitivity would in part determine their ability to discriminate between temporal modulation rates was examined. Temporal modulation transfer functions (TMTFs) obtained in an amplitude modulation detection (AMD) task were compared to threshold functions obtained in an amplitude modulation rate discrimination (AMRD) task. Statistically significant nonlinear correlations were observed between the two measures. In experiment 2, results of loudness-balancing showed small increases in the loudness of modulated over unmodulated stimuli beyond a modulation depth of 16%. Results of experiment 3 indicated small but statistically significant effects of level-roving on the overall gain of the TMTF, but no impact of level-roving on the average shape of the TMTF across subjects. This suggested that level-roving simply increased the task difficulty for most listeners, but did not indicate increased use of intensity cues under more challenging conditions. Data obtained with one subject, however, suggested that the most sensitive listeners may derive some benefit from intensity cues in these tasks. Overall, results indicated that intensity cues did not play an important role in temporal envelope processing by the average CI listener.	\N	\N
21912929	Previous research examining cross-modal conflicts in object recognition has often made use of animal vocalizations and images, which may be considered natural and ecologically valid, thus strengthening the association in the congruent condition. The current research tested whether the same cross-modal conflict would exist for man-made object sounds as well as comparing the speed and accuracy of auditory processing across the two object categories. Participants were required to attend to a sound paired with a visual stimulus and then respond to a verification item (e.g., "Dog?"). Sounds were congruent (same object), neutral (unidentifiable image), or incongruent (different object) with the images presented. In the congruent and neutral condition, animals were recognized significantly faster and with greater accuracy than man-made objects. It was hypothesized that in the incongruent condition, no difference in reaction time or error rate would be found between animals and man-made objects. This prediction was not supported, indicating that the association between an object's sound and image may not be that disparate when comparing animals to man-made objects. The findings further support cross-modal conflict research for both the animal and man-made object category. The most important finding, however, was that auditory processing is enhanced for living compared to nonliving objects, a difference only previously found in visual processing. Implications relevant to both the neuropsychological literature and sound research are discussed.	\N	\N
21913927	In prior studies, we have used a conditional linkage between rare deviations in a regular sound pattern to determine if the auditory system can use the first deviation to anticipate the probable features of the second deviation (i.e., make a conditional inference). This study was designed to test two hypotheses about why the mismatch negativity (MMN) to a duration deviant sound seems more susceptible to conditional inference effects. The MMNs to duration and frequency glide deviant sounds were significantly smaller when their occurrence was conditionally linked to the identity of a prior deviant as opposed to when they occurred randomly in a sequence. Results provide support for the learned conditional inference interpretation of reduced MMN size to linked deviants. We discuss alternate explanations and conclude that conditional inference studies could provide insight into the dynamics of probability-based prediction in the auditory system.	\N	\N
21920411	Tinnitus is described as an auditory perception in the absence of any external sound source. Tinnitus loudness has been correlated to sustained high frequency gamma-band activity in auditory cortex. It remains unknown whether unilateral tinnitus is always generated in the left auditory cortex, irrespective of the side on which the tinnitus is perceived, or in the contralateral auditory cortex. In order to solve this enigma source localized electroencephalographic (EEG) recordings of a homogenous group of unilateral left and right-sided tinnitus patients presenting with noise-like tinnitus was analyzed. Based on a region of interest analysis, the most important result of this study is that tinnitus lateralization depended on the gamma-band activity of the contralateral parahippocampal area. As for the auditory cortex no differences were found between left-sided and right-sided tinnitus patients. However, in comparison to a control group both left and right-sided tinnitus patients had an increased gamma-band activity in both the left and right primary and secondary auditory cortex. Thus whereas in tinnitus the primary and secondary auditory cortices of both sides are characterized by increased gamma-band activity, the side on which the tinnitus is perceived relates to gamma-band activity in the contralateral parahippocampal area.	\N	\N
21926628	The purpose of this study was to determine the reliability of the electrophysiological binaural beat steady state response as a gauge of temporal fine structure coding, particularly as it relates to the aging auditory system. The hypothesis was that the response would be more robust in a lower, than in a higher, frequency region and in younger, than in older, adults. Two experiments were undertaken. The first measured the 40 Hz binaural beat steady state response elicited by tone pairs in two frequency regions: lower (390 and 430 Hz tone pair) and higher (810 and 850 Hz tone pair). Frequency following responses (FFRs) evoked by the tones were also recorded. Ten young adults with normal hearing participated. The second experiment measured the binaural beat and FFRs in older adults but only in the lower frequency region. Fourteen older adults with relatively normal hearing participated. Response metrics in both experiments included response component signal-to-noise ratio (F statistic) and magnitude-squared coherence. Experiment 1 showed that FFRs were elicited in both frequency regions but were more robust in the lower frequency region. Binaural beat responses elicited by the lower frequency pair of tones showed greater amplitude fluctuation within a participant than the respective FFRs. Experiment 2 showed that older adults exhibited similar FFRs to younger adults, but proportionally fewer older participants showed binaural beat responses. Age differences in onset responses were also observed. The lower prevalence of the binaural beat response in older adults, despite the presence of FFRs, provides tentative support for the sensitivity of this measure to age-related deficits in temporal processing. However, the lability of the binaural beat response advocates caution in its use as an objective measure of fine structure coding.	\N	\N
21928934	An experiment is reported that investigates the relation between the suffix effect and the effect of irrelevant sound on the serial recall of short sequences of spoken material. The main issue was whether there is an effect of irrelevant sound under articulatory suppression in the presence of a spoken suffix. As in Hanley and Bakopoulou (2003), the irrelevant sound comprised speech that was presented during the retention interval. When a spoken suffix appeared at the end of the list, a significant effect of irrelevant sound remained when participants were able to rehearse list items. However, it disappeared under articulatory suppression. The effects of irrelevant sound remained significant under suppression when the suffix was an auditory tone but was confined to the final position of the serial position curve. These results parallel those reported by Jones, Macken, and Nicholls (2004) and Jones, Hughes, and Macken (2006) when they examined the effect of articulatory suppression on the phonological similarity effect. The results are consistent with Jones et al.'s (2006, 2004) view that an acoustic-perceptual representation of the terminal list items is the source of the effects of irrelevant sound and phonological similarity when they occur in the presence of articulatory suppression.	\N	\N
21928935	Serial recall from working memory is known to be impaired by the presence of irrelevant background speech, but several prior studies have concluded that the magnitude of the impairment is independent of the phonological relationship between to-be-remembered (TBR) and to-be-ignored (TBI) sources of information. In the present study, we examined the influence of between-stream phonological similarity in serial recall while attending to a heretofore uncontrolled variable, the phonetic feature. We found that TBI items sharing many phonetic features with TBR items produced significantly stronger working-memory impairments than TBI items with minimal phonetic feature overlap. In addition, participants were more likely to report remembering incorrect items that incorporated phonological characteristics of the TBI stream in the high-overlap condition. These findings provide evidence for subphonemic between-stream interactions and suggest that multiple parallel processes contribute to the irrelevant speech effect. We propose that a 2-component model, which combines the assumptions of process- and content-based accounts for the irrelevant speech effect, offers the best explanation for these findings.	\N	\N
21930137	In daily communication, we often use indirect speech to convey our intention. However, little is known about the brain mechanisms that underlie the comprehension of indirect speech. In this study, we conducted a functional MRI experiment using a scenario reading task to compare the neural activity induced by an indirect reply (a type of indirect speech) and a literal sentence. Participants read a short scenario consisting of three sentences. The first two sentences explained the situation of the protagonists, whereas the third sentence had an indirect, literal, or unconnected meaning. The indirect reply condition primarily activated the bilateral fronto-temporal networks (Brodmann's Areas (BA) 47 and 21) and the dorso-medial prefrontal cortex (dmPFC). In the literal sentence condition, only the left fronto-temporal network (BA 45 and 21) and the dmPFC (posterior region) were activated. In addition, we found greater activation resulting from comprehension of an indirect reply than from literal sentence comprehension in the dmPFC, the left middle frontal area (BA 9), the bilateral inferior frontal area (BA 9/47), and the right middle temporal area (BA 21). Our findings indicate that the right and left fronto-temporal networks play a crucial role in detecting contextual violations, whereas the medial frontal cortex is important for generating inferences to make sense of remarks within a context.	\N	\N
21932257	To examine how musical expertise tunes the brain to subtle metric anomalies in an ecological musical context, we presented piano compositions ending on standard and deviant cadences (endings) to expert pianists and musical laymen, while high-density EEG was recorded. Temporal expectancies were manipulated by substituting standard "masculine" cadences at metrically strong positions with deviant, metrically unaccented, "feminine" cadences. Experts detected metrically deviant cadences better than laymen. Analyses of event-related potentials demonstrated that an early P3a-like component (~150-300 ms), elicited by musical closure, was significantly enhanced at frontal and parietal electrodes in response to deviant endings in experts, whereas a reduced response to deviance occurred in laymen. Putative neuronal sources contributing to the modulation of this component were localized in a network of brain regions including bilateral supplementary motor areas, middle and posterior cingulate cortex, precuneus, associative visual areas, as well as in the right amygdala and insula. In all these regions, experts showed enhanced responses to metric deviance. Later effects demonstrated enhanced activations within the same brain network, as well as higher processing speed for experts. These results suggest that early brain responses to metric deviance in experts may rely on motor representations mediated by the supplementary motor area and motor cingulate regions, in addition to areas involved in self-referential imagery and relevance detection. Such motor representations could play a role in temporal sensory prediction evolved from musical training and suggests that rhythm evokes action more strongly in highly trained instrumentalists.	\N	\N
21934538	The processing of case-marking and argument structures was investigated in children at the age of 3 years, 4 years and 6 months, and 6 years. Two event-related potential (ERP) experiments were conducted in a case-marked language, i.e. German, comparing the processing of (a) double-nominative violations with subject-initial structures and (b) double-accusative violations with object-initial structures. It is known that for both violation types, adults display a biphasic N400/P600 ERP response, reflecting thematic-semantic, and syntactic processes. For double-nominative violations, 3-year-old children already show an adult-like processing pattern revealing their abilities to repair the tested structure. For double-accusative violations, ERP results indicate developmental processing differences with even 6-year-old children not showing an adult pattern. This suggests a late development of the complete function of the accusative case.	\N	\N
21936745	To evaluate the feasibility, the duration and results of sedation by intrarectal pentobarbital and oral alimemazine for auditory brain stem responses (ABR) and auditory steady-state responses (ASSR) recordings in children aged 2 to 5 years. Prospective study. 180 consecutive children aged 2 to 5 years, referred for language retardation and/or behavioral problems, who could not be tested by behavioral methods, underwent ABR and ASSR recordings. The children who did not spontaneously nap were sedated by intrarectal pentobarbital eventually potentiated by oral alimemazine. A spontaneous nap was obtained in only 23 cases, 72 children received only pentobarbital, and 85 received both pentobarbital and alimemazine. Even so, recording was impossible in 16 cases, and interrupted before completion of the ASSR recordings in 45 cases. Children went to sleep in average 64 min +/- 40. The average recording time for the ABR was 20 minutes, and for the ASSR 25 minutes. Sedation by pentobarbital, eventually completed by oral alimemazine, allows ABR and/or ASSR recordings in 89.8% of the children who did not nap in the recording room, and is therefore a good alternative to general anesthesia in these children.	\N	\N
21940982	The goal of this study was to assess the functional utility of transient noise reduction (TNR) algorithms available in hearing aids via speech intelligibility and user preferences. Two pairs of hearing aids, 1 pair each from Siemens and Unitron, were programmed for 17 hearing impaired individuals after a hearing evaluation. Intelligibility was measured for each participant for sentences presented in quiet, with 2 types of transient noise, multitalker babble, and in a combination of each type of transient noise and multitalker babble. Each condition was tested with TNR activated and TNR deactivated in a counterbalanced, single-blinded format. Subjective ratings of overall speech understanding, comfort, and sound quality were obtained for each condition. A significant improvement in speech intelligibility was measured with the TNR activated when speech was presented in multitalker babble, in the presence of chair clang transient noises, and when combining these noises. Activation of the TNR algorithm did not result in significant improvements for any of the subjective ratings. While improvements were limited to certain conditions, specifically those with the chair clang transient and/or multitalker babble, TNR appears to offer an incremental step in improving the listening experience for hearing aid users.	\N	\N
21945467	The different response characteristics of the different auditory cortical responses under conventional central masking conditions were examined by comparing the effects of contralateral white noise on the cortical component of 40-Hz auditory steady state fields (ASSFs) and the N100 m component in auditory evoked fields (AEFs) for tone bursts using a helmet-shaped magnetoencephalography system in 8 healthy volunteers (7 males, mean age 32.6 years). The ASSFs were elicited by monaural 1000 Hz amplitude modulation tones at 80 dB SPL, with the amplitude modulated at 39 Hz. The AEFs were elicited by monaural 1000 Hz tone bursts of 60 ms duration (rise and fall times of 10 ms, plateau time of 40 ms) at 80 dB SPL. The results indicated that continuous white noise at 70 dB SPL presented to the contralateral ear did not suppress the N100 m response in either hemisphere, but significantly reduced the amplitude of the 40-Hz ASSF in both hemispheres with asymmetry in that suppression of the 40-Hz ASSF was greater in the right hemisphere. Different effects of contralateral white noise on these two responses may reflect different functional auditory processes in the cortices.	\N	\N
21954871	This study examined the development of uncertainty monitoring in early childhood. Specifically, this study tested the prediction that preschoolers can reflect on their sense of certainty about the likely accuracy of their decisions, and it examined whether this ability differs across domains. Three-, 4-, and 5-year-olds (N = 74) completed a perceptual identification and a lexical identification task in which they reported whether they were certain or uncertain about their answers. Results showed that even 3-year-olds provided confidence judgments that discriminated accurate from inaccurate responses, but this discrimination increased with age. Furthermore, results suggest that 3-year-olds primarily rely on response latency to assess certainty, whereas older preschoolers do not. Overall, these findings suggest that uncertainty monitoring emerges and develops during the preschool years.	\N	\N
21962945	While grammatical aspects of language are preserved, executive deficits are prominent in Lewy body spectrum disorder (LBSD), including Parkinson's disease (PD), Parkinson's dementia (PDD) and dementia with Lewy bodies (DLB). We examined executive control during sentence processing in LBSD by assessing temporary structural ambiguities. Using an on-line word detection procedure, patients heard sentences with a syntactic structure that has high-compatibility or low-compatibility with the main verb's statistically preferred syntactic structure, and half of the sentences were lengthened strategically between the onset of the ambiguity and its resolution. We found selectively slowed processing of lengthened ambiguous sentences in the PDD/DLB subgroup. This correlated with impairments on measures of executive control. Regression analyses related the working memory deficit during ambiguous sentence processing to significant cortical thinning in frontal and parietal regions. These findings emphasize the role of prefrontal disease in the executive limitations that interfere with processing ambiguous sentences in LBSD.	\N	\N
21967269	Six experiments studied relative frequency judgment and recall of sequentially presented items drawn from 2 distinct categories (i.e., city and animal). The experiments show that judged frequencies of categories of sequentially encountered stimuli are affected by certain properties of the sequence configuration. We found (a) a first-run effect whereby people overestimated the frequency of a given category when that category was the first repeated category to occur in the sequence and (b) a dissociation between judgments and recall; respondents may judge 1 event more likely than the other and yet recall more instances of the latter. Specifically, the distribution of recalled items does not correspond to the frequency estimates for the event categories, indicating that participants do not make frequency judgments by sampling their memory for individual items as implied by other accounts such as the availability heuristic (Tversky & Kahneman, 1973) and the availability process model (Hastie & Park, 1986). We interpret these findings as reflecting the operation of a judgment heuristic sensitive to sequential patterns and offer an account for the relationship between memory and judged frequencies of sequentially encountered stimuli.	\N	\N
21973363	Spectral-ripple discrimination has been used widely for psychoacoustical studies in normal-hearing, hearing-impaired, and cochlear implant listeners. The present study investigated the perceptual mechanism for spectral-ripple discrimination in cochlear implant listeners. The main goal of this study was to determine whether cochlear implant listeners use a local intensity cue or global spectral shape for spectral-ripple discrimination. The effect of electrode separation on spectral-ripple discrimination was also evaluated. Results showed that it is highly unlikely that cochlear implant listeners depend on a local intensity cue for spectral-ripple discrimination. A phenomenological model of spectral-ripple discrimination, as an "ideal observer," showed that a perceptual mechanism based on discrimination of a single intensity difference cannot account for performance of cochlear implant listeners. Spectral modulation depth and electrode separation were found to significantly affect spectral-ripple discrimination. The evidence supports the hypothesis that spectral-ripple discrimination involves integrating information from multiple channels.	\N	\N
21974502	Thresholds of vowel formant discrimination for F1 and F2 of isolated vowels with full and partial vowel spectra were measured for normal-hearing listeners at fixed and roving speech levels. Performance of formant discrimination was significantly better for fixed levels than for roving levels with both full and partial spectra. The effect of vowel spectral range was present only for roving levels, but not for fixed levels. These results, consistent with studies of profile analysis, indicated different perceptual mechanisms for listeners to discriminate vowel formant frequency at fixed and roving levels.	\N	\N
21986211	Hearing loss is routinely estimated from the audiogram, even though this measure gives only a rough approximation of hearing. Indeed, cochlear regions functioning poorly, if at all, called dead regions, are not detected by a simple audiogram. To detect cochlear dead regions, additional measurements of psychophysical tuning curves or thresholds in background noise (TEN test) are required. A first aim of this study was to assess the presence of dead regions after impulse noise trauma using psychophysical tuning curves. The procedure we used was based on a compromise between the need to collect reliable estimates of psychophysical tuning curves and the limited time available to obtain these estimates in a hospital setting. Psychophysical tuning curves were measured using simultaneous masking with a 2-alternative forced choice paradigm, where the target was randomly placed in one of the two masker presentations. It is well known that some components of noise-induced hearing loss are reversible. A second aim of this study was to examine the potential recovery of dead regions after acoustic trauma. A third issue addressed in this article was the relationship between noise-induced dead regions and tinnitus. We found that 70% of the subjects had dead regions after noise trauma, while 88% reported tinnitus. Moreover, we found that the extent of dead regions probably diminished in about 50% of subjects, which highlights the ability of the human auditory system to recover from noise-induced hearing loss.	\N	\N
21993050	Prescriptive methods have been at the core of modern hearing aid fittings for the past several decades. Every decade or so, there have been revisions to existing methods and/or the emergence of new methods that become widely used. In 2001 Byrne et al provided a comparison of insertion gain for generic prescriptive methods available at that time. The purpose of this article was to compare National Acoustic Laboratories-Non-linear 1 (NAL-NL1), National Acoustic Laboratories-Non-linear 2 (NAL-NL2), Desired Sensation Level Multistage Input/Output (DSL m[i/o]), and Cambridge Method for Loudness Equalization 2-High-Frequency (CAMEQ2-HF) prescriptive methods for adults on the amplification characteristics of prescribed insertion gain and compression ratio. Following the differences observed in prescribed insertion gain among the four prescriptive methods, analyses of predicted specific loudness, overall loudness, and bandwidth of cochlear excitation and effective audibility as well as speech intelligibility of the international long-term average speech spectrum (ILTASS) at an average conversational input level were completed. These analyses allow for the discussion of similarities and differences among the present-day prescriptive methods. The impact of insertion gain differences among the methods is examined for seven hypothetical hearing loss configurations using models of loudness perception and speech intelligibility. Hearing loss configurations for adults of various types and degrees were selected, five of which represent sensorineural impairment and were used by Byrne et al; the other two hearing losses provide an example of mixed and conductive impairment. Prescribed insertion gain data were calculated in 1/3-octave frequency bands for each of the seven hearing losses from the software application of each prescriptive method over multiple input levels. The insertion gain data along with a diffuse field-to-eardrum transfer function were used to calculate output levels at the eardrums of the hypothetical listeners. Levels of hearing loss and output were then used in the Moore and Glasberg loudness model and the ANSI S3.5-1997 Speech Intelligibility Index model. NAL-NL2 and DSL m[i/o] provided comparable overall loudness of approximately 8 sones for the five sensorineural hearing losses for a 65 dB SPL ILTASS input. This loudness was notably less than that perceived by a normal-hearing person for the same input signal, 18.6 sones. NAL-NL2 and DSL m[i/o] also provided comparable predicted speech intelligibility in quiet and noise. CAMEQ2-HF provided a greater average loudness, similar to NAL-NL1, with more high-frequency bandwidth but no significant improvement to predicted speech intelligibility. Definite variation in prescribed insertion gain was present among the prescriptive methods. These differences when averaged across the hearing losses were, by and large, negligible with regard to predicted speech intelligibility at normal conversational speech levels. With regard to loudness, DSL m[i/o] and NAL-NL2 provided the least overall loudness, followed by CAMEQ2-HF and NAL-NL1 providing the most loudness. CAMEQ2-HF provided the most audibility at high frequencies; even so, the audibility became less effective for improving speech intelligibility as hearing loss severity increased.	\N	\N
22013241	Interactions between auditory and somatosensory information are relevant to the neural processing of speech since speech processes and certainly speech production involves both auditory information and inputs that arise from the muscles and tissues of the vocal tract. We previously demonstrated that somatosensory inputs associated with facial skin deformation alter the perceptual processing of speech sounds. We show here that the reverse is also true, that speech sounds alter the perception of facial somatosensory inputs. As a somatosensory task, we used a robotic device to create patterns of facial skin deformation that would normally accompany speech production. We found that the perception of the facial skin deformation was altered by speech sounds in a manner that reflects the way in which auditory and somatosensory effects are linked in speech production. The modulation of orofacial somatosensory processing by auditory inputs was specific to speech and likewise to facial skin deformation. Somatosensory judgments were not affected when the skin deformation was delivered to the forearm or palm or when the facial skin deformation accompanied nonspeech sounds. The perceptual modulation that we observed in conjunction with speech sounds shows that speech sounds specifically affect neural processing in the facial somatosensory system and suggest the involvement of the somatosensory system in both the production and perceptual processing of speech.	\N	\N
22023487	The aim of this study was to assess differences between real ear insertion gains (REIG) measured with the modified pressure concurrent equalization (MPCE) and modified pressure stored equalization (MPSE) methods for open fittings in a typical audiology patient population. REIGs were compared for the two methods using a warble tone sweep at 65 dB SPL. The differences between the two methods at 0.25, 0.5, 1, 2, 3, 4 and 6 kHz were recorded. Eighty-three ears of a consecutive sample of 48 candidates for open-fit hearing aids were included. The mean difference between MPSE and MPCE REIGs was less than 1 dB at all frequencies. Analysis of variance showed that the main effect of method was not significant, and there was no significant interaction between method and frequency. The results for the MPSE and MPCE methods did not differ significantly for the patients with mild-to-moderate hearing losses tested here, for whom REIGs were generally less than 20 dB. Further research is needed to identify the REIG values at which the differences between MPCE and MPSE methods become clinically significant.	\N	\N
22030970	Frontonasal dysplasia (FND) is a rare malformative complex affecting the frontal portion of the face, the eyes and the nose; it may occur singly or associated with other clinical signs. No systematic studies describing hearing in this condition were found. To evaluate hearing sensitivity and sound stimulus conduction from cochlea to brainstem in patients with clinical signs of FND. 21 patients with isolated or syndromic FND were submitted to a clinical (otological/vestibular antecedents and otoscopy) and instrumental (pure tone and speech audiometry, tympanometry and brainstem auditory evoked response) hearing evaluation. A clinical, cross-sectional observational prospective study. Hearing thresholds were normal in 15 (70%) patients, abnormal in 5 (25%), mostly with conductive hearing loss; one patient did not cooperate with testing. The tympanometric curve was type A in 30 (72%) ears, type C in 5 (12%), type As in 4 (9%) and type B in 3 (7%). The auditory brainstem response (ABR) showed no abnormalities. Patients with FND showed no abnormalities in the auditory system from cochlea to brainstem in this study. Mild conductive hearing loss found in some is probably related to cleft palate. Further evaluation of hearing pathways at higher levels is recommended.	\N	\N
22030972	Accurate information about type, degree, and configuration of hearing loss are necessary for successful audiological early interventions. Auditory brainstem response with tone burst stimuli (TB ABR) and auditory steady-state response (ASSR) exams provide this information. To analyze the clinical applicability of TB ABR and ASSR at 2 kHz in infants, comparing responses in full-term and premature neonates. The study was cross-sectional, clinical and experimental. Subjects consisted of 17 premature infants and 19 full-term infants. TB ABR and ASSR exams at 2000 Hz were done during natural sleep. The electrophysiological minimum response obtained with TB ABR was 32.4 dBnHL (52.4 dBSPL); the ASSR minimum was 13.8 dBHL (26.4 dBSPL). The exams required 21.1 min and 22 min, respectively. Premature and full-term infant responses showed no statistically significant differences, except for auditory steady-state response duration. Both exams have clinical applicability at 2 kHz in infants, with 20 min of duration, on average. In general, there are no differences between premature and full-term individuals.	\N	\N
22033983	We are constantly exposed to our own face and voice, and we identify our own faces and voices as familiar. However, the influence of self-identity upon self-speech perception is still uncertain. Speech perception is a synthesis of both auditory and visual inputs; although we hear our own voice when we speak, we rarely see the dynamic movements of our own face. If visual speech and identity are processed independently, no processing advantage would obtain in viewing one's own highly familiar face. In the present experiment, the relative contributions of facial and vocal inputs to speech perception were evaluated with an audiovisual illusion. Our results indicate that auditory self-speech conveys a processing advantage, whereas visual self-speech does not. The data thereby support a model of visual speech as dynamic movement processed separately from speaker recognition.	\N	\N
22035565	Frequency modulation (FM) is an important building block of communication signals for animals and human. Attempts to predict the response of central neurons to FM sounds have not been very successful, though achieving successful results could bring insights regarding the underlying neural mechanisms. Here we proposed a new method to predict responses of FM-sensitive neurons in the auditory midbrain. First we recorded single unit responses in anesthetized rats using a random FM tone to construct their spectro-temporal receptive fields (STRFs). Training of neurons in the artificial neural network to respond to a second random FM tone was based on the temporal information derived from the STRF. Specifically, the time window covered by the presumed trigger feature and its delay time to spike occurrence were used to train a finite impulse response neural network (FIRNN) to respond to this random FM. Finally we tested the model performance in predicting the response to another similar FM stimuli (third random FM tone). We found good performance in predicting the time of responses if not also the response magnitudes. Furthermore, the weighting function of the FIRNN showed temporal 'bumps' suggesting temporal integration of synaptic inputs from different frequency laminae. This article is part of a Special Issue entitled: Neural Coding.	\N	\N
22037719	The aim of this study was to investigate audio-vestibular function in patients with essential tremor. Twenty-three patients with essential tremor (46 ears) and 21 health control subjects (42 ears) were included in the present study. Patients and comparison subjects were matched for age and gender. All patient and control subjects underwent pure tone audiometric test, tympanogram, transient-evoked otoacoustic emissions and auditory brainstem response. Vestibular system was evaluated by bitermal caloric test. Comparison of variables between the groups was performed. Investigation of the relationship between parameters about ET disease and hearing levels were also studied. Pure tone thresholds significantly differed between patients and controls in 250 and 500 Hz frequencies (p < 0.05). There was no statistically significant difference in 1,000, 2,000, 4,000, and 6,000 Hz frequencies in essential tremor patients in comparison to the control subjects. A correlation between tremor severity and audiometric scores in low frequencies was not found. In addition, statistical analysis did not demonstrate a correlation between audiometric scores and tremor duration. The otoacoustic emission responses were found significantly different in patient and control group. The latencies of waves I, V and I-V inter-peak latencies on the ABR were not different between the groups. Our findings indicated that, abnormalities are due to cochlea rather than the retro cochlear pathology which is responsible for hearing loss associated with essential tremor.	\N	\N
22056210	When speaking or producing music, people rely in part on auditory feedback - the sounds associated with the performed action. Three experiments investigated the degree to which alterations of auditory feedback (AAF) during music performances influence the experience of agency (i.e., the sense that your actions led to auditory events) and the possible link between agency and the disruptive effect of AAF on production. Participants performed short novel melodies from memory on a keyboard. Auditory feedback during performances was manipulated with respect to its pitch contents and/or its synchrony with actions. Participants rated their experience of agency after each trial. In all experiments, AAF reduced judgments of agency across conditions. Performance was most disrupted (measured by error rates and slowing) when AAF led to an ambiguous experience of agency, suggesting that there may be some causal relationship between agency and disruption. However, analyses revealed that these two effects were probably independent. A control experiment verified that performers can make veridical judgments of agency.	\N	\N
22057984	Binaural hearing in cochlear implant (CI) users can be achieved either by bilateral implantation or bimodally with a contralateral hearing aid (HA). Binaural-bimodal hearing has the advantage of complementing the high-frequency electric information from the CI by low-frequency acoustic information from the HA. We examined the contribution of a contralateral HA in 25 adult implantees to their perception of fundamental frequency-cued speech characteristics (initial consonant voicing, intonation, and emotions). Testing with CI alone, HA alone, and bimodal hearing showed that all three characteristics were best perceived under the bimodal condition. Significant differences were recorded between bimodal and HA conditions in the initial voicing test, between bimodal and CI conditions in the intonation test, and between both bimodal and CI conditions and between bimodal and HA conditions in the emotion-in-speech test. These findings confirmed that such binaural-bimodal hearing enhances perception of these speech characteristics and suggest that implantees with residual hearing in the contralateral ear may benefit from a HA in that ear.	\N	\N
22067074	The irrelevant sound effect (ISE) describes reduced verbal short-term memory during irrelevant changing-state sounds which consist of different and distinct auditory tokens. Steady-state sounds lack such changing-state features and do not impair performance. An EEG experiment (N=16) explored the distinguishing neurophysiological aspects of detrimental changing-state speech (3-token sequence) compared to ineffective steady-state speech (1-token sequence) on serial recall performance. We analyzed evoked and induced activity related to the memory items as well as spectral activity during the retention phase. The main finding is that the behavioral sound effect was exclusively reflected by attenuated token-induced gamma activation most pronounced between 50-60 Hz and 50-100 ms post-stimulus onset. Changing-state speech seems to disrupt a behaviorally relevant ongoing process during target presentation (e.g., the serial binding of the items).	\N	\N
22073929	The majority of the patients with unilateral auditory neuropathy spectrum disorder (UANSD) were pediatric and mostly showed a great degree of hearing loss when diagnosed. Abnormal auditory brainstem response (ABR) and preserved otoacoustic emissions (OAEs) and/or cochlear microphonics (CM) were important features to differentiate it from common sensorineural deafness and central nerve hearing loss. To identify the clinical characteristics of patients with UANSD. This was a retrospective study involving 14 patients diagnosed as having UANSD between 2004 and 2010 in the Chinese PLA Hospital. In all, 50% of the cases were males (1:1 sex ratio) and the average age of onset was 4.1 years. Of the 14 affected ears with UANSD in these cases, 6 were left-sided, while 8 were right-sided. Of the 14 contralateral ears, 4 presented with sensorineural hearing loss, while the other 10 showed normal hearing. The degree of hearing loss in the 14 affected ears varied, including moderate in 1, moderately severe in 4, severe in 5, and profound in 4. ABRs were absent in the 14 affected ears, while the OAEs, and/or CM were present.	\N	\N
22074449	Stapedotomy is, in our opinion, the technique of choice in stapes surgery. The precision of this technique allows clinicians to perform the surgical procedure in day surgery under local anesthesia. There is a strong emphasis on increasing the number of elective day surgery cases, especially in the patients' best interest, as it decreases the likelihood of late cancellation and hospital-acquired morbidity. A prospective study was performed to determine whether stapes surgery for otosclerosis could be performed safely in an outpatient setting. We present a series of stapes surgery cases for otosclerosis performed on a day-case basis. We performed a classic stapedotomy in 9 patients, a reverse classic step stapedotomy in 2 patients, a partial reverse classic step stapedotomy in 11 patients, and a hemi-stapedectomy in two patients. Three of 24 patients (12.5%) treated with classic stapedotomy, 1 patient with partial reverse classic step stapedotomy, and 1 patient with hemi-stapedectomy were formally admitted to the hospital after surgery (length of stay, 23 h). The indications were vertigo (two patients) and asthenia (one patient). These patients were treated under general anesthesia. Two of these patients resided more than 250 km away from the hospital.	\N	\N
22082232	The present study investigated the lexical representations underlying the production of English schwa words. Two types of schwa words were compared: words with a schwa in poststress position (e.g., mackerel), whose schwa and reduced variants differ in a categorical way, and words with a schwa in prestress position (e.g., salami), whose variants differ in a noncategorical way. Participants named pseudohomophones and matched pseudowords corresponding to schwa and reduced variants of these words. Results revealed an advantage for pseudohomophones over matched pseudowords for both variants of poststress schwa words but only for schwa variants of prestress schwa words. As the pseudohomophone advantage is assumed to reflect the activation of a phonologically matching stored phonological representation, these results suggest that both variants of poststress schwa words are lexically represented while only schwa variants of prestress schwa words are. This result extends the proposal that words with two categorically distinct variants are stored in the production lexicon with 2 representations to another language and demonstrates that this 2-lexeme account does not generalize to pronunciation variants differing from one another in a noncategorical fashion. This finding challenges one of the widely shared assumption of generative models of word production: that content words have only 1 phonological representation. On the other hand, it provides further evidence in favor of another fundamental assumption of these models: that lexical representations are abstract sets of segments rather than fully detailed exemplars.	\N	\N
22087888	To examine the role of perceived gender on fricative identification, a study was conducted in which listeners identified /s/-/∫/ and /s/-/θ/ continua combined with vowels produced by a man and a woman. These were acoustically modified to be consistent with different-sized vocal tracts (VT), and were presented with pictures of men or women. Listeners identified more tokens of /s/ in the /s/-/∫/ and more tokens of /θ/ in the /s/-/θ/ continuum when these sounds were combined with men's vowels, with vowels consistent with a 17 cm VT, and with pictures of men. Results support the hypothesis that listeners incorporate information about talker gender during fricative perception.	\N	\N
22087912	Cochlear hearing loss is often associated with a loss of basilar-membrane (BM) compression, which in turn may contribute to degraded processing of suprathreshold stimuli. Behavioral estimates of compression may therefore be useful as long as they are valid over a wide range of levels and frequencies. Additivity of forward masking (AFM) may provide such a measure, but research to date lacks normative data from normal-hearing (NH) listeners at high sound levels, which is necessary to evaluate data from hearing-impaired (HI) listeners. The present study measured AFM in six NH listeners for signal frequencies of 500, 1500, and 4000 Hz in the presence of background noise, designed to elevate signal thresholds to levels similar to those experienced by HI listeners. Results consistent with compressive BM responses were found for all six listeners at 500 Hz, five listeners at 1500 Hz, but only two listeners at 4000 Hz. Further measurements in the absence of background noise also indicated a lack of consistent compression at 4000 Hz at higher signal levels, in contrast to earlier results collected at lower levels. A better understanding of this issue will be required before AFM can be used as a general behavioral estimate of BM compression.	\N	\N
22087920	The factors influencing the stream segregation of discrete tones and the perceived continuity of discrete tones as continuing through an interrupting masker are well understood as separate phenomena. Two experiments tested whether perceived continuity can influence the build-up of stream segregation by manipulating the perception of continuity during an induction sequence and measuring streaming in a subsequent test sequence comprising three triplets of low and high frequency tones (LHL-[ellipsis (horizontal)]). For experiment 1, a 1.2-s standard induction sequence comprising six 100-ms L-tones strongly promoted segregation, whereas a single extended L-inducer (1.1 s plus 100-ms silence) did not. Segregation was similar to that following the single extended inducer when perceived continuity was evoked by inserting noise bursts between the individual tones. Reported segregation increased when the noise level was reduced such that perceived continuity no longer occurred. Experiment 2 presented a 1.3-s continuous inducer created by bridging the 100-ms silence between an extended L-inducer and the first test-sequence tone. This configuration strongly promoted segregation. Segregation was also increased by filling the silence after the extended inducer with noise, such that it was perceived like a bridging inducer. Like physical continuity, perceived continuity can promote or reduce test-sequence streaming, depending on stimulus context.	\N	\N
22087922	This work was aimed at determining whether binaural interference occurs in electric hearing, and if so, whether it occurs as a consequence of perceptual grouping (central explanation) or if it is related to the spread of excitation in the cochlea (peripheral explanation). Six bilateral cochlear-implant listeners completed a series of experiments in which they judged the lateral position of a target pulse train, lateralized via interaural time or level differences, in the presence of an interfering diotic pulse train. The target and interferer were presented at widely separated electrode pairs (one basal and one apical). The results are broadly similar to those reported for acoustic hearing. All listeners but one showed significant binaural interference in at least one of the stimulus conditions. In all cases of interference, a robust recovery was observed when the interferer was presented as part of an ongoing stream of identical pulse trains, suggesting that the interference was at least partly centrally mediated. Overall, the results suggest that both simultaneous and sequential grouping mechanisms operate in electric hearing, at least for stimuli with a wide tonotopic separation.	\N	\N
22087923	The present study examined the effect of combined spectral and temporal enhancement on speech recognition by cochlear-implant (CI) users in quiet and in noise. The spectral enhancement was achieved by expanding the short-term Fourier amplitudes in the input signal. Additionally, a variation of the Transient Emphasis Spectral Maxima (TESM) strategy was applied to enhance the short-duration consonant cues that are otherwise suppressed when processed with spectral expansion. Nine CI users were tested on phoneme recognition tasks and ten CI users were tested on sentence recognition tasks both in quiet and in steady, speech-spectrum-shaped noise. Vowel and consonant recognition in noise were significantly improved with spectral expansion combined with TESM. Sentence recognition improved with both spectral expansion and spectral expansion combined with TESM. The amount of improvement varied with individual CI users. Overall the present results suggest that customized processing is needed to optimize performance according to not only individual users but also listening conditions.	\N	\N
22093438	In auditory-visual synaesthesia, all kinds of sound can induce additional visual experiences. To identify the brain regions mainly involved in this form of synaesthesia, functional magnetic resonance imaging (fMRI) has been used during non-linguistic sound perception (chords and pure tones) in synaesthetes and non-synaesthetes. Synaesthetes showed increased activation in the left inferior parietal cortex (IPC), an area involved in multimodal integration, feature binding and attention guidance. No significant group-differences could be detected in area V4, which is known to be related to colour vision and form processing. The results support the idea of the parietal cortex acting as sensory nexus area in auditory-visual synaesthesia, and as a common neural correlate for different types of synaesthesia.	\N	\N
22095215	The behavioral and neurofunctional consequences of blindness often include performance enhancements and recruitment of occipital regions for nonvisual tasks. How the neuroanatomical changes resulting from this sensory loss relate to these functional changes is, however, less clear. Previous studies using cortical thickness (CT) measures have shown thicker occipital cortex in early-blind (EB) individuals compared with sighted controls. We hypothesized that this finding reflects the crossmodal plasticity often observed in blind individuals and thus could reflect behavioral adaptations. To address this issue, CT measures in blind (early and late) and sighted subjects were obtained along with several auditory behavioral measures in an attempt to relate behavioral and neuroanatomical changes. Group contrasts confirmed previous results in showing thicker occipital cortex in the EB. Regression analyses between CT measures across the whole brain of all blind individuals with the behavioral scores from 2 tasks in which EB subjects were superior (pitch and melody discrimination) showed that CT of occipital areas was directly related to behavioral enhancements. These findings constitute a compelling demonstration that anatomical changes in occipital areas are directly related to heightened behavioral abilities in the blind and hence support the idea that these anatomical features reflect adaptive compensatory plasticity.	\N	\N
22097102	Daily life in today's society is filled with moments of high state anxiety. State anxiety is the amount of anxiety one is experiencing in the present moment; it is not a personality trait. Many people need simple, cost-effective ways to self-regulate themselves so they can sleep, be more productive, and attend to their activities of daily life. Therefore, the present study questioned whether listening to a steady beat will decrease feelings of state anxiety in healthy subjects. Participants (N=36) between the ages of 20 and 50 volunteered for the study. During this study, experimental anxiety was induced and the Visual Analog Scale served as the measurement tool for both tests. Subjects in the control group sat in silence, while subjects in the experimental group listened to a steady beat of 66 beats per minute. The results of an independent-samples t test indicated significant differences between the groups on the posttest measure, t (34)=2.41, p=.02. Subjects who listened to the steady beat reported less anxiety than subjects who sat in silence. This study suggests that steady beat alone can reduce state anxiety, thus providing a cost-effective and accessible means for self-regulation in the midst of high state anxiety.	\N	\N
22101495	The purpose of the present study was to establish whether the validity effect produced by masked eye gaze cues should be attributed to strictly reflexive mechanisms or to volitional top-down mechanisms. While we find that masked eye gaze cues are effective in producing a validity effect in a central cueing paradigm, we also find that the efficacy of masked gaze cues is sharply constrained by the experimental context. Specifically, masked gaze cues only produced a validity effect when they appeared in the context of unmasked and predictive gaze cues. Unmasked gaze cues, in contrast, produced reliable validity effects across a range of experimental contexts, including Experiment 4 where 80% of the cues were invalid (counter-predictive). Taken together, these results suggest that the effective processing of masked gaze cues requires volitional control, whereas the processing of unmasked (clearly visible) gaze cues appears to benefit from both reflexive and top-down mechanisms.	\N	\N
22102362	The neural events that lead to successful or failed detection of suprathreshold sounds are not well established. In this experiment, event-related potentials (ERPs) and functional magnetic resonance imaging (fMRI) were recorded while participants performed two tasks: a primary difficult duration judgment task on a sequence of tones presented to one ear, and a secondary target detection task on an auditory oddball stream presented to the other ear. The paradigm was designed to elicit competition and variability in detection of auditory targets despite identical input. Successful detection of auditory targets was associated mainly with greater fMRI activity in superior parietal cortex and thalamus. In the ERPs, successful detection was linked with a larger fronto-central negativity at 200-400 ms, and a later centro-posterior positivity. Failure to detect targets was associated with greater fMRI signal in the default mode network, a significantly smaller electrical fronto-central negativity and no late positivity. These findings demonstrate that variability in auditory detection is related to modulation of activity in multimodal parietal and frontal networks active ∼ 200 ms after target onset. Results are consistent with a limited capacity and late selection view of attention.	\N	\N
22107896	Auditory perception and learning take place during the third trimester of gestation. Fetuses and newborns who lack typical auditory experience can go on to develop typical socioemotional attachment and language, given a supportive environment. For hospitalized preterm infants in developmentally sensitive neonatal intensive care units, detrimental effects of deviant early auditory experience may be remediated by later experience, but much is unknown about the causes of language deficits of prematurity. Prenatal auditory stimulation programs that incorporate audio speakers against the maternal belly should be discouraged because of possible overstimulation effects on the developing auditory system and sleep/wake state organization.	\N	\N
22108539	Tracing the temporal structure of acoustic events is crucial in order to efficiently adapt to dynamic changes in the environment. In turn, regularity in temporal structure may facilitate tracing of the acoustic signal and its likely spatial source. However, temporal processing in audition extends beyond a domain-general facilitatory function. Temporal regularity and temporal order of auditory events correspond to contextually extracted, statistically sampled relations among sounds. These relations are the backbone of prediction in audition, determining both when an event is likely to occur (temporal structure) and also what type of event can be expected at a specific point in time (formal structure, e.g. spectral information). Here, we develop a model of temporal processing in audition and speech that involves a division of labor between the cerebellum and the basal ganglia in tracing acoustic events in time. As for the cerebellum and its associated thalamo-cortical connections, we refer to its role in the automatic encoding of event-based temporal structure with high temporal precision, while the basal ganglia-thalamo-cortical system engages in the attention-dependent evaluation of longer-range intervals. Recent electrophysiological and neurofunctional evidence suggests that neocortical processing of spectral structure relies on concurrent extraction of event-based temporal information. We propose that spectrotemporal predictive processes may be facilitated by subcortical coding of relevant changes in sound energy as temporal event markers.	\N	\N
22111542	The objectives were: (1) to examine the effects of a directional microphone with different directivity patterns and different microphone combinations on wind noise levels at the hearing aid output; and (2) to derive strategies appropriate for hearing aid selection and future designs. The in-situ frequency responses of a behind-the-ear hearing aid (BTE1) were matched when the hearing aid was programmed to dipole, hypercardioid, cardioids, or adaptive microphone mode. The in-situ frequency responses of another hearing aid (BTE2) were matched among an omnidirectional microphone (OMNI), an adaptive directional microphone (ADM), and a combination of an omnidirectional microphone at low frequencies and an adaptive directional microphone at high frequencies (MIXED). Flow noise was recorded at flow velocities of 0, 4.5, 9.0, and 13.5 m/s. Measurements were repeated for the hypercardioid pattern of BTE1. Flow noise recorded using directional microphones with four directivity patterns and using OMNI, ADM, and MIXED. Directional microphones with different directivity patterns generated similar flow noise levels. ADM yielded higher overall levels than OMNI and MIXED, which had similar overall levels. The adaptive directional microphone is the most versatile microphone for use in wind. The mixed microphone mode is a viable wind noise reduction option.	\N	\N
22115685	Cochlear implants have become a viable treatment option for individuals who present with severe to profound hearing loss. While there are several parameters that affect the successful use of this technology, quality programming of the cochlear implant system is crucial. This review chapter focuses on general device programming techniques, programming techniques specific to children, objective programming techniques, a brief overview of programming parameters of the currently commercially available multichannel systems, and managing patient complaints and device failures. The chapter also provides what the authors believe the future may hold for new programming techniques.	\N	\N
22119935	The loudness dependence of the auditory evoked potential (LDAEP) is considered a noninvasive in vivo marker of central serotonergic functioning in humans. Nevertheless, results of genetic association studies point towards a modulation of this biomarker by dopaminergic neurotransmission. We examined the effect of dopaminergic modulation on the LDAEP using L-3,4-dihydroxyphenylalanine (levodopa)/benserazide (Madopar®) as a challenge agent in healthy volunteers. A double-blind placebo-controlled challenge design was chosen. Forty-two healthy participants (21 females and 21 males) underwent two LDAEP measurements, following a baseline LDAEP measurement either placebo or levodopa (levodopa 200 mg/benserazide 50 mg) were given orally. Changes in the amplitude and dipole source activity of the N1/P2 intensities (60, 70, 80, 90, and 100 dB) were analyzed. The participants of neither the levodopa nor the placebo group showed any significant LDAEP alterations compared to the baseline measurement. The test-retest reliability (Cronbachs Alpha) between baseline and intervention was 0.966 in the verum group and 0.759 in the placebo group, respectively. The administration of levodopa showed no effect on the LDAEP. These findings are in line with other trials using dopamine receptor agonists.	\N	\N
22122114	In this article we report on listener categorization of meaningful environmental sounds. A starting point for this study was the phenomenological taxonomy proposed by Gaver (1993b). In the first experimental study, 15 participants classified 60 environmental sounds and indicated the properties shared by the sounds in each class. In a second experimental study, 30 participants classified and described 56 sounds exclusively made by solid objects. The participants were required to concentrate on the actions causing the sounds independent of the sound source. The classifications were analyzed with a specific hierarchical cluster technique that accounted for possible cross-classifications, and the verbalizations were submitted to statistical lexical analyses. The results of the first study highlighted 4 main categories of sounds: solids, liquids, gases, and machines. The results of the second study indicated a distinction between discrete interactions (e.g., impacts) and continuous interactions (e.g., tearing) and suggested that actions and objects were not independent organizational principles. We propose a general structure of environmental sound categorization based on the sounds' temporal patterning, which has practical implications for the automatic classification of environmental sounds.	\N	\N
22122401	To assess the potential risk of hearing loss to young listeners, due to the use of personal listening devices (PLDs). The study included two parts: (1) A self-report questionnaire on music listening habits, and (2) Physical measurements of preferred listening levels, in quiet and in everyday background noise. Young teenagers aged 13 to 17 years. Part 1 included 289 participants with mean age of 14 years. Part 2 included 11 and 74 participants (2A and 2B) with a mean age of 15 years. Eleven listened to PLDs in quiet conditions (2A) and 74 in everyday background noise (2B). Questionnaire main findings indicated that most of the participants reported high or very high volume settings and demonstrated low awareness towards loud music listening consequences. Physical measurements corrected for diffuse field indicated mean preferred listening levels of: 82 (SD = 9) dBA in quiet, and 89 (SD = 9) dBA in the presence of background noise. The potential risk to hearing of PLDs users was calculated using the 8 hour equivalent level. More than 25% of the participants in the noisy condition were found to be at risk according to occupational damage risk criteria NIOSH, 1998.	\N	\N
22123457	Evidence for cortical sensory activation in the human fetus at the beginning of the third trimester of pregnancy was provided in a recent imaging study. Although hearing is functional before birth, it is not clear whether recognition of the mother's voice is learned in utero or rapidly following delivery. We developed an original fMRI procedure that allows for the specific exploration of fetal brain response to auditory stimuli. This procedure provides the first in vivo evidence for the development of maternal voice recognition in utero between 33 and 34 weeks of gestation. This methodology could have crucial implications in the study of fetal cognition.	\N	\N
22133495	A role for the cerebellum in cognition has been proposed based on studies suggesting a profile of cognitive deficits due to cerebellar stroke. Such studies are limited in the determination of the detailed organisation of cerebellar subregions that are critical for different aspects of cognition. In this study we examined the correlation between cognitive performance and cerebellar integrity in a specific degeneration of the cerebellar cortex: Spinocerebellar Ataxia type 6 (SCA6). The results demonstrate a critical relationship between verbal working memory and grey matter density in superior (bilateral lobules VI and crus I of lobule VII) and inferior (bilateral lobules VIIIa and VIIIb, and right lobule IX) parts of the cerebellum. We demonstrate that distinct cerebellar regions subserve different components of the prevalent psychological model for verbal working memory based on a phonological loop. The work confirms the involvement of the cerebellum in verbal working memory and defines specific subsystems for this within the cerebellum.	\N	\N
22137677	We assessed the relationship between brain structure and function in 10 individuals with specific language impairment (SLI), compared to six unaffected siblings, and 16 unrelated control participants with typical language. Voxel-based morphometry indicated that grey matter in the SLI group, relative to controls, was increased in the left inferior frontal cortex and decreased in the right caudate nucleus and superior temporal cortex bilaterally. The unaffected siblings also showed reduced grey matter in the caudate nucleus relative to controls. In an auditory covert naming task, the SLI group showed reduced activation in the left inferior frontal cortex, right putamen, and in the superior temporal cortex bilaterally. Despite spatially coincident structural and functional abnormalities in frontal and temporal areas, the relationships between structure and function in these regions were different. These findings suggest multiple structural and functional abnormalities in SLI that are differently associated with receptive and expressive language processing.	\N	\N
22143297	To demonstrate whether there are differences in the outcomes of children with cochlear implants using the techniques between mastoidectomy with posterior tympanotomy (MPTA) and suprameatal approach (SMA). A total of 44 congenitally deaf children who underwent cochlear implantation before the age of 5 years at the Sixth Hospital Affiliated to Shanghai Jiao tong University from January 2005 to March 2008 were included in this study. Children with severe mental retardation or with cochlear malformations were excluded. Each group had 22 patients; however, 4 patients in the SMA group and 5 in the MPTA group were not included in this study because the assessments for these patients were not available. All children were assessed before surgery and 6, 12, and 24 months after surgery with Categories of Auditory Performance (CAP) and Speech Intelligibility Rating (SIR). Each assessment was given by the child's speech therapist in the familiar environment of the child's home or school. At each interval, the CAP and SIR scores of each group were compared. For the both groups, CAP and SIR scores increased with the time of implant usage during the follow-up period after implantation. However, there were no significant differences in scores of CAP and SIR at the 4 time points between the SMA group and the MPTA group. Intelligible speech and auditory performance of children with cochlear implantation using the SMA were good. There were no differences between children implanted with the SMA technique versus the MPTA technique.	\N	\N
22155324	Temporal congruency promotes perceptual binding of multisensory inputs. Here, we used EEG frequency-tagging to track cortical activities elicited by auditory and visual inputs separately, in the form of steady-state evoked potentials (SS-EPs). We tested whether SS-EPs could reveal a dynamic coupling of cortical activities related to the binding of auditory and visual inputs conveying synchronous vs. non-synchronous temporal periodicities, or beats. The temporally congruent audiovisual condition elicited markedly enhanced auditory and visual SS-EPs, as compared to the incongruent condition. Furthermore, an increased inter-trial phase coherence of both SS-EPs was observed in that condition. Taken together, these observations indicate that temporal congruency enhances the processing of multisensory inputs at sensory-specific stages of cortical processing, possibly through a dynamic binding by synchrony of the elicited activities and/or improved dynamic attending. Moreover, we show that EEG frequency-tagging with SS-EPs constitutes an effective tool to explore the neural dynamics of multisensory integration in the human brain.	\N	\N
22163041	Insects often communicate by sound in mixed species choruses; like humans and many vertebrates in crowded social environments they thus have to solve cocktail-party-like problems in order to ensure successful communication with conspecifics. This is even more a problem in species-rich environments like tropical rainforests, where background noise levels of up to 60 dB SPL have been measured. Using neurophysiological methods we investigated the effect of natural background noise (masker) on signal detection thresholds in two tropical cricket species Paroecanthus podagrosus and Diatrypa sp., both in the laboratory and outdoors. We identified three 'bottom-up' mechanisms which contribute to an excellent neuronal representation of conspecific signals despite the masking background. First, the sharply tuned frequency selectivity of the receiver reduces the amount of masking energy around the species-specific calling song frequency. Laboratory experiments yielded an average signal-to-noise ratio (SNR) of -8 dB, when masker and signal were broadcast from the same side. Secondly, displacing the masker by 180° from the signal improved SNRs by further 6 to 9 dB, a phenomenon known as spatial release from masking. Surprisingly, experiments carried out directly in the nocturnal rainforest yielded SNRs of about -23 dB compared with those in the laboratory with the same masker, where SNRs reached only -14.5 and -16 dB in both species. Finally, a neuronal gain control mechanism enhances the contrast between the responses to signals and the masker, by inhibition of neuronal activity in interstimulus intervals. Thus, conventional speaker playbacks in the lab apparently do not properly reconstruct the masking noise situation in a spatially realistic manner, since under real world conditions multiple sound sources are spatially distributed in space. Our results also indicate that without knowledge of the receiver properties and the spatial release mechanisms the detrimental effect of noise may be strongly overestimated.	\N	\N
22166679	To evaluate the effect of different lipid fractions on auditory brainstem evoked responses in hyperlipidaemia. We conducted a single institution (medical college), prospective, cross-sectional study of 25 hyperlipidaemic patients and 25 normolipidaemic controls, all with a normal hearing threshold on pure tone audiometry. Brainstem evoked response audiometry results were recorded in both groups. The hyperlipidaemic group were further divided into two subgroups, based on the serum value of each lipid fraction: those with less than and those with greater than the mean serum value. These two subgroups were further compared with the control group. The hyperlipidaemic and normolipidaemic groups had statistically significant differences for all audiometry waves apart from the wave I and the III-V interpeak latencies. The subgroups had a statistically significant difference in brainstem evoked responses. We found a statistically significant association between low-density lipoproteins and many waveforms in the hyperlipidaemic group. We found that low-density lipoproteins were significantly associated with many waveforms in hyperlipidaemic patients. Thus, low-density lipoproteins may be important in auditory dysfunction.	\N	\N
22171054	Oscillatory entrainment mechanisms are invoked during attentional processing of rhythmically occurring stimuli, whereby their phase alignment regulates the excitability state of neurons coding for anticipated inputs. These mechanisms have been examined in the delta band (1-3 Hz), where entrainment frequency matches the stimulation rate. Here, we investigated entrainment for subdelta rhythmic stimulation, recording from intracranial electrodes over human auditory cortex during an intersensory audiovisual task. Audiovisual stimuli were presented at 0.67 Hz while participants detected targets within one sensory stream and ignored the other. It was found that entrainment operated at twice the stimulation rate (1.33 Hz), and this was reflected by higher amplitude values in the FFT spectrum, cyclic modulation of alpha-amplitude, and phase-amplitude coupling between delta phase and alpha power. In addition, we found that alpha-amplitude was relatively increased in auditory cortex coincident with to-be-ignored auditory stimuli during attention to vision. Thus, the data suggest that entrainment mechanisms operate within a delimited passband such that for subdelta task rhythms, oscillatory harmonics are invoked. The phase of these delta-entrained oscillations modulates alpha-band power. This may in turn increase or decrease responsiveness to relevant and irrelevant stimuli, respectively.	\N	\N
22171970	Coupling of thalamocortical networks through synchronous oscillations at gamma frequencies (30-80 Hz) has been suggested as a mechanism for binding of auditory sensory information into an object representation, which then becomes accessible for perception and cognition. This study investigated whether contralateral noise interferes with this step of central auditory processing. Neuromagnetic 40-Hz oscillations were examined in young healthy participants while they listened to amplitude-modulated sound in one ear and a multi-talker masking noise in the contralateral ear. Participants were engaged in a gap-detection task, for which their behavioural performance declined under masking. The amplitude modulation of the stimulus elicited steady 40-Hz oscillations with sources in bilateral auditory cortices. Analysis of the temporal dynamics of phase synchrony between source activity and the stimulus revealed two oscillatory components; the first was indicated by an instant onset in phase synchrony with the stimulus while the second showed a 200-ms time constant of gradual increase in phase synchrony after phase resetting by the gap. Masking abolished only the second component. This coincided with masking-related decrease of the P2 wave of the transient auditory-evoked responses whereas the N1 wave, reflecting early sensory processing, was unaffected. Given that the P2 response has been associated with object representation, we propose that the first 40-Hz component is related to representation of low-level sensory input whereas the second is related to internal auditory processing in thalamocortical networks. The observed modulation of oscillatory activity is discussed as reflecting a neural mechanism critical for speech understanding in noise.	\N	\N
22172546	Wernicke's aphasia is a condition which results in severely disrupted language comprehension following a lesion to the left temporo-parietal region. A phonological analysis deficit has traditionally been held to be at the root of the comprehension impairment in Wernicke's aphasia, a view consistent with current functional neuroimaging which finds areas in the superior temporal cortex responsive to phonological stimuli. However behavioural evidence to support the link between a phonological analysis deficit and auditory comprehension has not been yet shown. This study extends seminal work by Blumstein, Baker, and Goodglass (1977) to investigate the relationship between acoustic-phonological perception, measured through phonological discrimination, and auditory comprehension in a case series of Wernicke's aphasia participants. A novel adaptive phonological discrimination task was used to obtain reliable thresholds of the phonological perceptual distance required between nonwords before they could be discriminated. Wernicke's aphasia participants showed significantly elevated thresholds compared to age and hearing matched control participants. Acoustic-phonological thresholds correlated strongly with auditory comprehension abilities in Wernicke's aphasia. In contrast, nonverbal semantic skills showed no relationship with auditory comprehension. The results are evaluated in the context of recent neurobiological models of language and suggest that impaired acoustic-phonological perception underlies the comprehension impairment in Wernicke's aphasia and favour models of language which propose a leftward asymmetry in phonological analysis.	\N	\N
22176307	The parents' evaluation of aural/oral performance of children (PEACH) scale was developed to assess the effectiveness of amplification for children, based on a systematic use of parents' observations of children's performance in real-world environments. The purpose of the present study was to adapt the PEACH scale into the Malay language, and to collect normative data on a group of children with normal hearing. The participants were parents of 74 children aged between 3 months and 13 years of age. Parents were requested to observe their children's auditory/oral behavior in everyday life and to record their observations in the PEACH booklet. High internal consistency (Cronbach's alpha = 0.93) and item-total correlation were found (0.52-0.85). Similar to the published norms for English-speaking children, near-perfect scores were achieved by Malaysian children around 40 months of age. The adapted version can be used to evaluate amplification for children in the Malay speaking environment. The normative curve relating age to scores for the Malay PEACH can be used as a reference against which functional aural/oral performance of hearing-impaired Malaysian children can be evaluated.	\N	\N
22177319	To compare the audiologic outcome and feasibility of bone-anchored hearing aid (BAHA) and external auditory canal reconstruction (EACR) surgeries in pediatric patients presenting a congenital aural atresia (CAA). A retrospective chart review of 40 patients operated in our tertiary pediatric care center between 2002 and 2010 was performed. 20 patients underwent EACR, whereas another 20 patients were implanted with a BAHA device. Air conduction (AC), bone conduction (BC), pure tone average (PTA) and speech discrimination score (SDS) were compared preoperatively, and hearing gain (HG) postoperatively at 6 and at 12 months at frequencies of 500, 1000, 2000 and 4000 Hz. Operative time, complications and associated microtia were documented as well. EACR patients were graded retrospectively upon Jahrsdoerfer's classification. Preoperative AC were significantly different between groups, at 500, 1000 and 2000 Hz but not at 4000 Hz. BAHA group compared postoperatively to EACR group showed significantly a superior HG of 46.9 ± 7.0 dB (p<0.001) and of 39.8(7) ± 7.2(6.9)dB (p<0.001) at 6 months and at 1 year, respectively. Moreover, aided air thresholds from the EACR group revealed an audiologic status similar to those of the BAHA group patients, at 6 months and one year postoperatively. Both groups had a similar evolution of their BC, as well as of the incidence of complications. We report one case of transient facial paralysis in the EACR group. Total operative time is significantly lower (p<0.001) for a BAHA implantation (56 ± 21 min) than for EACR surgery (216 ± 174 min). No preoperative or postoperative correlation (Pearson correlation test; p>0.05) was found between patient's Jahrsdoerfer's score and their audiologic outcome. HG does not seem to be influenced by the presence of microtia. EACR, although constituting an attractive option, does not give acceptable results alone. It can however, when combined to conventional air conduction hearing aids, provide excellent audiologic outcomes comparable to BAHA. BAHA implantation is a reliable, safe and efficient therapeutic option that allows a significantly better audiologic outcome when compared to unaided EACR for patients with CAA.	\N	\N
22178340	Determine the prevalence of 35delG mutation in GJB2 gene in patients with prelingual deafness of no defined etiology whose underwent cochlear implant in the Otolaryngology Department at the Hospital de Clínicas de Porto Alegre and compare the speech recognition index using an open-set of sentences according to the presence or absence of the 35delG mutation. Cross-sectional study nested in a cohort. Were analyzed 37 patients with indeterminate etiology for deafness that underwent to cochlear implant. DNA was extracted and the mutations were studied using Polymerase Chain Reaction followed by gene sequencing. The prevalence of 35delG mutation was 11%. The speech recognition index was 72% in the group with 35delG mutation, and 30% in the group without this mutation (p>0.05). Prevalence of 35delG mutation in this study confirmed findings in the Brazilian literature. There was a clinically significant difference in hearing performance in patients with 35delG. Absence of statistical significance in this result might be attributed to the small number of patients with 35delG in our sample.	\N	\N
22178454	When speech is interrupted by noise, listeners often perceptually "fill-in" the degraded signal, giving an illusion of continuity and improving intelligibility. This phenomenon involves a neural process in which the auditory cortex (AC) response to onsets and offsets of acoustic interruptions is suppressed. Since meaningful visual cues behaviorally enhance this illusory filling-in, we hypothesized that during the illusion, lip movements congruent with acoustic speech should elicit a weaker AC response to interruptions relative to static (no movements) or incongruent visual speech. AC response to interruptions was measured as the power and inter-trial phase consistency of the auditory evoked theta band (4-8 Hz) activity of the electroencephalogram (EEG) and the N1 and P2 auditory evoked potentials (AEPs). A reduction in the N1 and P2 amplitudes and in theta phase-consistency reflected the perceptual illusion at the onset and/or offset of interruptions regardless of visual condition. These results suggest that the brain engages filling-in mechanisms throughout the interruption, which repairs degraded speech lasting up to ~250 ms following the onset of the degradation. Behaviorally, participants perceived speech continuity over longer interruptions for congruent compared to incongruent or static audiovisual streams. However, this specific behavioral profile was not mirrored in the neural markers of interest. We conclude that lip-reading enhances illusory perception of degraded speech not by altering the quality of the AC response, but by delaying it during degradations so that longer interruptions can be tolerated.	\N	\N
22178980	When hearing thresholds are measured with high-frequency resolution there is a pseudo-periodic variation in thresholds across frequency of up to 15-20dB. This variation is called threshold fine structure (previously referred to as threshold microstructure). Consequently, estimates of auditory status based on threshold measures can depend greatly on the specific frequency evaluated. The impact of threshold fine structure on the prediction of auditory status was examined by measuring detection thresholds of pure tones (providing an indication of threshold fine structure) and comparing them with thresholds obtained using linear sweeps, sinusoidally frequency modulated tones, and narrow-band noise. Spontaneous otoacoustic emissions (SOAEs) were also obtained to confirm the established relationship between threshold fine structure and SOAEs. Thresholds obtained using linear sweeps and narrow-band noise provided stable threshold estimates indicating that such threshold estimates were less influenced by threshold fine structure. Consequently, thresholds obtained with these stimuli may provide estimates of cochlear status less dependent of the exact frequency being evaluated, permitting better prediction of performance on other psychoacoustic measures (such as cochlear tuning and loudness perception) and the properties of their more objective measures (such as otoacoustic emissions).	\N	\N
22180019	The purpose of the study was to determine why perceived spatial separation provides a greater release from informational masking in Chinese than English when target sentences in each of the languages are masked by other talkers speaking the same language. Monolingual speakers of English and Mandarin Chinese listened to semantically anomalous sentences in their own language when 1 of 3 maskers was present (speech-spectrum noise, a 2-talker speech masker in the same language, and a 2-talker speech masker in the other language). Both groups benefitted equally from spatial separation when the maskers were speech-spectrum noise or cross-language. Chinese listeners benefitted less from spatial separation than did English listeners when a same-language masker was used. Performance was scored in terms of the number of target words correctly identified; because Chinese target words were composed of 2 "stand-alone" morphemes, the authors also scored Chinese target words as correct when either of the morphemes was correctly identified. When this was done, Chinese and English listeners benefitted equally from spatial separation in all conditions. These results support a model in which release from informational masking in both monolingual English and Chinese listeners occurs because spatial separation facilitates morpheme access in both languages.	\N	\N
22183905	To evaluate the long-term results and predictive factors of a good outcome with the use of a total ossicular replacement prosthesis in children. Retrospective case review. Tertiary referral center. The study included 114 children (116 ears). A total of 116 ears underwent total ossicular chain reconstruction with a titanium prosthesis. Cartilage was always used for tympanic membrane reconstruction. Audiological results were evaluated according to the guidelines of the American Academy of Otolaryngology-Head and Neck Surgery. Predictive factors of audiological results were determined. Logistic regression and χ(2) tests were used for statistical analysis. The mean age at surgery was 9.8 years. Ossiculoplasty was performed during second-look surgery in 91 ears (78.4%) and during another stage in 25 ears (21.6%). The first-stage procedure was always performed for cholesteatoma. Audiometric results were available for 116 ears at 1 year, for 89 ears (76.7%) at 2 years, and for 42 ears (36.2%) at 5 years. Closure of the average air-bone gap (ABG) to within 20 dB was achieved in 65 ears (56%) at 1 year. The mean (SD) preoperative and postoperative (at 1 year) ABGs were 41.0 (9.5) dB and 22.4 (12.6) dB, respectively. There were no cases of extrusion, but 17 luxations of the prosthesis were confirmed by computed tomography. Luxation occurred on average at 31.4 months. Only three 4000-Hz degradations of bone conduction were reported, with no dead ears. We examined 3 predictive factors of auditory results: preoperative ABG, footplate status, and postoperative otoscopic findings. Total ossiculoplasty is a reliable technique in children. Long-term hearing outcomes are stable and satisfactory, but luxation can occur at any time. Preoperative ABG and footplate status are negative predictive factors of auditory results.	\N	\N
22196341	It has recently been conjectured that dyslexia arises from abnormal auditory sampling. What sampling rate is altered and how it affects reading remains unclear. We hypothesized that by impairing phonemic parsing abnormal low-gamma sampling could yield phonemic representations of unusual format and disrupt phonological processing and verbal memory. Using magnetoencephalography and behavioral tests, we show in dyslexic subjects a reduced left-hemisphere bias for phonemic processing, reflected in less entrainment to ≈30 Hz acoustic modulations in left auditory cortex. This deficit correlates with measures of phonological processing and rapid naming. We further observed enhanced cortical entrainment at rates beyond 40 Hz in dyslexics and show that this particularity is associated with a verbal memory deficit. These data suggest that a single auditory anomaly, i.e., phonemic oversampling in left auditory cortex, accounts for three main facets of the linguistic deficit in dyslexia.	\N	\N
22196745	Prosody can be expressed not only by modification to the timing, stress and intonation of auditory speech but also by modifying visual speech. Studies have shown that the production of visual cues to prosody is highly variable (both within and across speakers), however behavioural studies have shown that perceivers can effectively use such visual cues. The latter result suggests that people are sensitive to the type of prosody expressed despite cue variability. The current study investigated the extent to which perceivers can match visual cues to prosody from different speakers and from different face regions. Participants were presented two pairs of sentences (consisting of the same segmental content) and were required to decide which pair had the same prosody. Experiment 1 tested visual and auditory cues from the same speaker and Experiment 2 from different speakers. Experiment 3 used visual cues from the upper and the lower face of the same talker and Experiment 4 from different speakers. The results showed that perceivers could accurately match prosody even when signals were produced by different speakers. Furthermore, perceivers were able to match the prosodic cues both within and across modalities regardless of the face area presented. This ability to match prosody from very different visual cues suggests that perceivers cope with variation in the production of visual prosody by flexibly mapping specific tokens to abstract prosodic types.	\N	\N
22199181	In perception studies, it is common to use vowel stimuli from standardized recordings or synthetic stimuli created using values from well-known published research. Although the use of standardized stimuli is convenient, unconsidered dialect and regional accent differences may introduce confounding effects. The goal of this study was to examine the effect of regional accent variation on vowel identification. The authors analyzed formant values of 8 monophthong vowels produced by 12 talkers from the region where the research took place and compared them with standardized vowels. Fifteen listeners with normal hearing identified synthesized vowels presented in varying levels of noise and at varying spectral distances from the local-dialect values. Acoustically, local vowels differed from standardized vowels, and distance varied across vowels. Perceptually, there was a robust effect of accent similarity such that identification was reduced for vowels at greater distances from local values. Researchers and clinicians should take care in choosing stimuli for perception experiments. It is recommended that regionally validated vowels be used instead of relying on standardized vowels in vowel perception tasks.	\N	\N
22199197	The current study measured, objectively and subjectively, how changes in speech rate affect recognition of English passages in bilingual listeners. Ten native monolingual, 20 English-dominant bilingual, and 20 non-English-dominant bilingual listeners repeated target words in English passages at five speech rates (unprocessed, two expanded, and two compressed), in quiet and in noise. For noise conditions, performance was measured at a signal-to-noise ratio that was determined through an adaptive procedure to avoid ceiling and floor effects. Listeners also made subjective judgments of speech rate, speech clarity, and performance confidence. In noise, stepwise improvement was observed as rate slowed down. A similar effect was not found in quiet. This pattern in performance was largely comparable across listener groups but was most robust in English-dominant listeners. Changes in speech rate and presence of noise significantly affected listeners' subjective ratings; however, no intergroup differences were observed for any of the subjective ratings. Bilingual listeners benefited from slow speech rates, more evidently so in noise than in quiet. Their performance, however, did not reach a monolingual level, even at the most favorable rate. Nonetheless, all listeners reported comparable confidence when processing temporally manipulated English passages.	\N	\N
22207311	We used eyetracking, perceptual discrimination, and production tasks to examine the influences of perceptual similarity and linguistic experience on word recognition in nonnative (L2) speech. Eye movements to printed words were tracked while German and Dutch learners of English heard words containing one of three pronunciation variants (/t/, /s/, or /f/) of the interdental fricative /θ/. Irrespective of whether the speaker was Dutch or German, looking preferences for target words with /θ/ matched the preferences for producing /s/ variants in German speakers and /t/ variants in Dutch speakers (as determined via the production task), while a control group of English participants showed no such preferences. The perceptually most similar and most confusable /f/ variant (as determined via the discrimination task) was never preferred as a match for /θ/. These results suggest that linguistic experience with L2 pronunciations facilitates recognition of variants in an L2, with effects of frequency outweighing effects of perceptual similarity.	\N	\N
22212698	Auditory-evoked potentials represent the response of the auditory pathway to an auditory stimulus. Specific language impairment (SLI) children have delayed language development with difficulties in both understanding and producing spoken language. Hence, the purpose of this study was to determine whether a group of children with SLI had abnormal changes in the auditory middle latency response (AMLR). AMLR was obtained for 19 SLI children and they were studied and compared to normal. Audiological assessment and speech language tests were done for the study group. The results revealed no significant statistical differences between SLI children and the normal with regard to AMLR (P > 0.05). Our results suggest that children with SLI do not have abnormal auditory system response at the level measured by AMLR casting doubt on affection of the hypnotized origin of AMLR, mainly primary auditory cortex, as a cause for delayed language development in those children.	\N	\N
22212767	The LiSN & Learn auditory training software was developed specifically to improve binaural processing skills in children with suspected central auditory processing disorder who were diagnosed as having a spatial processing disorder (SPD). SPD is defined here as a condition whereby individuals are deficient in their ability to use binaural cues to selectively attend to sounds arriving from one direction while simultaneously suppressing sounds arriving from another. As a result, children with SPD have difficulty understanding speech in noisy environments, such as in the classroom. To develop and evaluate the LiSN & Learn auditory training software for children diagnosed with the Listening in Spatialized Noise-Sentences Test (LiSN-S) as having an SPD. The LiSN-S is an adaptive speech-in-noise test designed to differentially diagnose spatial and pitch-processing deficits in children with suspected central auditory processing disorder. Participants were nine children (aged between 6 yr, 9 mo, and 11 yr, 4 mo) who performed outside normal limits on the LiSN-S. In a pre-post study of treatment outcomes, participants trained on the LiSN & Learn for 15 min per day for 12 weeks. Participants acted as their own control. Participants were assessed on the LiSN-S, as well as tests of attention and memory and a self-report questionnaire of listening ability. Performance on all tasks was reassessed after 3 mo where no further training occurred. The LiSN & Learn produces a three-dimensional auditory environment under headphones on the user's home computer. The child's task was to identify a word from a target sentence presented in background noise. A weighted up-down adaptive procedure was used to adjust the signal level of the target based on the participant's response. On average, speech reception thresholds on the LiSN & Learn improved by 10 dB over the course of training. As hypothesized, there were significant improvements in posttraining performance on the LiSN-S conditions where the target and distracter stimuli are spatially separated and which specifically evaluate binaural processing ability (p ranging from <.003 to .0001, η2 ranging from 0.694 to 0.873). In contrast, there was no improvement on the LiSN-S control conditions where the target and distracter stimuli emanate from the same direction (p ranging from .07 to .86, η2 ranging from 0.362 to 0.004). Significant improvements were found posttraining on measures of memory, on one measure of attention, and on self-reported ratings of listening ability. There were no significant differences between post- and 3 mo posttraining scores on any of the assessment tools. The initial LiSN & Learn study has shown that children as young as 6 yr of age are able to complete the training (although some coaxing was needed in a minority of cases). Both parents and children have reported benefits from the training, and feedback from the trial has resulted in extra features being added to the software. In order to further evaluate the efficacy of LiSN & Learn to remediate binaural processing deficits in children a clinical trial is currently under way utilizing a randomized blinded control group design.	\N	\N
22212768	The Australian version of the Listening in Spatialized Noise-Sentences Test (LiSN-S) was originally developed to assess auditory stream segregation skills in children aged 6 to 11 yr with suspected central auditory processing disorder. The LiSN-S creates a three-dimensional auditory environment under headphones. A simple repetition-response protocol is used to assess a listener's speech reception threshold (SRT) for target sentences presented in competing speech maskers. Performance is measured as the improvement in SRT in decibels gained when either pitch, spatial, or both pitch and spatial cues are incorporated in the maskers. To collect additional normative data on the Australian LiSN-S for adolescents and adults up to 60 yr of age, to analyze the effects of age on LiSN-S performance, to examine retest reliability in the older population, and to extrapolate findings from the Australian data so that the North American version of the test can also be used clinically with older adults. In a descriptive design, normative and test-retest reliability data were collected from adolescents and adults and combined with previously published data from Australian children aged 6 to 11 yr. One hundred thirty-two participants with normal hearing aged 12 yr, 0 mo, to 60 yr, 7 mo, took part in the normative data study. Fifty-five participants returned between 2 and 4 mo after the initial assessment for retesting. Analysis of variance revealed a significant effect of age on LiSN-S performance (p < .01 for all LiSN-S measures, ηp2 ranging from 0.16 to 0.54). On the low and high cue SRT measures, planned contrasts revealed significant differences between adults and children aged 13 yr and younger, as well as between 50- to 60-yr-olds and younger adults aged 18-29 yr. Whereas there were significant differences between adults and children on the talker, spatial, and total advantage measures, there were no significant differences in performance in adults aged 18-60 yr. There was a small but significant improvement on retest ranging from 0.5 to 1.2 dB across the four LiSN-S test conditions (p ranging from .01 to <.001). However, there was no significant difference between test and retest on the advantage measures (p ranging from .143 to .768). Test-retest differences across all LiSN-S measures were significantly correlated (r ranging from 0.2 to 0.7, p ranging from .023 to <.00000001) and did not differ as a function of age (p ranging from .178 to .980). As there was no significant difference among adults aged 18-60 yr on the LiSN-S talker, spatial, and total advantage measures, it appears that the decline in ability to understand speech in noise experienced by 50- to 60-yr-olds is not related to their ability to use either spatial or pitch cues. This result suggests that some other factor/s contributes to the decline in speech perception in noise experienced by older adults that is reported in the literature and was demonstrated in this study on the LiSN-S low and high cue SRT measures.	\N	\N
22213908	Contrasting results have been reported regarding the phonetic acquisition of bilinguals. A lack of discrimination has been observed for certain native contrasts in 8-month-old Catalan-Spanish bilingual infants (Bosch & Sebastián-Gallés, 2003a), though not in French-English bilingual infants (Burns, Yoshida, Hill & Werker, 2007; Sundara, Polka & Molnar, 2008). At present, the data for Catalan-Spanish bilinguals constitute an exception in the early language acquisition literature. This study contributes new findings that show that Catalan-Spanish bilingual infants do not lose the capacity to discriminate native contrasts. We used an adaptation of the anticipatory eye movement paradigm (AEM; McMurray & Aslin, 2004) to explore this question. In two experiments we tested the ability of infants from Catalan and Spanish monolingual families and from Catalan-Spanish bilingual families to discriminate a Spanish-Catalan common and a Catalan-specific vowel contrast. Results from both experiments revealed that Catalan-Spanish bilingual infants showed the same discrimination abilities as those shown by their monolingual peers, even in a phonetic contrast that had not been discriminated in previous studies. Our results demonstrate that discrimination can be observed in 8-month-old bilingual infants when tested with a measure not based on recovery of attention. The high ratio of cognates in Spanish and Catalan may underlie the reason why bilinguals failed to discriminate the native vowels when tested with the familiarization-preference procedure but succeeded with the AEM paradigm.	\N	\N
22216557	The purpose of this research was twofold: firstly, to develop a music perception test (MPT) for hearing-aid users, and secondly, to evaluate the influence of non-linear frequency compression (NFC) on music perception with the use of the self-compiled test. This article focuses on the description of the development and validation of the MPT. To date, the main direction in frequency-lowering hearing-aid studies has been in relation to speech perception abilities. As hearing-aid technology has improved, interest has grown in musical perception as a dimension that could improve hearing-aid users' quality of life. The MPT was designed to evaluate different aspects of rhythm, timbre, pitch and melody. The development of the MPT could be described as design-based. Phase 1 of the study included test development and recording, while phase 2 entailed presentation of stimuli to normal hearing listeners (n = 15) and hearing-aid users (n = 4). Based on the findings of phase 2, item analysis was performed to eliminate or change stimuli that resulted in high error rates. During phase 3 the adapted version of the test was performed on a smaller group of normal hearing listeners (n = 4) and 20 hearing-aid users. Results proved that adults with normal hearing as well as adults using hearing aids were able to complete all the sub-tests of the MPT, although hearing-aid users scored lower on the various sub-tests than normal hearing listeners. For the rhythm section of the MPT normal hearing listeners scored on average 93.8% versus 75.5% of hearing-aid users; for the timbre section the scores were 83% versus 62.3% respectively. Normal hearing listeners obtained an average score of 86.3% for the pitch section and 88.2% for the melody section, compared with the 70.8% and 61.9% respectively obtained by hearing-aid users. This implies that the MPT can be used successfully for assessment of music perception in hearing-aid users within the South African context and may therefore result in more effective hearing-aid fittings taking place. The test can be used as a counselling tool to assist audiologists and patients in understanding the problems they experience regarding music perception, and might be used for future musical training in areas where participants experience problems in customising individual fittings.	\N	\N
22217385	Various recent studies attest that reading involves creating an implicit prosodic representation of the written text which may systematically affect the resolution of syntactic ambiguities in sentence comprehension. Research up to now suggests that implicit prosody itself depends on a partial syntactic analysis of the text, raising the question of whether implicit prosody contributes to the parsing process, or whether it merely interprets the syntactic analysis. The present reading experiments examine the influence of stress-based linguistic rhythm on the resolution of local lexical-syntactic ambiguities in German. Both speech production data from unprepared oral reading and eye-tracking results from silent reading demonstrate that readers favor syntactic analyses that allow for a prosodic representation in which stressed and unstressed syllables alternate rhythmically. The findings contribute evidence confirming immediate and guiding effects of linguistic rhythm on the earliest stages of syntactic parsing in reading.	\N	\N
22221469	Auditory sustained responses have been recently suggested to reflect neural processing of speech sounds in the auditory cortex. As periodic fluctuations below the pitch range are important for speech perception, it is necessary to investigate how low frequency periodic sounds are processed in the human auditory cortex. Auditory sustained responses have been shown to be sensitive to temporal regularity but the relationship between the amplitudes of auditory evoked sustained responses and the repetitive rates of auditory inputs remains elusive. As the temporal and spectral features of sounds enhance different components of sustained responses, previous studies with click trains and vowel stimuli presented diverging results. In order to investigate the effect of repetition rate on cortical responses, we analyzed the auditory sustained fields evoked by periodic and aperiodic noises using magnetoencephalography. Sustained fields were elicited by white noise and repeating frozen noise stimuli with repetition rates of 5-, 10-, 50-, 200- and 500 Hz. The sustained field amplitudes were significantly larger for all the periodic stimuli than for white noise. Although the sustained field amplitudes showed a rising and falling pattern within the repetition rate range, the response amplitudes to 5 Hz repetition rate were significantly larger than to 500 Hz. The enhanced sustained field responses to periodic noises show that cortical sensitivity to periodic sounds is maintained for a wide range of repetition rates. Persistence of periodicity sensitivity below the pitch range suggests that in addition to processing the fundamental frequency of voice, sustained field generators can also resolve low frequency temporal modulations in speech envelope.	\N	\N
22224482	We reported a case of an elderly female patient affected by musical hallucinations (MHs) as the unique symptom of a right temporal ischemic stroke. A functional magnetic resonance imaging examination was performed in the patient and in five age- and sex-matched normal controls (NC) to detect the complex neural substrate subserving MHs in such a context. Although an activation pattern involving the primary auditory cortex and the temporal associative areas bilaterally was found in the patient and NC, a significant increased activation mostly located in right temporal cortex (in the ischemic area), was observed in the patient. Further functional neuroimaging studies should be performed to detect the complex neural pathways underlying MHs and to find out differences between these hallucinations and real music perception.	\N	\N
22227006	Aging disrupts neural timing, reducing the nervous system's ability to precisely encode sound. Given that the neural representation of temporal features is strengthened with musical training in young adults, can musical training offset the negative impact of aging on neural processing? By comparing auditory brainstem timing in younger and older musicians and nonmusicians to a consonant-vowel speech sound /da/. we document a musician's resilience to age-related delays in neural timing.	\N	\N
22232409	To compare the development of phonological skills in children with specific language impairment (SLI) with and without literacy delay and to examine whether kindergarten phonological skills could discriminate these 2 groups. In a longitudinal study, 8 children with SLI and literacy delay, 10 children with SLI and normal literacy, and 14 typically developing children were studied from the last year of kindergarten to the start of Grade 3. A wide range of phonological tasks (phonological awareness [PA], verbal short-term memory [vSTM], and rapid automatized naming [RAN]) were administered yearly. The SLI group with literacy delay scored significantly lower than the typically developing children on almost all phonological tasks in all grades, whereas the SLI group with normal literacy scored significantly lower only on demanding PA and vSTM tasks. A combination of kindergarten PA and RAN skills could correctly classify 75% of the children with SLI. By including vSTM, the discriminatory value did not increase. Children with SLI and normal literacy at age 8;1 [years;months] continued to have difficulties with demanding PA and vSTM tasks. Children with SLI and poor PA and RAN in kindergarten were at high risk of developing literacy problems in a transparent orthography.	\N	\N
22237762	The objective of the study was to compare the performance of cochlear implantation between post-meningitic and non-meningitic patients, and to evaluate the impact on hearing outcome of technical advances in cochlear implant technology. Retrospective chart review was used as the study design. Twenty adults with post-meningitic profound hearing loss receiving unilateral or bilateral cochlear implants between 1990 and 2008 were tested. Results were compared to a control group of 46 adults implanted for a non-meningitic hearing loss, with the same pre-operative speech scores. Speech scores were poorer in post-meningitic patients compared to those of control group, whatever the duration after implantation (p < 0.0001). Speech scores of subjects implanted and fitted before 2001 were compared to those of subjects implanted after 2001, with the same duration of hearing loss. Performance improved with implants and processors available after 2001, with a magnitude of improvement higher in post-meningitic patients (p < 0.0001 and p < 0.05 in post-meningitic and control groups, respectively, two-way ANOVA). Consequently, speech scores of post-meningitic patients implanted after 2001 achieved those of control subjects (two-way ANOVA). Advances in cochlear implant technology and coding strategy improve hearing outcome in post-meningitic adult patients, who now achieve similar performance as those of non-meningitic patients.	\N	\N
22246139	Dynamic-range compression is routinely used in bilaterally fitted hearing devices. The objective of this study was to investigate how compression applied independently at each ear affects spatial perception in normal-hearing listeners and to relate the effects to changes in binaural cues caused by the compression for different types of sound. A semantic-differential method was used to measure the spatial attributes of sounds. Eleven normal-hearing participants responded to questions addressing certainty of location, diffuseness, movement, image splits, and externalization of sounds. Responses were given on seven-point scales between pairs of opposing terms. Stimuli included speech and a range of synthetic sounds with varying characteristics. Head-related transfer functions were used to simulate a source at an azimuth of -60° or +60°. Three processing conditions were compared: (1) an unprocessed reference condition; (2) fast-acting, wide-dynamic-range compression operating independently at each ear; and (3) imposition of a static bias in interaural level difference (ILD) equivalent to that generated by the compression under steady state conditions. All processing was applied in a high-frequency channel above 2 kHz. The three processing conditions were compared separately in two bandwidth conditions: a high-pass condition in which the high-frequency channel was presented to listeners in isolation and a full-bandwidth condition in which the high-frequency channel was recombined with the unprocessed low-frequency channel. Hierarchical cluster analysis was used to group related questions based on similarity of participants' responses. This led to the calculation of composite scores for four spatial attributes: "diffuseness," "movement," "image split," and "externalization." Compared with the unprocessed condition, fast-acting compression significantly increased diffuseness, movement, and image-split scores and significantly reduced externalization scores. The effects of compression were greater when listeners heard the high-frequency channel in isolation than when it was recombined with the unprocessed low-frequency channel. The effects were apparent only for sounds containing gradual onsets and offsets, including speech. Dynamic compression had a much more pronounced effect on the spatial attributes of sounds than imposition of a static bias in ILD. Fast-acting compression at high frequencies operating independently at each ear can adversely affect the spatial attributes of sounds in normal-hearing listeners by increasing diffuseness, increasing or giving rise to a sense of movement, causing images to split, and affecting the externalization of sounds. The effects are reduced, but not eliminated, when listeners have access to undisturbed low-frequency cues. Sounds containing gradual onsets and offsets, including speech, are most affected. The effects arise primarily as a result of relatively slow changes in ILD that are generated as the sound level at one or both ears crosses the compression threshold. The results may have implications for the use of compression in bilaterally fitted hearing devices, specifically in relation to spatial perception in dynamic situations.	\N	\N
22248574	Feedback connections among auditory cortical regions may play an important functional role in processing naturalistic speech, which is typically considered a problem solved through serial feed-forward processing stages. Here, we used fMRI to investigate whether activity within primary auditory cortex (PAC) is sensitive to the perceived clarity of degraded sentences. A region-of-interest analysis using probabilistic cytoarchitectonic maps of PAC revealed a modulation of activity, in the most primary-like subregion (area Te1.0), related to the intelligibility of naturalistic speech stimuli that cannot be driven by stimulus differences. Importantly, this effect was unique to those conditions accompanied by a perceptual increase in clarity. Connectivity analyses suggested sources of input to PAC are higher-order temporal, frontal and motor regions. These findings are incompatible with feed-forward models of speech perception, and suggest that this problem belongs amongst modern perceptual frameworks in which the brain actively predicts sensory input, rather than just passively receiving it.	\N	\N
22251287	Previous behavioural research suggests that infants possess phonologically detailed representations of the vowels and consonants in familiar words. These tasks examine infants' sensitivity to mispronunciations of a target label in the presence of a target and distracter image. Sensitivity to the mispronunciation may, therefore, be contaminated by the degree of mismatch between the distracter label and the heard mispronounced label. Event-related potential (ERP) studies allow investigation of infants' sensitivity to the relationship between a heard label (correct or mispronounced) and the referent alone using single picture trials. ERPs also provide information about the timing of lexico-phonological activation in infant word recognition. The current study examined 14-month-olds' sensitivity to vowel mispronunciations of familiar words using ERP data from single picture trials. Infants were presented with familiar images followed by a correct pronunciation of its label, a vowel mispronunciation or a phonologically unrelated non-word. The results support and extend previous behavioural findings that 14-month-olds are sensitive to mispronunciations of the vowels in familiar words using an ERP task. We suggest that the presence of pictorial context reinforces infants' sensitivity to mispronunciations of words, and that mispronunciation sensitivity may rely on infants accessing the cross-modal associations between word forms and their meanings.	\N	\N
22256834	This study investigated the impact of an established behavioural dysarthria treatment on acoustic and perceptual measures of speech in two adults with Down syndrome (DS) and dysarthria to obtain preliminary measures of treatment effect, effect size and treatment feasibility. A single-subject A-B-A experimental design was used to measure the effects of the Lee Silverman Voice treatment (LSVT®) on speech in two adults with DS and dysarthria. Dependent measures included vocal sound pressure level (dB SPL), phonatory stability and listener intelligibility scores. Statistically significant improvements (p < 0.05) in vocal dB SPL and phonatory stability were present following treatment in both participants. Speech intelligibility scores improved in one of the two participants. These data suggest that people with DS and dysarthria can respond positively to intensive speech treatment such as LSVT. Further investigations are needed to develop speech treatments specific to DS.	\N	\N
22265373	We discuss experimental support for the existence of a corollary discharge signal of attention movement control and its formulation in terms of the corollary discharge of attention model of attention movement (CODAM). The data is from fMRI, MEG and EEG activity observed about 200 ms after stimulus onset in various attention paradigms and in which the activity is mainly sited in parietal and extra-striate visual areas. Moreover the data arises from neural activity observed before report of a subject's experience occurs. The overall experimental support for the existence of a copy of the attention movement control signal generates, it is suggested, a viable route to explore the relation between this signal and human consciousness, as concluded in the paper.	\N	\N
22280585	Despite many studies investigating auditory spatial impressions in rooms, few have addressed the impact of simultaneous visual cues on localization and the perception of spaciousness. The current research presents an immersive audiovisual environment in which participants were instructed to make auditory width judgments in dynamic bi-modal settings. The results of these psychophysical tests suggest the importance of congruent audio visual presentation to the ecological interpretation of an auditory scene. Supporting data were accumulated in five rooms of ascending volumes and varying reverberation times. Participants were given an audiovisual matching test in which they were instructed to pan the auditory width of a performing ensemble to a varying set of audio and visual cues in rooms. Results show that both auditory and visual factors affect the collected responses and that the two sensory modalities coincide in distinct interactions. The greatest differences between the panned audio stimuli given a fixed visual width were found in the physical space with the largest volume and the greatest source distance. These results suggest, in this specific instance, a predominance of auditory cues in the spatial analysis of the bi-modal scene.	\N	\N
22280586	When speech is in competition with interfering sources in rooms, monaural indicators of intelligibility fail to take account of the listener's abilities to separate target speech from interfering sounds using the binaural system. In order to incorporate these segregation abilities and their susceptibility to reverberation, Lavandier and Culling [J. Acoust. Soc. Am. 127, 387-399 (2010)] proposed a model which combines effects of better-ear listening and binaural unmasking. A computationally efficient version of this model is evaluated here under more realistic conditions that include head shadow, multiple stationary noise sources, and real-room acoustics. Three experiments are presented in which speech reception thresholds were measured in the presence of one to three interferers using real-room listening over headphones, simulated by convolving anechoic stimuli with binaural room impulse-responses measured with dummy-head transducers in five rooms. Without fitting any parameter of the model, there was close correspondence between measured and predicted differences in threshold across all tested conditions. The model's components of better-ear listening and binaural unmasking were validated both in isolation and in combination. The computational efficiency of this prediction method allows the generation of complex "intelligibility maps" from room designs.	\N	\N
22280718	The high soprano range was investigated by acoustic and electroglottographic measurements of 12 sopranos and high-speed endoscopy of one of these. A single laryngeal transition was observed on glissandi above the primo passaggio. It supports the existence of two distinct laryngeal mechanisms in the high soprano range: M2 and M3, underlying head and whistle registers. The laryngeal transition occurred gradually over several tones within the interval D#5-D6. It occurred over a wider range and was completed at a higher pitch for trained than untrained sopranos. The upper limit of the laryngeal transition during glissandi was accompanied by pitch jumps or instabilities, but, for most singers, it did not coincide with the upper limit of R1:f(0) tuning (i.e., tuning the first resonance to the fundamental frequency). However, pitch jumps could also be associated with changes in resonance tuning. Four singers demonstrated an overlap range over which they could sing with a full head or fluty resonant quality. Glottal behaviors underlying these two qualities were similar to the M2 and M3 mechanisms respectively. Pitch jumps and discontinuous glottal and spectral changes characteristic of a M2-M3 laryngeal transition were observed on decrescendi produced within this overlap range.	\N	\N
22289805	Human speech perception is highly resilient to acoustic distortions. In addition to distortions from external sound sources, degradation of the acoustic structure of the sound itself can substantially reduce the intelligibility of speech. The degradation of the internal structure of speech happens, for example, when the digital representation of the signal is impoverished by reducing its amplitude resolution. Further, the perception of speech is also influenced by whether the distortion is transient, coinciding with speech, or is heard continuously in the background. However, the complex effects of the acoustic structure and continuity of the distortion on the cortical processing of degraded speech are unclear. In the present magnetoencephalography study, we investigated how the cortical processing of degraded speech sounds as measured through the auditory N1m response is affected by variation of both the distortion type (internal, external) and the continuity of distortion (transient, continuous). We found that when the distortion was continuous, the N1m was significantly delayed, regardless of the type of distortion. The N1m amplitude, in turn, was affected only when speech sounds were degraded with transient internal distortion, which resulted in larger response amplitudes. The results suggest that external and internal distortions of speech result in divergent patterns of activity in the auditory cortex, and that the effects are modulated by the temporal continuity of the distortion.	\N	\N
22292057	To the extent that sensorineural systems are efficient, redundancy should be extracted to optimize transmission of information, but perceptual evidence for this has been limited. Stilp and colleagues recently reported efficient coding of robust correlation (r = .97) among complex acoustic attributes (attack/decay, spectral shape) in novel sounds. Discrimination of sounds orthogonal to the correlation was initially inferior but later comparable to that of sounds obeying the correlation. These effects were attenuated for less-correlated stimuli (r = .54) for reasons that are unclear. Here, statistical properties of correlation among acoustic attributes essential for perceptual organization are investigated. Overall, simple strength of the principal correlation is inadequate to predict listener performance. Initial superiority of discrimination for statistically consistent sound pairs was relatively insensitive to decreased physical acoustic/psychoacoustic range of evidence supporting the correlation, and to more frequent presentations of the same orthogonal test pairs. However, increased range supporting an orthogonal dimension has substantial effects upon perceptual organization. Connectionist simulations and Eigenvalues from closed-form calculations of principal components analysis (PCA) reveal that perceptual organization is near-optimally weighted to shared versus unshared covariance in experienced sound distributions. Implications of reduced perceptual dimensionality for speech perception and plausible neural substrates are discussed.	\N	\N
22292257	To investigate the effect of regular scuba diving on the hearing thresholds of sport divers who have no history of noise exposure or ear-related accidents. Comprehensive topographic examination of the peripheral hearing system of sport divers. Cross-sectional study. General sport diving community. 81 sport divers with a mean of 300 dives each were compared to a control group of 81 non-divers. Participants were classified into three age groups. Examination included microscopic otoscopy, tympanometry, pure-tone audiometry (PTA) including air and bone conduction, speech audiometry and otoacoustic emissions (OAE). PTA suggested significant differences of the hearing thresholds at several frequencies between sport divers and non-divers in all age groups, although a Bonferroni correction for multiple testing was applied. Interestingly, the results were contradictory. Divers obtained better hearing results in air conduction, whereas non-divers showed better results in bone conduction. Speech audiometry and OAE did not reveal significant differences. There are no published studies of the peripheral cochlear system of divers that have used a combination of PTA, speech audiometry and OAE. All studies suggesting hearing impairment in divers were based on PTA and might have been influenced by a lack of accuracy of PTA. Our results suggest that diving does not adversely affect the hearing system of sport divers. A thorough test battery of audiological methods implying PTA, speech audiometry and OAE may contribute to offer more reliable results to answer the question of whether commercial or military divers are at higher risk for hearing detoriation.	\N	\N
22293014	More than 100 years ago, Huey (1908/1968) indicated that the upper part of words was more relevant for perception than the lower part. Here we examined whether mutilated words, in their upper/lower portions (e.g., ), can automatically access their word units in the mental lexicon. To that end, we conducted four masked repetition priming experiments with the lexical decision task. Results showed that mutilated primes produced a sizeable masked repetition priming effect. Furthermore, the magnitude of the masked repetition priming effect was greater when the upper part of the primes was preserved than when the lower portion was preserved-this was the case not only when the mutilated words were presented in lower case but also when the mutilated words were presented in upper case. Taken together, these findings suggest that the front-end of computational models of visual-word recognition should be modified to provide a more realistic account at the level of letter features.	\N	\N
22305992	To form a unified percept of our environment, the human brain integrates information within and across the senses. This MEG study investigated interactions within and between sensory modalities using a frequency analysis of steady-state responses that are elicited time-locked to periodically modulated stimuli. Critically, in the frequency domain, interactions between sensory signals are indexed by crossmodulation terms (i.e. the sums and differences of the fundamental frequencies). The 3 × 2 factorial design, manipulated (1) modality: auditory, visual or audiovisual (2) steady-state modulation: the auditory and visual signals were modulated only in one sensory feature (e.g. visual gratings modulated in luminance at 6 Hz) or in two features (e.g. tones modulated in frequency at 40 Hz & amplitude at 0.2 Hz). This design enabled us to investigate crossmodulation frequencies that are elicited when two stimulus features are modulated concurrently (i) in one sensory modality or (ii) in auditory and visual modalities. In support of within-modality integration, we reliably identified crossmodulation frequencies when two stimulus features in one sensory modality were modulated at different frequencies. In contrast, no crossmodulation frequencies were identified when information needed to be combined from auditory and visual modalities. The absence of audiovisual crossmodulation frequencies suggests that the previously reported audiovisual interactions in primary sensory areas may mediate low level spatiotemporal coincidence detection that is prominent for stimulus transients but less relevant for sustained SSR responses. In conclusion, our results indicate that information in SSRs is integrated over multiple time scales within but not across sensory modalities at the primary cortical level.	\N	\N
22306805	In human communication, direct speech (e.g., Mary said, "I'm hungry") is perceived as more vivid than indirect speech (e.g., Mary said that she was hungry). This vividness distinction has previously been found to underlie silent reading of quotations: Using functional magnetic resonance imaging (fMRI), we found that direct speech elicited higher brain activity in the temporal voice areas (TVA) of the auditory cortex than indirect speech, consistent with an "inner voice" experience in reading direct speech. Here we show that listening to monotonously spoken direct versus indirect speech quotations also engenders differential TVA activity. This suggests that individuals engage in top-down simulations or imagery of enriched supra-segmental acoustic representations while listening to monotonous direct speech. The findings shed new light on the acoustic nature of the "inner voice" in understanding direct speech.	\N	\N
22310087	To review outcomes following paediatric cholesteatoma surgery performed between 1999 and 2009 in a tertiary paediatric ENT unit. Retrospective case note review. A total of 137 mastoid procedures were recorded. Fifty-four per cent of children were observed to have disease involving the entire middle-ear cleft and mastoid complex. The revision rate was 25 per cent. Time to recurrence was one to three years in 17 patients, three to six years in five patients, and six to nine years in three cases. Eight of 25 revision cases demonstrated spontaneous improvement in air conduction thresholds following primary surgery. A high facial ridge and inadequate meatoplasty correlated highly with disease recurrence. Children tend to present with aggressive disease. Disease extent and ossicular chain involvement are associated with a higher risk of recurrent disease. Spontaneous improvement in hearing thresholds following cholesteatoma surgery should alert the clinician to recurrent disease.	\N	\N
22310374	The use of cochlear implants in the rehabilitation of hearing-impaired patients is now widely established and offers great benefits for children. To evaluate these benefits, the Evaluation of Auditory Responses to Speech (EARS®) assessment tool was designed in 1995. The objectives of this study were to assess the auditory perceptual skills in a large paediatric population over time, as well as to provide standardised values. An international multicentre study was conducted in 35 clinics from 1996 to 2009. During this period, 765 children were assessed with the EARS in 10 test intervals: pre-operative, first fitting and then 1, 3, 6, and 12 months after the first fitting and annually thereafter, up to a maximum period of 5 years. The auditory skills improved significantly over time for all speech perception tests and questionnaires as well as between single test intervals: pre-operative to 6 months, 6 months to 1 year and 1 year to 2 years. Standardised values of the children stratified according to their age at implantation were calculated. The auditory perceptual skills significantly improved over time. The standardised values will help professionals set therapeutic goals and counsel parents accordingly.	\N	\N
22314920	Although cochlear implant (CI) users frequently report deterioration of sound quality when listening to music, few methods exist to quantify these subjective claims. 1) To design a novel research method for quantifying sound quality perception in CI users during music listening; 2) To validate this method by assessing one attribute of music perception, bass frequency perception, which is hypothesized to be relevant to overall musical sound quality perception. Limitations in bass frequency perception contribute to CI-mediated sound quality deteriorations. The proposed method will quantify this deterioration by measuring CI users' impaired ability to make sound quality discriminations among musical stimuli with variable amounts of bass frequency removal. A method commonly used in the audio industry (multiple stimulus with hidden reference and anchor [MUSHRA]) was adapted for CI users, referred to as CI-MUSHRA. CI users and normal hearing controls were presented with 7 sound quality versions of a musical segment: 5 high pass filter cutoff versions (200-, 400-, 600-, 800-, 1000-Hz) with decreasing amounts of bass information, an unaltered version ("hidden reference"), and a highly altered version (1,000-1,200 Hz band pass filter; "anchor"). Participants provided sound quality ratings between 0 (very poor) and 100 (excellent) for each version; ratings reflected differences in perceived sound quality among stimuli. CI users had greater difficulty making overall sound quality discriminations as a function of bass frequency loss than normal hearing controls, as demonstrated by a significantly weaker correlation between bass frequency content and sound quality ratings. In particular, CI users could not perceive sound quality difference among stimuli missing up to 400 Hz of bass frequency information. Bass frequency impairments contribute to sound quality deteriorations during music listening for CI users. CI-MUSHRA provided a systematic and quantitative assessment of this reduced sound quality. Although the effects of bass frequency removal were studied here, we advocate CI-MUSHRA as a user-friendly and versatile research tool to measure the effects of a wide range of acoustic manipulations on sound quality perception in CI users.	\N	\N
22316007	To measure the acceptable noise level (ANL) with and without noise reduction algorithms (NRAs), and to predict ΔANL, i.e. the difference in acceptable noise level with and without NRAs. The ANL test was applied to three NRAs. Furthermore, the measured ΔANL was predicted using several methods based on either the calculation of the signal-to-noise ratio or correlation methods of the processed signals with an unprocessed reference signal. Ten normal-hearing and eleven hearing-impaired subjects accomplished the ANL test. In general, the ANL test could determine an increased acceptance of noise with some NRAs. However, great inter-individual differences also resulted that were attributed to audible distortions when an NRA was used. Prediction of the mean measured DANL was possible, but individual prediction of DANL failed due to inter-individual differences. Mean DANL was predicted more accurately for hearing-impaired subjects when individual hearing loss was taken into account. The ANL test is a suitable tool for measuring the advantage of one NRA. A prediction of the measured individual ΔANL failed. However, mean DANL could be predicted with some methods. Furthermore, the individual hearing loss should be taken into account for a more accurate prediction for hearing-impaired subjects.	\N	\N
22325920	Factors affecting perceptions of occupational suitability were examined for speakers who stutter and speakers who do not stutter. In Experiment 1, 58 adults who do not stutter heard one of two audio recordings (less severe stuttering, more severe stuttering) of a speaker who stuttered. Participants rated the speaker's communicative functioning, personal attributes, and suitability for 32 occupations, along with perceptions of the occupations' speaking demands and educational requirements. Perceived speaking demand strongly affected occupational suitability ratings at both levels of stuttering severity. In Experiment 2, 58 additional adults who do not stutter heard a recording of another adult in one of two conditions (fluent speech, pseudo-stuttering), and provided the same ratings as in Experiment 1. In the pseudo-stuttering condition, participants' perceptions of occupational speaking demand again had a strong effect on occupational suitability ratings. In the fluent condition, suitability ratings were affected primarily by perceived educational demand; perceived speaking demand was of secondary importance. Across all participants in Experiment 2, occupational suitability ratings were associated with ratings of the speaker's personal attributes and communicative functioning. In both experiments, speakers who stuttered received lower suitability ratings for high speaking demand occupations than for low speaking demand occupations. Ratings for many high speaking occupations, however, fell just below the midpoint of the occupational suitability scale, suggesting that participants viewed these occupations as less appropriate, but not necessarily inappropriate, for people who stutter. Overall, the findings support the hypothesis that people who stutter may face occupational stereotyping and/or role entrapment in work settings. At the end of this activity the reader will be able to (a) summarize main findings on research related to the work-related experiences of people who stutter, (b) describe factors that affect perceptions of which occupations are best suited for speakers who stutter and speakers who do not stutter, and (c) discuss how findings from the present study relate to previous findings on occupational advice for people who stutter.	\N	\N
22326589	The present study was aimed at investigating the relationship between the mismatch negativity (MMN) and psychoacoustical effects of sequential streaming on comodulation masking release (CMR). The influence of sequential streaming on CMR was investigated using a psychoacoustical alternative forced-choice procedure and electroencephalography (EEG) for the same group of subjects. The psychoacoustical data showed, that adding precursors comprising of only off-signal-frequency maskers abolished the CMR. Complementary EEG data showed an MMN irrespective of the masker envelope correlation across frequency when only the off-signal-frequency masker components were present. The addition of such precursors promotes a separation of the on- and off-frequency masker components into distinct auditory objects preventing the auditory system from using comodulation as an additional cue. A frequency-specific adaptation changing the representation of the flanking bands in the streaming conditions may also contribute to the reduction of CMR in the stream conditions, however, it is unlikely that adaptation is the primary reason for the streaming effect. A neurophysiological correlate of sequential streaming was found in EEG data using MMN, but the magnitude of the MMN was not correlated with the audibility of the signal in CMR experiments. Dipole source analysis indicated different cortical regions involved in processing auditory streaming and modulation detection. In particular, neural sources for processing auditory streaming include cortical regions involved in decision-making.	\N	\N
22326590	The primary goal of this study was to characterize the variability in auditory-nerve temporal response patterns obtained with the electrically evoked compound action potential (ECAP) within and across a relatively large group of cochlear-implant recipients. ECAPs were recorded in response to each of 21 pulses in a pulse train for five rates (900, 1200, 1800, 2400, and 3500 pps) and three cochlear regions (basal, middle, and apical). An alternating amplitude pattern was typically observed across the pulse train for slower rates, reflecting refractory properties of individual nerve fibers. For faster rates, the alternation ceased and overall amplitudes were substantially lower relative to the first pulse in the train, reflecting cross-fiber desynchronization. The following specific parameters were examined: (1) the rate at which the alternating pattern ceased (termed stochastic rate), (2) the alternation depth and the rate at which the maximum alternation occurred, and (3) the average normalized ECAP amplitude across the pulse train (measure of overall adaptation/desynchronization). Data from 29 ears showed that stochastic rates for the group spanned the entire range of rates tested. The majority of subjects (79%) had different stochastic rates across the three cochlear regions. The stochastic rate occurred most frequently at 2400 pps for basal and middle electrodes, and at 3500 pps for apical electrodes. Stimulus level was significantly correlated with stochastic rate, where higher levels yielded faster stochastic rates. The maximum alternation depth averaged 19% of the amplitude for the first pulse. Maximum alternation occurred most often at 1800 pps for basal and apical electrodes, and at 1200 pps for middle electrodes. These differences suggest some independence between alternation depth and stochastic rate. Finally, the overall amount of adaptation or desynchronization ranged from 63% (for 900 pps) to 23% (for 3500 pps) of the amplitude for the first pulse. Differences in temporal response properties across the cochlea within subjects may have implications for developing new speech-processing strategies that employ varied rates across the array.	\N	\N
22326591	There is evidence that humans represent numbers in the form of a mental number line (MNL). Here we show that the MNL modulates the representation of visual and haptic space both in healthy individuals and right-brain-damaged patients, both with and without left unilateral spatial neglect (USN). Participants were asked to estimate the midpoint of visually or haptically explored rods while listening to task-irrelevant stimuli: a small digit ("2"), a large digit ("8"), or a non-numerical auditory stimulus ("blah"). In a control silent condition, the bisection error of USN patients was biased rightwards (namely, the marker of USN) only in the visual modality. Regardless of the direction of the bisection error committed in silent trials, listening to the small digit shifted the perceived midline leftwards, and listening to the large digit shifted the perceived midline rightwards, compared to a control condition in which a neutral syllable ("blah") was presented. The shift induced by listening to numbers occurred independently of the modality of response (i.e., both in vision and haptics), and in every group of participants. Interestingly, the effect of auditory numbers processing on space estimation was overall larger for haptically than for visually explored space in all participants. In conclusion, the present data show that listening to irrelevant numbers affects space perception also in patients with left USN, indicating that the spatial representation and attention processes disrupted by USN are not involved in these numerical magnitude-spatial effects.	\N	\N
22326876	Individuals diagnosed with schizophrenia show deficiencies of basic neurophysiological sorting mechanisms. This study further investigated this issue, focusing on the two phenomena, laterality of coding and auditory forward masking. A specific audiometric method for use in psychiatry was the measuring set up to register brain stem audiograms (ABRs). A sample of 49 schizophrenic patients was compared with three control groups consisting of healthy reference subjects (n=49), attention deficit hyperactivity disorder (ADHD) patients (n=29), Asperger syndrome (AS) patients (n=13) and drug-induced psychotic patients (n=14). Schizophrenic patients showed significant abnormal laterality of brainstem activity in wave II of the auditory brainstem response (ABR) in comparison with all other study groups. Forward masking effects in the superior olive complex were coded significantly differently by schizophrenic patients compared to control groups except for the AS group. The results suggest deficits in the coding of auditory stimuli in the lower parts of the auditory pathway in schizophrenia and indicate that increased peripheral lateral asymmetry and forward masking aberrances could be neurophysiological markers for the disorder.	\N	\N
22327619	Visual cues are known to aid auditory processing when they provide direct information about signal content, as in lip reading. However, some studies hint that visual cues also aid auditory perception by guiding attention to the target in a mixture of similar sounds. The current study directly tests this idea for complex, nonspeech auditory signals, using a visual cue providing only timing information about the target. Listeners were asked to identify a target zebra finch bird song played at a random time within a longer, competing masker. Two different maskers were used: noise and a chorus of competing bird songs. On half of all trials, a visual cue indicated the timing of the target within the masker. For the noise masker, the visual cue did not affect performance when target and masker were from the same location, but improved performance when target and masker were in different locations. In contrast, for the chorus masker, visual cues improved performance only when target and masker were perceived as coming from the same direction. These results suggest that simple visual cues for when to listen improve target identification by enhancing sounds near the threshold of audibility when the target is energetically masked and by enhancing segregation when it is difficult to direct selective attention to the target. Visual cues help little when target and masker already differ in attributes that enable listeners to engage selective auditory attention effectively, including differences in spectrotemporal structure and in perceived location.	\N	\N
22329567	To determine the optimal seating position in a noisy classroom for students with unilateral hearing loss (UHL) without any auditory rehabilitation as compared to normal-hearing adults and student peers. Speech discrimination scores (SDS) for babble noise at distances of 3, 4, 6, 8, and 10 m from a speaker were measured in a simulated classroom measuring 300 m3 (reverberation time = 0.43 s). Students with UHL (n = 25, 10-19 years old), normal-hearing students (n = 25), and normal-hearing adults (n = 25). The SDS for the normal-hearing adults at the 3, 4, 6, 8, and 10 m distances were 90.0±6.4%, 84.7±7.9%, 80.6±10.0%, 75.5±12.6%, and 68.8±13.0%, respectively. Those for the normal-hearing students were 90.1±6.2%, 78.1±9.4%, 66.4±10.7%, 61.8±11.2%, and 60.8±10.9%. Those for the UHL group were 81.7±9.0%, 70.2±12.4%, 62.1±17.2%, 52.4±17.1%, and 48.9±17.9%. The UHL group needed a seating position of 4.35 m to achieve an equivalent mean SDS as those for normal-hearing adults seated at 10 m. Likewise, the UHL group needed to be seated at 6.27 m to have an equivalent SDS as the normal-hearing students seated at 10 m. Students with UHL in noisy classrooms require seating ranging from 4.35 m to no further than 6.27 m away from a teacher to obtain a SDS comparable to normal hearing adults and student peers.	\N	\N
22337493	Complete psychometric functions for phoneme and word recognition scores at 8 signal-to-noise ratios from -15 dB to 20 dB were generated for the first 10, 20, and 25, as well as all 50, three-word presentations of the Tri-Word or Computer Assisted Speech Recognition Assessment (CASRA) Test (Gelfand, 1998) based on the results of 12 normal-hearing young adult participants from the original study. The psychometric functions for both phoneme and word scores were very similar and essentially overlapping for all set sizes. Performance on the shortened tests accounted for 98.8% to 99.5% of the full (50-set) test variance with phoneme scoring, and 95.8% to 99.2% of the full test variance with word scoring. Shortening the tests accounted for little if any of the variance in the slopes of the functions. The psychometric functions for abbreviated versions of the Tri-Word speech recognition test using 10, 20, and 25 presentation sets were described and are comparable to those of the original 50-presentation approach for both phoneme and word scoring in healthy, normal-hearing, young adult participants.	\N	\N
22341758	The neural mechanisms used in tone rises and falls in Mandarin were investigated. Nine participants were scanned while they named one-character pictures that required rising or falling tone responses in Mandarin: the left insula and right putamen showed stronger activation between rising and falling tones; the left brainstem showed weaker activation between rising and falling tones. Connectivity analysis showed that the significant projection from the laryngeal motor cortex to the brainstem which was present in rising tones was absent in falling tones. Additionally, there was a significant difference between the connection from the insula to the laryngeal motor cortex which was negative in rising tones but positive in falling tones. These results suggest that the significant projection from the laryngeal motor cortex to the brainstem used in rising tones was not active in falling tones. The connection from the left insula to the laryngeal motor cortex that differs between rising and falling tones may control whether the rise mechanism is active or not.	\N	\N
22343068	Interaural intensity disparities (IIDs), the cues all animals use to localize high frequency sounds, are initially processed in the lateral superior olive (LSO) by a subtractive process where inputs from one ear excite and inputs from the other ear inhibit LSO neurons. Such cells are called excitatory-inhibitory (EI) neurons and are prominent not only in the LSO but also in higher nuclei, which include the dorsal nucleus of the lateral lemniscus (DNLL) and inferior colliculus (IC). The IC is of particular interest since its EI cells receive diverse innervation patterns from a large number of lower nuclei, which include the DNLLs and LSOs, and thus comprise a population with diverse binaural properties. The first part of this review focuses on the circuits that create EI cells in the LSO, DNLL and IC. The second section then turns to the responses evoked by dynamic IIDs that change over time, as with multiple sounds that emanate from different regions of space or moving sound sources. I show that many EI neurons in the IC respond to dynamic IIDs in ways that are not predictable from their responses to static IIDs, IIDs presented one at a time. In the final section, results from in vivo whole cell recording in the IC are presented and address the connectional basis for the responsiveness to dynamic IIDs. The principal conclusion is that EI cells comprise a diverse population. The diversity is created by the particular set of inputs each EI type receives and is expressed in the differences in the responses to dynamic IIDs that are generated by those inputs. These results show that the construction of EI neurons in the IC imparts features that not only encode the location of an individual sound source, but also that allow animals to determine the direction of a moving sound and to focus and localize a single sound in midst of many sounds, as typically occurs in the daily lives of all animals.	\N	\N
22344314	To assess the effects of spatial frequency and phase alignment of mask components in pattern masking, target threshold vs. mask contrast (TvC) functions for a sine-wave grating (S) target were measured for five types of mask: a sine-wave grating (S), a square-wave grating (Q), a missing fundamental square-wave grating (M), harmonic complexes consisting of phase-scrambled harmonics of a square wave (Qp), and harmonic complexes consisting of phase-scrambled harmonics of a missing fundamental square wave (Mp). Target and masks had the same fundamental frequency (0.46 cpd) and the target was added in phase with the fundamental frequency component of the mask. Under monocular viewing conditions, the strength of masking depends on phase relationships among mask spatial frequencies far removed from that of the target, at least 3 times the target frequency, only when there are common target and mask spatial frequencies. Under dichoptic viewing conditions, S and Q masks produced similar masking to each other and the phase-scrambled masks (Qp and Mp) produced less masking. The results suggest that pattern masking is spatial frequency broadband in nature and sensitive to the phase alignments of spatial components.	\N	\N
22352523	Knowledge-based speech recognition systems extract acoustic cues from the signal to identify speech characteristics. For channel-deteriorated telephone speech, acoustic cues, especially those for stop consonant place, are expected to be degraded or absent. To investigate the use of knowledge-based methods in degraded environments, feature extrapolation of acoustic-phonetic features based on Gaussian mixture models is examined. This process is applied to a stop place detection module that uses burst release and vowel onset cues for consonant-vowel tokens of English. Results show that classification performance is enhanced in telephone channel-degraded speech, with extrapolated acoustic-phonetic features reaching or exceeding performance using estimated Mel-frequency cepstral coefficients (MFCCs). Results also show acoustic-phonetic features may be combined with MFCCs for best performance, suggesting these features provide information complementary to MFCCs.	\N	\N
22352610	Recent acoustic descriptions have shown that Spanish and Portuguese vowels are produced differently in Europe and Latin America. The present study investigates whether comparable between-variety differences exist in vowel perception. Spanish, Peruvian, Portuguese, and Brazilian listeners were tested in a vowel identification task with stimuli sampled from the whole vowel space. The mean perceived first (F1) and second formant (F2) of every vowel category were compared across varieties. For both languages, perception exhibited the same between-variety differences as production for F1 but not F2, which suggests correspondence between produced F1 and perceived vowel height but not between F2 and frontness.	\N	\N
22352612	It is hypothesized that in sine-wave replicas of natural speech, lexical tone recognition would be severely impaired due to the loss of F0 information, but the linguistic information at the sentence level could be retrieved even with limited tone information. Forty-one native Mandarin-Chinese-speaking listeners participated in the experiments. Results showed that sine-wave tone-recognition performance was on average only 32.7% correct. However, sine-wave sentence-recognition performance was very accurate, approximately 92% correct on average. Therefore the functional load of lexical tones on sentence recognition is limited, and the high-level recognition of sine-wave sentences is likely attributed to the perceptual organization that is influenced by top-down processes.	\N	\N
22352622	The combined effect of low-pass filtering (cut-off frequencies between 500 and 3000 Hz) and periodic interruptions (1.5 and 10 Hz) on speech intelligibility was investigated. When combined, intelligibility was lower than each manipulation alone, even in some conditions where there was no effect from a single manipulation (such as the fast interruption rate of 10 Hz). By using young normal-hearing listeners, potential suprathreshold deficits and aging effects that may occur due to hearing impairment were eliminated. Thus, the results imply that reduced audibility of high-frequency speech components may partially explain the reduced intelligibility of interrupted speech in hearing impaired persons.	\N	\N
22352624	In the context of binaural audio rendering, choosing the best head-related transfer function (HRTF) for an individual from large databases poses several problems. This study proposes a method to reduce the size of a given HRTF database. Participants, 45 in total, were asked to rate the quality of binaural synthesis for 46 HRTFs. The lack of reciprocity in the ratings was noted. Results were used to create a perceptually optimized HRTF subset which satisfied all participants' judgments. The subset was validated using localization tests on a separate group of subjects with results showing reduced errors when subjects were given their best choice, rather than their worst choice HRTF.	\N	\N
22353565	Exposure to synchronous but spatially discordant auditory and visual inputs produces adaptive recalibration of the respective localization processes, which manifest themselves in measurable aftereffects. Here we report two experiments that examined the time course of visual recalibration of apparent sound location in order to establish the build-up and dissipation of recalibration. In Experiment 1 participants performed a sound localization task before and during exposure to an auditory-visual discrepancy. In Experiment 2, participants performed a sound localization task before and after 60, 180 or 300 exposures to the discrepancy and aftereffects were measured across a series of post-adaptation sound localization trials. The results show that recalibration is very fast. Substantial aftereffects are obtained after only 18-24 exposures and asymptote appears to be reached between 60 and 180 exposures. The rate of adaptation was independent of the size of the discrepancy. The retention of the aftereffect was strong, as we found no dissipation, not even after as few as 60 exposure trials.	\N	\N
22356177	Talkers hyperarticulate vowels when communicating with listeners that require increased speech intelligibility. Vowel hyperarticulation is said to be motivated by knowledge of the listener's linguistic needs because it typically occurs in speech to infants, foreigners and hearing-impaired listeners, but not to non-verbal pets. However, the degree to which vowel hyperarticulation is determined by feedback from the listener is surprisingly less well understood. This study examines whether mothers' speech input is driven by knowledge of the infant's linguistic competence, or by the infant's feedback cues. Specifically, we manipulated (i) mothers' knowledge of whether they believed their infants could hear them or not, and (ii) the audibility of the speech signal available to the infant (full or partial audibility, or inaudible). Remarkably, vowel hyperarticulation was completely unaffected by mothers' knowledge; instead, there was a reduction in the degree of hyperarticulation such that vowels were hyperarticulated to the greatest extent in the full audibility condition, there was reduced hyperarticulation in the partially audible condition, and no hyperarticulation in the inaudible condition. Thus, while it might be considered adaptive to hyperarticulate speech to the hearing-impaired adult or infant, when these two factors (infant and hearing difficulty) are coupled, vowel hyperarticulation is sacrificed. Our results imply that infant feedback drives talker behavior and raise implications for intervention strategies used with carers of hearing-impaired infants.	\N	\N
22359341	To date, the underlying cognitive and neural mechanisms of absolute pitch (AP) have remained elusive. In the present fMRI study, we investigated verbal and tonal perception and working memory in musicians with and without absolute pitch. Stimuli were sine wave tones and syllables (names of the scale tones) presented simultaneously. Participants listened to sequences of five stimuli, and then rehearsed internally either the syllables or the tones. Finally participants indicated whether a test stimulus had been presented during the sequence. For an auditory stroop task, half of the tonal sequences were congruent (frequencies of tones corresponded to syllables which were the names of the scale tones) and half were incongruent (frequencies of tones did not correspond to syllables). Results indicate that first, verbal and tonal perception overlap strongly in the left superior temporal gyrus/sulcus (STG/STS) in AP musicians only. Second, AP is associated with the categorical perception of tones. Third, the left STG/STS is activated in AP musicians only for the detection of verbal-tonal incongruencies in the auditory stroop task. Finally, verbal labelling of tones in AP musicians seems to be automatic. Overall, a unique feature of AP appears to be the similarity between verbal and tonal perception.	\N	\N
22361102	The ability of infants to develop recognition of a common stress pattern that is language specific has been tested mainly in trochaic languages with a strong-weak (SW) stress pattern. The goals of the present study were: (a) to test Hebrew-learning infants on their stress pattern preference in the Hebrew language, for which the weak-strong (WS) stress pattern is the common one, and (b) to test whether the infants would generalize any preference for the common stress pattern in Hebrew to English words, which belong to a different rhythmic class. Fifty-six 9-month-old Hebrew-learning infants were tested on their preference for SW and WS stress patterns using Hebrew and English bisyllabic words with the head-turn preference procedure. The infants showed preference for WS Hebrew words but not for SW English words. Hebrew-learning infants recognize the common stress pattern in their native language, supporting language-specific distributional learning by infants. This recognition, however, is not generalized to a foreign language with different prosodic characteristics.	\N	\N
22361320	The aim of this study was to determine which level-dependent hearing aid digital signal-processing strategy (DSP) participants preferred when listening to music and/or performing a speech-in-noise task. Two receiver-in-the-ear hearing aids were compared: one using 32-channel adaptive dynamic range optimization (ADRO) and the other wide dynamic range compression (WDRC) incorporating dual fast (4 channel) and slow (15 channel) processing. The manufacturers' first-fit settings based on participants' audiograms were used in both cases. Results were obtained from 18 participants on a quick speech-in-noise (QuickSIN; Killion, Niquette, Gudmundsen, Revit, & Banerjee, 2004) task and for 3 music listening conditions (classical, jazz, and rock). Participants preferred the quality of music and performed better at the QuickSIN task using the hearing aids with ADRO processing. A potential reason for the better performance of the ADRO hearing aids was less fluctuation in output with change in sound dynamics. ADRO processing has advantages for both music quality and speech recognition in noise over the multichannel WDRC processing that was used in the study. Further evaluations of which DSP aspects contribute to listener preference are required.	\N	\N
22362394	Schizophrenia is associated with deficits in the ability to perceive emotion based on tone of voice. The basis for this deficit remains unclear, however, and relevant assessment batteries remain limited. The authors evaluated performance in schizophrenia on a novel voice emotion recognition battery with well-characterized physical features, relative to impairments in more general emotional and cognitive functioning. The authors studied a primary sample of 92 patients and 73 comparison subjects. Stimuli were characterized according to both intended emotion and acoustic features (e.g., pitch, intensity) that contributed to the emotional percept. Parallel measures of visual emotion recognition, pitch perception, general cognition, and overall outcome were obtained. More limited measures were obtained in an independent replication sample of 36 patients, 31 age-matched comparison subjects, and 188 general comparison subjects. Patients showed statistically significant large-effect-size deficits in voice emotion recognition (d=1.1) and were preferentially impaired in recognition of emotion based on pitch features but not intensity features. Emotion recognition deficits were significantly correlated with pitch perception impairments both across (r=0.56) and within (r=0.47) groups. Path analysis showed both sensory-specific and general cognitive contributions to auditory emotion recognition deficits in schizophrenia. Similar patterns of results were observed in the replication sample. The results demonstrate that patients with schizophrenia show a significant deficit in the ability to recognize emotion based on tone of voice and that this deficit is related to impairment in detecting the underlying acoustic features, such as change in pitch, required for auditory emotion recognition. This study provides tools for, and highlights the need for, greater attention to physical features of stimuli used in studying social cognition in neuropsychiatric disorders.	\N	\N
22366255	The aim of this study was to test a multimodal event-related potential (ERP) paradigm in chronic solvent encephalopathy (CSE) to develop a sensitive method for the clinical diagnostics to CSE. The study comprised 11 CSE patients and 13 healthy controls. We used three tasks: an auditory odd-ball (AUD), a visual detection (VIS), and a recognition memory (MEM) task. The auditory and visual stimuli were presented in single- and dual-task conditions. The auditory P300 amplitude in single-task condition was smaller in the patient group than in the control group at the parietal (Pz) but not at the frontal midline electrode location. The auditory P300 response in the dual task condition AUD+VIS was unrecognizable in 8 of 11 patients and in 1 of 13 controls and in the AUD+MEM condition in 10 of 11 patients and in 4 of 13 controls. In the AUD+MEM condition, the auditory P300 amplitude at Pz was smaller in the patient group than in the control group. Reaction time for auditory stimuli in both dual conditions as well as for visual stimuli in AUD+VIS condition were in the patient group prolonged. The ERP results indicate that CSE patients present with slowed performance speed and difficulties in allocation of attention. Based on ERP results, the disturbance in brain activity in CSE seems to affect posterior aspects of the frontoparietal continuity. The multimodal paradigm seems promising as a tool for the clinical diagnostics of CSE.	\N	\N
22367093	A major focus of recent attempts to enhance cochlear implant (CI) systems has been to increase the rate at which pulses are delivered to the electrode array. One basis for these attempts has been the expectation that faster stimulation rates would lead to an enhanced representation of temporal modulation information. However, there is recent physiological and behavioral evidence to suggest that the reverse may be the case. Here, the effects of stimulation rate on the perception of amplitude modulation were assessed using both modulation detection and modulation frequency discrimination tasks for a range of pulse rates extending considerably higher than the highest rate tested in previous studies and for different speech-relevant modulation frequencies. Detection of sinusoidal amplitude modulation was assessed in five CI users using monopolar pulse trains presented to a single electrode at rates of 482, 723, 1447, 2894, and 5787 pulses per second (pps). Adaptive procedures were used to find the minimal detectable modulation depth at modulation frequencies of 10 and 100 Hz and at carrier levels of 25%, 50%, and 75% of the electrode's dynamic range. Discrimination of modulation frequency was examined for the same range of pulse rates for the highest carrier level. Similar adaptive procedures determined the minimum increase in modulation frequency that could be detected relative to reference modulation frequencies of 10, 100, and 200 Hz. In both tasks, level roving was implemented to minimize possible loudness cues. Consistent with previous evidence, modulation detection thresholds were better for higher carrier levels and lower modulation frequencies. When modulation depth at threshold was expressed in terms of the ratio of the depth of the modulation and the carrier level in dB (i.e., 20 log m), performance was significantly better at lower pulse rates. However, when modulation depth was expressed relative to dynamic range, the effect of pulse rate was no longer significant, reflecting the fact that dynamic range increases with pulse rate. Modulation frequency discrimination clearly worsened with increasing modulation frequency, but there was no significant effect of pulse rate. In contrast to some recent evidence, no clearly harmful effect of higher pulse rates on modulation perception was found. However, even with very fast stimulation rates, tested over a wide range of modulation frequencies and with two different tasks, there is no evidence of benefit from faster stimulation rates in the perception of amplitude modulation.	\N	\N
22384211	Recent behavioral neuroscience research revealed that elementary reactive behavior can be improved in the case of cross-modal sensory interactions thanks to underlying multisensory integration mechanisms. Can this benefit be generalized to an ongoing coordination of movements under severe physical constraints? We choose a juggling task to examine this question. A central issue well-known in juggling lies in establishing and maintaining a specific temporal coordination among balls, hands, eyes and posture. Here, we tested whether providing additional timing information about the balls and hands motions by using external sound and tactile periodic stimulations, the later presented at the wrists, improved the behavior of jugglers. One specific combination of auditory and tactile metronome led to a decrease of the spatiotemporal variability of the juggler's performance: a simple sound associated to left and right tactile cues presented antiphase to each other, which corresponded to the temporal pattern of hands movement in the juggling task. A contrario, no improvements were obtained in the case of other auditory and tactile combinations. We even found a degraded performance when tactile events were presented alone. The nervous system thus appears able to integrate in efficient way environmental information brought by different sensory modalities, but only if the information specified matches specific features of the coordination pattern. We discuss the possible implications of these results for the understanding of the neuronal integration process implied in audio-tactile interaction in the context of complex voluntary movement, and considering the well-known gating effect of movement on vibrotactile perception.	\N	\N
22401989	We used structural magnetic resonance imaging (MRI) and voxel based morphometry (VBM) to investigate whether the efficiency of word processing in the non-native language (lexical efficiency) and the number of non-native languages spoken (2+ versus 1) were related to local differences in the brain structure of bilingual and multilingual speakers. We dissociate two different correlates for non-native language processing. Firstly, multilinguals who spoke 2 or more non-native languages had higher grey matter density in the right posterior supramarginal gyrus compared to bilinguals who only spoke one non-native language. This is interpreted in relation to previous studies that have shown that grey matter density in this region is related to the number of words learnt in bilinguals relative to monolinguals and in monolingual adolescents with high versus low vocabulary. Our second result was that, in bilinguals, grey matter density in the left pars opercularis was positively related to lexical efficiency in second language use, as measured by the speed and accuracy of lexical decisions and the number of words produced in a timed verbal fluency task. Grey matter in the same region was also negatively related to the age at which the second language was acquired. This is interpreted in terms of previous findings that associated the left pars opercularis with phonetic expertise in the native language.	\N	\N
22406661	Detection performance is impaired for a visual target presented in an apparent motion (AM) trajectory, and this AM interference weakens when orientation information is inconsistent between the target and AM stimuli. These indicate that the target is perceptually suppressed by internal object representations of AM stimuli established along the AM trajectory. Here, we showed that transient sounds presented together with AM stimuli could enhance the magnitude of AM interference. Furthermore, this auditory effect attenuated when frequencies of the sounds were inconsistent during AM. We also confirmed that the sounds wholly elevated the magnitude of AM interference irrespective of the inconsistency in orientation information between the target and AM stimuli when the saliency of the sounds was maintained. These results suggest that sounds can contribute to the robust establishment and spatiotemporal maintenance of the internal object representation of an AM stimulus.	\N	\N
22410729	To compare temporal aspects of peripheral neural responses and central auditory perception between groups of younger adult and elderly cochlear implant users. Cohort study. Academic hospital and cochlear implant center. Adult cochlear implant users aged 28 to 57 years in the younger group (n = 5) and 61 to 89 years (n = 9) in the elderly group. All subjects used Advanced Bionics devices. Diagnostic. Time constants of neural (i.e., electrically evoked compound action potentials [ECAPs]) and perceptual recovery from forward masking. Interstimulus intervals (ISIs) were varied in both experiments. ECAP recovery rates were equivalent between groups, and no correlation was found between ECAP recovery and age. No correlations were found between ECAP recovery and speech perception. Psychophysical recovery was significantly slower in the elderly compared with the younger subjects (p < 0.0005), with a significant effect of age (R2 = 0.70, p < 0.0005). At the longest ISI (240 ms), elderly subjects experienced a mean maximum threshold shift of 35.2% (relative to 1 ms ISI) versus 14.8% for younger subjects. There was a significant positive relationship between psychophysical recovery and consonant-nucleus-consonant word scores (R2 = 0.62, p < 0.001), although no relationship was found with Hearing in Noise Test sentences. These findings suggest that difficulties observed in speech perception by elderly CI users may be due to age-related changes in the central rather than peripheral auditory system. With further study, these results may provide information to allow clinicians to assess patients' temporal processing abilities and facilitate setting program parameters that will maximize their auditory perceptual experience with a cochlear implant.	\N	\N
22411592	Gender priming studies have demonstrated facilitation of noun production following pre-activation of a target noun's grammatical gender. Findings provide support for models in which syntactic information relating to words is stored within the lexicon and activated during lexical retrieval. Priming effects are observed in the context of determiner plus noun phrase production. Few studies demonstrate gender priming effects in bare noun production (i.e., nouns in isolation). We investigated the effects of English determiner primes on bare mass and count noun production. In two experiments, participants named pictures after exposure to primes involving congruent, incongruent and neutral determiners. Facilitation of noun production by congruent and neutral determiner primes was found in both experiments. The results suggest that noun phrase syntax is activated in lexical retrieval, even when not explicitly required for production. Post hoc analysis of the relative frequency of congruent and incongruent prime-target pairs provides support for a frequency-based interpretation of the data.	\N	\N
22423705	The frequency response and sensitivity of the ER-3A and ER-2 insert earphones are measured in the occluded-ear simulator using three ear canal extensions. Compared to the other two extensions, the DB 0370 (Brüel & Kjær), which is recommended by the international standards, introduces a significant resonance peak around 4500 Hz. The ER-3A has an amplitude response like a band-pass filter (1400 Hz, 6 dB/octave -4000 Hz, -36 dB/octave), and a group delay with "ripples" of up to ±0.5 ms, while the ER-2 has an amplitude response, and a group delay which are flat and smooth up to above 10000 Hz. Both earphones are used to record auditory brainstem responses, ABRs, from 22 normal-hearing ears in response to two chirps and a click at levels from 20 to 80 dB nHL. While the click-ABRs are slightly larger for ER-2 than for ER-3A, the chirp-ABRs are much larger for ER-2 than for ER-3A at levels below 60 dB nHL. With a simulated amplitude response of the ER-3A and the smooth group delay of the ER-2 it is shown that the increased chirp-ABR amplitude with the ER-2 is caused by its broader amplitude response and not by its smoother group delay.	\N	\N
22426232	Rapid information processing in the human brain is vital to survival in a highly dynamic environment. The key tool humans use to exchange information is spoken language, but the exact speed of the neuronal mechanisms underpinning speech comprehension is still unknown. Here we investigate the time course of neuro-lexical processing by analyzing neuromagnetic brain activity elicited in response to psycholinguistically and acoustically matched groups of words and pseudowords. We show an ultra-early dissociation in cortical activation elicited by these stimulus types, emerging ∼50 ms after acoustic information required for word identification first becomes available. This dissociation is the earliest brain signature of lexical processing of words so far reported, and may help explain the evolutionary advantage of human spoken language.	\N	\N
22436117	Assessment of interaural asymmetry (IA) on dichotic listening tests becomes challenging when accuracy on one or both ears are at ceiling. Cognitive task demands are often increased to avoid this situation, raising the possibility that non-auditory-specific processes will further influence IA estimation. To investigate the utility of low-pass filtered dichotic speech stimuli (dichotic filtered words [DFWs]) as a potential auditory-specific technique for increasing task difficulty in the dichotic listening paradigm. A prospective experimental study investigating differences in IA observed for a group of young adults on three dichotic listening tasks differentiated on the basis of stimulus type (unfiltered words, DFWs) and/or mode of test administration (divided attention [DIV]; directed attention [DIR]). Thirty-two adults between 18 and 34 yr of age participated in the study. Accuracy scores on each ear and normalized values of IA (via laterality index) served as dependent measures evaluated in a repeated-measures ANOVA design. Correlation and regression analyses were carried out to investigate potential relationships between participants' behavioral accuracy to experimental stimuli and the magnitude of observed IA. Behavioral profiles of IA were constructed for each participant. Using a traditional DIV test mode, DFW stimuli produced a significantly larger right-ear advantage (REA) as compared to unfiltered speech. The magnitude of the average REA to DFW stimuli was not statistically different between DIV and DIR test modes for the group. Inspection of individual performances, however, revealed that out of the participants who demonstrated meaningful IA during DIV, approximately half produced the same or greater amount of IA during DIR whereas half showed a relative decrease. Participants' accuracy to left-sided stimuli was most related to the magnitude of observed IA across tasks. The utility of low-pass filtered speech may be helpful in the evaluation of IA obtained during dichotic testing.	\N	\N
22436413	The aim of this study was to report speech performance in quiet and in noise, sound localization with cochlear implanted children bilaterally. Their performances were compared also in unilateral conditions. In addition, speech and language evaluation was analyzed. Twenty-three children implanted with Neurelec Digisonic SP devices in 3 tertiary centres were tested on a battery of speech perception tests in quiet and in noise. Localization was assessed by lateralization tasks (90° and 30°). Progress in speech and language development and subjective assessment of benefit were assessed using several rating scales and questionnaires (categories of auditory perception, speech intelligibility rating, family participating rating scale). Children scored better when tested in bilateral conditions rather than in unilateral conditions. In quiet, the mean scores for the poorer and better side were 52% and 73%, respectively. In the bilateral condition, the mean score increased to 83%. In noise, the mean scores were 39% and 57% respectively, which increased to a mean of 70% in the bilateral condition. Nine children (<9 years) completed the ±90° lateralization task. For both unilateral conditions performance was not significantly different from chance level. In the bilateral condition, the mean score was 86%. The ±30° lateralization score was completed by eight of the older children (>9 years). The scores in the unilateral conditions were closed to chance level, but significantly better in the bilateral condition (mean of 86%). Performances in bilateral conditions were significantly better than in unilateral conditions on speech perception in quiet and in noise. Localization was significantly better when tested in the bilateral condition for ±90° lateralization task for the younger children and the ±30° task for the older children. All these results supported the hypothesis than bilateral cochlear implantation is more beneficial than unilateral implantation in children.	\N	\N
22436438	It has been demonstrated that written and spoken language processing are tightly linked. Here we focus on the development of this relationship at the time children start reading and writing. We hypothesize that the newly acquired knowledge about graphemes shapes lexical access in neural spoken word recognition. A group of preliterate children (six years old) and two groups of beginning readers (six and eight years old) were tested in a spoken word identification task. Using word onset priming we compared behavioural and neural facilitation for target words in identical prime-target pairs (e.g., mon-monster) and in prime target pairs that varied in the first speech sound (e.g., non-monster, Variation condition). In both groups of beginning readers priming was less effective in the Variation condition than in the Identity condition. This was indexed by less behavioural facilitation and enhanced P350 amplitudes in the event related potentials (ERPs). In the group of preliterate children, by contrast, both conditions did not differ. Together these results reveal that lexical access in beginning readers is based on more acoustic detail than lexical access in preliterate children. The results are discussed in the light of bidirectional speech and print interactions in readers.	\N	\N
22445915	Developmental dyslexia is associated with impaired speech-in-noise perception. The goal of the present research was to further characterize this deficit in dyslexic adults. In order to specify the mechanisms and processing strategies used by adults with dyslexia during speech-in-noise perception, we explored the influence of background type, presenting single target-words against backgrounds made of cocktail party sounds, modulated speech-derived noise or stationary noise. We also evaluated the effect of three listening configurations differing in terms of the amount of spatial processing required. In a monaural condition, signal and noise were presented to the same ear while in a dichotic situation, target and concurrent sound were presented to two different ears, finally in a spatialised configuration, target and competing signals were presented as if they originated from slightly differing positions in the auditory scene. Our results confirm the presence of a speech-in-noise perception deficit in dyslexic adults, in particular when the competing signal is also speech, and when both signals are presented to the same ear, an observation potentially relating to phonological accounts of dyslexia. However, adult dyslexics demonstrated better levels of spatial release of masking than normal reading controls when the background was speech, suggesting that they are well able to rely on denoising strategies based on spatial auditory scene analysis strategies.	\N	\N
22465105	Increased early identification of hearing loss has led to infants younger than 24 months of age being implanted with cochlear implants. The objective of this study was to assess early speech development in children implanted with a cochlear implant before 24 months of age using the German questionnaire Elternfragebogen für Risikokinder 2 (ELFRA-2), and to compare these results to normative data of the ELFRA-2 in order to determine any performance differences. Two groups of children were included in this study. The first group included 6 children with a mean age at implantation of 11 months (range: 8-14 months). These children were tested by their parents or caretakers with the ELFRA-2 at the chronological age of 24 months. The second group included 9 children with a mean age at implantation of 13 months (range: 6-20 months) who were tested with the ELFRA-2 after 24 months of cochlear implant use. Comparison analyses of children tested with the ELFRA-2 demonstrated a statistically significant difference in all ELFRA-2 scales between children with cochlear implants (CIs) at the chronological age of 24 months and the norm group (productive vocabulary: p=0.002; syntax: p=0.003; and morphology: p<0.001), and no significant difference between children with CIs at 24 months of device use and the norm group in all scales (productive vocabulary: p=0.335; syntax: p=0.965; and morphology: p=0.304). Children implanted before 24 months of age reach a speech production level after 24 months of device use that is comparable to that of their normal hearing peers.	\N	\N
22477057	Response interference (or response conflict) refers to the phenomenon whereby response times to a target stimulus are longer in the presence of distractor stimuli that indicate contrary motor responses. Response interference has been observed even when the distractor stimuli cannot be discriminated above chance levels. These results raise the question of whether response interference might be driven automatically by the physical distractor stimuli, independently of one's subjective perception of the distractors. Using a modified version of the Eriksen flanker task, we applied metacontrast masks to the flanker stimuli and measured their subjective visibility after each trial. We found converging lines of evidence that the subjective perception of flankers contributed to response interference, over and above the contribution of automatic processing of the stimulus itself. A factorial analysis revealed that the objective, physical congruency of target and flankers and the subjective, perceptual congruency of target and flankers make additive, noninteracting contributions to target response interference, suggesting that the two interference effects originate from independent levels or stages of cognitive processing.	\N	\N
22480024	The majority of research on prosody in conversation to date has focused on exploring the role of individual prosodic features, such as certain types of pitch accent, pitch register or voice quality, for the accomplishment of specified social actions. From this research the picture emerges that when it comes to the implementation of specific actions at specific sequential locations conversationalists employ prosodic features systematically, but also with considerable variation, and indeed flexibility. This paper suggests a further line of enquiry, which pursues a wider, more fundamental role of prosody for interaction, and which does not focus on individual prosodic practices or features, but on participants' collaborative use of prosody for the implementation of one of the most basic interactional decisions: whether to continue a previously established action trajectory, or whether to start a new one. The data and findings of recent research make it clear that prosody, and in fact talk-in-interaction as such, is not appropriately defined by reference to individual features, speakers, locations and actions alone, but must be approached as a resource and negotiating strategy for social interaction. Prosody, therefore, must be described according to its role for both the accomplishment, and the coordination of actions across turns and participants.	\N	\N
22484251	It has been argued that the human visual system is optimized for identification of broadband objects embedded in stimuli possessing orientation averaged power spectra fall-offs that obey the 1/f(β) relationship typically observed in natural scene imagery (i.e., β=2.0 on logarithmic axes). Here, we were interested in whether individual spatial channels leading to recognition are functionally optimized for narrowband targets when masked by noise possessing naturalistic image statistics (β=2.0). The current study therefore explores the impact of variable β noise masks on the identification of narrowband target stimuli ranging in spatial complexity, while simultaneously controlling for physical or perceived differences between the masks. The results show that β=2.0 noise masks produce the largest identification thresholds regardless of target complexity, and thus do not seem to yield functionally optimized channel processing. The differential masking effects are discussed in the context of contrast gain control.	\N	\N
22485043	To examine the role of morphology in verbal working memory. Forty nine children, all native speakers of Arabic from the same region and of the same dialect, performed a Listening Word Span Task, whereby they had to recall Arabic uninflected words (i.e., base words), inflected words with regular (possessive) morphology, or inflected words with irregular (broken plural) morphology. Each of these words was at the end of a sentence (henceforth, target word). The participant's task was to listen to a series of sentences and then recall the target words. Recall of inflected words was significantly poorer than uninflected words, and recall of words with regular morphology was significantly poorer than recall of words with irregular morphology. These findings, albeit preliminary, suggest a role of morphology in verbal working memory. They also suggest that, at least in Arabic, regular morphological forms are decomposed into their component elements and hence impose an extra load on the central executive and episodic buffer components of working memory. Furthermore, in concert with findings from other studies, they suggest that the effect of morphology on working memory is probably language-specific. The clinical implications of the present findings are addressed.	\N	\N
22488914	The relationship between the evoked responses (ERPs/ERFs) and the event-related changes in EEG/MEG power that can be observed during sentence-level language comprehension is as yet unclear. This study addresses a possible relationship between MEG power changes and the N400m component of the event-related field. Whole-head MEG was recorded while subjects listened to spoken sentences with incongruent (IC) or congruent (C) sentence endings. A clear N400m was observed over the left hemisphere, and was larger for the IC sentences than for the C sentences. A time-frequency analysis of power revealed a decrease in alpha and beta power over the left hemisphere in roughly the same time range as the N400m for the IC relative to the C condition. A linear regression analysis revealed a positive linear relationship between N400m and beta power for the IC condition, not for the C condition. No such linear relation was found between N400m and alpha power for either condition. The sources of the beta decrease were estimated in the LIFG, a region known to be involved in semantic unification operations. One source of the N400m was estimated in the left superior temporal region, which has been related to lexical retrieval. We interpret our data within a framework in which beta oscillations are inversely related to the engagement of task-relevant brain networks. The source reconstructions of the beta power suppression and the N400m effect support the notion of a dynamic communication between the LIFG and the left superior temporal region during language comprehension.	\N	\N
22501035	Masked detection thresholds can often be improved by introducing coherent masker amplitude modulation across frequency, a phenomenon referred to as comodulation masking release (CMR). While CMR can be large for detection, it is smaller for supra-threshold tasks, such as intensity discrimination. In this experiment, frequency discrimination for a 1000-Hz tone near threshold was found to be poorer in an amplitude-modulated than a steady bandpass noise. These results parallel previous findings for intensity discrimination. Although this study examined the relatively simple task of frequency discrimination, the results may have implications for more complex tasks, such as speech recognition in fluctuating noise.	\N	\N
22502488	Simultaneous, on-frequency masking is commonly assumed to be linear with increasing noise intensity. However, some evidence suggests that, expressed in terms of signal-to-noise ratio changes with background level changes, masking slopes can vary from 0 dB/dB. These results and evidence from a large sample of subjects with normal and impaired hearing demonstrate level-dependent changes in masking, large individual differences in masking among subjects with similar thresholds in quiet, and significant correlations of masking slope with other estimates of auditory function measured in the same backgrounds.	\N	\N
22503556	Several studies show that the perception of occlusion may affect various aspects of motion perception. Here we present data indicating that occlusion cues also influence the visual interpolation of sampled motion. Normally, sampled motion stimuli are perceived as less smooth and jerkier when the spatial gaps between successive presentations of the "moving" target stimulus increase. Adding surfaces occluding the spatial gaps, however, we found that the perceived smoothness of motion was not only better, but also independent of the gap width. We argue that this effect occurs because the visual system attributes the interruptions in the motion path to occlusion rather than to the moving object itself.	\N	\N
22503904	Motion-induced blindness (MIB) is an illusory phenomenon, in which a static target surrounded by moving distracters is perceived to disappear. We determined the electrocorticographic (ECoG) correlates of MIB. While undergoing intracranial ECoG recording, a patient with focal epilepsy was instructed to report the transitions of a visual target, which was designed to illusorily or physically disappear and reappear. We then determined the neural modulations associated with illusory and physical transitions of the target. We also tested whether the phase of local delta activity could predict exclusively illusory transitions. High-gamma activity at 80-150 Hz was attenuated in the fusiform region prior to the reports of illusory and real visual target disappearance. Conversely, such high-gamma activity was augmented prior to the report of real target reappearance. Exclusively around illusory disappearance but not around real one, the delta phases in the fusiform region showed a highly skewed distribution with preference of the negative peak. Neuronal modulations in the fusiform region may be involved in visual awareness, while spontaneous fluctuations of neural states entrained on delta rhythm may be involved in generation of MIB. Our study increases our understanding of the mechanisms of visual awareness.	\N	\N
22505222	Scholars have documented similarities in the way voice and music convey emotions. By using functional magnetic resonance imaging (fMRI) we explored whether these similarities imply overlapping processing substrates. We asked participants to trace changes in either the emotion or pitch of vocalizations and music using a joystick. Compared to music, vocalizations more strongly activated superior and middle temporal cortex, cuneus, and precuneus. However, despite these differences, overlapping rather than differing regions emerged when comparing emotion with pitch tracing for music and vocalizations, respectively. Relative to pitch tracing, emotion tracing activated medial superior frontal and anterior cingulate cortex regardless of stimulus type. Additionally, we observed emotion specific effects in primary and secondary auditory cortex as well as in medial frontal cortex that were comparable for voice and music. Together these results indicate that similar mechanisms support emotional inferences from vocalizations and music and that these mechanisms tap on a general system involved in social cognition.	\N	\N
22509533	It has been proposed that OAEs be classified not on the basis of the stimuli used to evoke them, but on the mechanisms that produce them (Shera and Guinan, 1999). One branch of this taxonomy focuses on a coherent reflection model and explicitly describes interrelationships between spontaneous emissions (SOAEs) and stimulus-frequency emissions (SFOAEs). The present study empirically examines SOAEs and SFOAEs from individual ears within the context of model predictions, using a low stimulus level (20 dB SPL) to evoke SFOAEs. Emissions were recorded from ears of normal-hearing young adults, both with and without prominent SOAE activity. When spontaneous activity was observed, SFOAEs demonstrated a localized increase about the SOAE peaks. The converse was not necessarily true though, i.e., robust SFOAEs could be measured where no SOAE peaks were observed. There was no significant difference in SFOAE phase-gradient delays between those with and without observable SOAE activity. However, delays were larger for a 20 dB SPL stimulus level than those previously reported for 40 dB SPL. The total amount of SFOAE phase accumulation occurring between adjacent SOAE peaks tended to cluster about an integral number of cycles. Overall, the present data appear congruous with predictions stemming from the coherent reflection model and support the notion that such comparisons ideally are made with emissions evoked using relatively lower stimulus levels.	\N	\N
22509989	This study investigated the effect of short-term visual deprivation on auditory steady-state response (ASSR) to amplitude-modulated tones. Magnetoencephalography data were acquired while subjects performed an auditory detection task under both monaural and dichotic presentation conditions. Analyses were performed on the spectral power, mean amplitudes and dipole positions of the ASSR at the onset of blindfolding, as well as after 2, 4 and 6 h of visual deprivation. Results show a modulation of the spectral power of the ASSR at the frequencies that were present in the stimulus after 6 h of sensory deprivation, and this was especially true for the dichotic condition. Moreover, participants showed two spectral peaks in the occipital cortex at the end of the visual deprivation period, a phenomenon normally observed in the auditory cortex. Our results shed light not only on the timeline associated with short-term crossmodal recruitment of input-deprived sensory cortices but also demonstrate that the visual cortex can display auditory cortex-like functioning in response to the ASSR. Importantly, our results also highlight the importance of taking into consideration individual differences when investigating crossmodal plastic phenomena. Indeed, the occipital spectral peaks were only observed in half the subjects following short-term deprivation.	\N	\N
22511853	Several studies have reported optimal population decoding of sensory responses in two-alternative visual discrimination tasks. Such decoding involves integrating noisy neural responses into a more reliable representation of the likelihood that the stimuli under consideration evoked the observed responses. Importantly, an ideal observer must be able to evaluate likelihood with high precision and only consider the likelihood of the two relevant stimuli involved in the discrimination task. We report a new perceptual bias suggesting that observers read out the likelihood representation with remarkably low precision when discriminating grating spatial frequencies. Using spectrally filtered noise, we induced an asymmetry in the likelihood function of spatial frequency. This manipulation mainly affects the likelihood of spatial frequencies that are irrelevant to the task at hand. Nevertheless, we find a significant shift in perceived grating frequency, indicating that observers evaluate likelihoods of a broad range of irrelevant frequencies and discard prior knowledge of stimulus alternatives when performing two-alternative discrimination.	\N	\N
22513340	Both functional magnetic resonance imaging (fMRI) and event-related brain potential (ERP) studies have shown that verbal working memory plays an important role during sentence processing. There is growing evidence from outside of sentence processing that human alpha oscillations (7-13 Hz) play a critical role in working memory. This study aims to link this to the sentence processing domain. Time-frequency analyses and source localization were performed on electroencephalography (EEG) data that were recorded during the processing of auditorily presented sentences involving either a short or a long distance between an argument (subject or object) and the respective sentence-final verb. We reasoned that oscillatory activity in the alpha band should increase during sentences with longer argument-verb distances, since decreased temporal proximity should result in increased memory demands. When verbal working memory-intensive long-dependency sentences were compared to short-dependency sentences, a sustained oscillatory enhancement at 10 Hz was found during storage prior to the sentence-final verb, turning into a transient power increase in the beta band (13-20 Hz) at the sentence-final verb. The sources of the alpha oscillations were localized to bilaterally occipital and left parietal cortices. Only the source activity in the left parietal cortex was negatively correlated with verbal working memory abilities. These findings indicate that the parsimonious role of alpha oscillations in domain-general working memory can be extended to language, that is, sentence processing. We suggest that the function of left parietal cortex underlying verbal working memory storage during sentence processing is to inhibit the premature release of verbal information that will subsequently be integrated.	\N	\N
22517303	Professional and community concerns about the potentially dangerous noise levels for common leisure activities has led to increased interest on providing hearing health information to participants. However, noise reduction programmes aimed at leisure activities (such as music listening) face a unique difficulty. The noise source that is earmarked for reduction by hearing health professionals is often the same one that is viewed as pleasurable by participants. Furthermore, these activities often exist within a social setting, with additional peer influences that may influence behavior. The current study aimed to gain a better understanding of social-based factors that may influence an individual's motivation to engage in positive hearing health behaviors. Four hundred and eighty-four participants completed questionnaires examining their perceptions of the hearing risk associated with listening to music listening and asking for estimates of their own and their peer's music listening behaviors. Participants were generally aware of the potential risk posed by listening to personal stereo players (PSPs) and the volumes likely to be most dangerous. Approximately one in five participants reported using listening volumes at levels perceived to be dangerous, an incidence rate in keeping with other studies measuring actual PSP use. However, participants showed less awareness of peers' behavior, consistently overestimating the volumes at which they believed their friends listened. Misperceptions of social norms relating to listening behavior may decrease individuals' perceptions of susceptibility to hearing damage. The consequences of hearing health promotion are discussed, along with suggestions relating to the development of new programs.	\N	\N
22521874	Although activity in premotor and motor cortices is commonly observed in neuroimaging studies of spoken language processing, the degree to which this activity is an obligatory part of everyday speech comprehension remains unclear. We hypothesised that rather than being a unitary phenomenon, the neural response to speech perception in motor regions would differ across listeners as a function of individual cognitive ability. To examine this possibility, we used functional magnetic resonance imaging (fMRI) to investigate the neural processes supporting speech perception by comparing active listening to pseudowords with matched tasks that involved reading aloud or repetition, all compared to acoustically matched control stimuli and matched baseline tasks. At a whole-brain level there was no evidence for recruitment of regions in premotor or motor cortex during speech perception. A focused region of interest analysis similarly failed to identify significant effects, although a subset of regions approached significance, with notable variability across participants. We then used performance on a battery of behavioural tests that assessed meta-phonological and verbal short-term memory abilities to investigate the reasons for this variability, and found that individual differences in particular in low phonotactic probability pseudoword repetition predicted participants' neural activation within regions in premotor and motor cortices during speech perception. We conclude that normal listeners vary in the degree to which they recruit premotor and motor cortex as a function of short-term memory ability. This is consistent with a resource-allocation approach in which recruitment of the dorsal speech processing pathway depends on both individual abilities and specific task demands.	\N	\N
22522927	Humans possess a remarkable ability to attend to a single speaker's voice in a multi-talker background. How the auditory system manages to extract intelligible speech under such acoustically complex and adverse listening conditions is not known, and, indeed, it is not clear how attended speech is internally represented. Here, using multi-electrode surface recordings from the cortex of subjects engaged in a listening task with two simultaneous speakers, we demonstrate that population responses in non-primary human auditory cortex encode critical features of attended speech: speech spectrograms reconstructed based on cortical responses to the mixture of speakers reveal the salient spectral and temporal features of the attended speaker, as if subjects were listening to that speaker alone. A simple classifier trained solely on examples of single speakers can decode both attended words and speaker identity. We find that task performance is well predicted by a rapid increase in attention-modulated neural selectivity across both single-electrode and population-level cortical responses. These findings demonstrate that the cortical representation of speech does not merely reflect the external acoustic environment, but instead gives rise to the perceptual aspects relevant for the listener's intended goal.	\N	\N
22524352	In various paradigms of modern neurosciences of music, experts of Western classical music have displayed superior brain architecture when compared with individuals without explicit training in music. In this paper, we show that chord violations embedded in musical cadences were neurally processed in a facilitated manner also by musicians trained in Finnish folk music. This result, obtained by using early right anterior negativity (ERAN) as an index of harmony processing, suggests that tonal processing is advanced in folk musicians by their long-term exposure to both Western and non-Western music.	\N	\N
22524356	Recent research has shown that music training enhances music-related sensorimotor associations, such as the relationship between a key press on the keyboard and its associated musical pitch (auditory feedback). Such results suggest that the role of auditory feedback in performance may be based on learned associations that are task specific. Here, results from various studies will be presented that suggest that the real state of affairs is more complex. Several recent studies have shown similar effects of altered auditory feedback during piano performance for pianists and individuals with no piano training. Other recent research suggests dramatic differences between pianists and nonmusicians concerning the influence of auditory feedback on melody switching that suggest greater influence of auditory feedback among nonmusicians than pianists. Taken together, results suggest that musical training refines preexisting sensorimotor associations.	\N	\N
22524361	This paper examines the role of mental imagery in music performance. Self-reports by musicians, and various other sources of anecdotal evidence, suggest that covert auditory, motor, and/or visual imagery facilitate multiple aspects of music performance. The cognitive and motor mechanisms that underlie such imagery include working memory, action simulation, and internal models. Together these mechanisms support the generation of anticipatory images that enable thorough action planning and movement execution that is characterized by efficiency, temporal precision, and biomechanical economy. In ensemble performance, anticipatory imagery may facilitate interpersonal coordination by enhancing online predictions about others' action timing. Overlap in brain regions subserving auditory imagery and temporal prediction is consistent with this view. It is concluded that individual differences in anticipatory imagery may be a source of variation in expressive performance excellence and the quality of ensemble cohesion. Engaging in effortful musical imagery is therefore justified when artistic perfection is the goal.	\N	\N
22524378	Congenital amusia is a neurodevelopmental disorder of musical perception and production. Much research has focused on characterizing the deficits within this special population; however, it is also important from both a psychological and educational perspective to determine which aspects of the disorder may be subject to change because this will also constrain theorizing about the nature of the disorder, as well as facilitating possible future remediation programs. In this small-scale study, a professional singing teacher used a broad-brush intervention approach with five individuals diagnosed with congenital amusia. The compensatory elements were designed to enhance vocal efficiency and health, singing technique, musical understanding, pitch perception, and production. Improvements were observed in most individuals in perception, indexed via the Montreal Battery for the Evaluation of Amusia scale subtest and in the vocal performance of familiar songs. The workshop setting gave a unique opportunity for observation and discussion to inform further investigations of this disorder.	\N	\N
22525854	When people experience an unchanging sensory input for a long period of time, their perception tends to switch stochastically and unavoidably between alternative interpretations of the sensation; a phenomenon known as perceptual bi-stability or multi-stability. The huge variability in the experimental data obtained in such paradigms makes it difficult to distinguish typical patterns of behaviour, or to identify differences between switching patterns. Here we propose a new approach to characterising switching behaviour based upon the extraction of transition matrices from the data, which provide a compact representation that is well-understood mathematically. On the basis of this representation we can characterise patterns of perceptual switching, visualise and simulate typical switching patterns, and calculate the likelihood of observing a particular switching pattern. The proposed method can support comparisons between different observers, experimental conditions and even experiments. We demonstrate the insights offered by this approach using examples from our experiments investigating multi-stability in auditory streaming. However, the methodology is generic and thus widely applicable in studies of multi-stability in any domain.	\N	\N
22534571	Event Related Potentials (ERPs) were recorded from Spanish-English bilinguals (N=10) to test pre-attentive speech discrimination in two language contexts. ERPs were recorded while participants silently read magazines in English or Spanish. Two speech contrast conditions were recorded in each language context. In the phonemic in English condition, the speech sounds represented two different phonemic categories in English, but represented the same phonemic category in Spanish. In the phonemic in Spanish condition, the speech sounds represented two different phonemic categories in Spanish, but represented the same phonemic categories in English. Results showed pre-attentive discrimination when the acoustics/phonetics of the speech sounds match the language context (e.g., phonemic in English condition during the English language context). The results suggest that language contexts can affect pre-attentive auditory change detection. Specifically, bilinguals' mental processing of stop consonants relies on contextual linguistic information.	\N	\N
22537033	To develop, optimize, and evaluate a new Spanish sentence test in noise. The test comprises a basic matrix of ten names, verbs, numerals, nouns, and adjectives. From this matrix, test lists of ten sentences with an equal syntactical structure can be formed at random, with each list containing the whole speech material. The speech material represents the phoneme distribution of the Spanish language. The test was optimized for measuring speech reception thresholds (SRTs) in noise by adjusting the presentation levels of the individual words. Subsequently, the test was evaluated by independent measurements investigating the training effects, the comparability of test lists, open-set vs. closed-set test format, and performance of listeners of different Spanish varieties. In total, 68 normal-hearing native Spanish-speaking listeners. SRTs measured using an adaptive procedure were 6.2 ± 0.8 dB SNR for the open-set and 7.2 ± 0.7 dB SNR for the closed-set test format. The residual training effect was less than 1 dB after using two double-lists before data collection. No significant differences were found for listeners of different Spanish varieties indicating that the test is applicable to Spanish as well as Latin American listeners. Test lists can be used interchangeably.	\N	\N
22541369	Neuroimaging studies of English suggest that speech comprehension engages two interdependent systems: a bilateral fronto-temporal network responsible for general perceptual and cognitive processing, and a specialised left-lateralised network supporting specifically linguistic processing. Using fMRI we test this hypothesis in Polish, a Slavic language with rich and diverse morphology. We manipulated general perceptual complexity (presence or absence of an onset-embedded stem, e.g. kotlet 'cutlet' vs. kot 'cat') and specifically linguistic complexity (presence of an inflectional affix, e.g. dom 'house, Nom' vs. dom-u 'house, Gen'). Non-linguistic complexity activated a bilateral network, as in English, but we found no differences between inflected and uninflected nouns. Instead, all types of words activated left inferior frontal areas, suggesting that all Polish words can be considered linguistically 'complex' in processing terms. The results support a dual network hypothesis, but highlight differences between languages like English and Polish, and underline the importance of cross-linguistic comparisons.	\N	\N
22542727	Impaired auditory sensitivity to amplitude rise time (ART) has been suggested to be a primary deficit in developmental dyslexia. The present study investigates whether impaired ART-sensitivity at a pre-reading age precedes and predicts later emerging reading problems in a sample of Dutch children. An oddball paradigm, with a deviant that differed from the standard stimulus in ART, was administered to 41-month-old children (30 genetically at-risk for developmental dyslexia and 14 controls) with concurrent EEG measurement. A second deviant that differed from the standard stimulus in frequency served as a control deviant. Grade two reading scores were used to divide the at-risks in a typical-reading and a dyslexic subgroup. We found that both ART- and frequency processing were related to later reading skill. We however also found that irrespective of reading level, the at-risks in general showed impaired basic auditory processing when compared to controls and that it was impossible to discriminate between the at-risk groups on basis of both auditory measures. A relatively higher quality of early expressive syntactic skills in the typical-reading at-risk group might indicate a protective factor against negative effects of impaired auditory processing on reading development. Based on these results we argue that ART- and frequency-processing measures, although they are related to reading skill, lack the power to be considered single-cause predictors of developmental dyslexia. More likely, they are genetically driven risk factors that may add to cumulative effects on processes that are critical for learning to read.	\N	\N
22543320	The purpose of this study was to determine daily noise doses and 8-hour time weighted averages for rock band musicians, crew members, and spectators during a typical rehearsal and performance using both Occupational Safety and Health Administration (OSHA) and National Institute of Occupational Safety and Health (NIOSH) measurement criteria. Personal noise dosimetry was completed on five members of a rock band during one 2-hr rehearsal and one 4-hr performance. Time-weighted averages (TWA) and daily dose values were calculated using both OSHA and NIOSH criteria and compared to industry guidelines for enrollment in hearing conservation programs and the use of hearing protection devices. TWA values ranged from 84.3 to 90.4 dBA (OSHA) and from 90.0 to 96.4 dBA (NIOSH) during the rehearsal. The same values ranged from 91.0 to 99.7 dBA (OSHA) and 94.0 to 102.8 dBA (NIOSH) for the performance. During the rehearsal, daily noise doses ranged from 45.54% to 106.7% (OSHA) and from 317.74% to 1396.07% (NIOSH). During the performance, doses ranged from 114.66% to 382.49% (OSHA) and from 793.31% to 5970.15% (NIOSH). The musicians in this study were exposed to dangerously high levels of noise and should be enrolled in a hearing conservation programs. Hearing protection devices should be worn, especially during performances. The OSHA measurement criteria yielded values significantly more conservative than those produced by NIOSH criteria. Audiologists should counsel musician-patients about the hazards of excessive noise (music) exposure and how to protect their hearing.	\N	\N
22559370	The "combined-stimulation advantage" refers to an improvement in speech recognition when cochlear-implant or vocoded stimulation is supplemented by low-frequency acoustic information. Previous studies have been interpreted as evidence for "super-additive" or "synergistic" effects in the combination of low-frequency and electric or vocoded speech information by human listeners. However, this conclusion was based on predictions of performance obtained using a suboptimal high-threshold model of information combination. The present study shows that a different model, based on Gaussian signal detection theory, can predict surprisingly large combined-stimulation advantages, even when performance with either information source alone is close to chance, without involving any synergistic interaction. A reanalysis of published data using this model reveals that previous results, which have been interpreted as evidence for super-additive effects in perception of combined speech stimuli, are actually consistent with a more parsimonious explanation, according to which the combined-stimulation advantage reflects an optimal combination of two independent sources of information. The present results do not rule out the possible existence of synergistic effects in combined stimulation; however, they emphasize the possibility that the combined-stimulation advantages observed in some studies can be explained simply by non-interactive combination of two information sources.	\N	\N
22559371	Preliminary data [M. Epstein and M. Florentine, Ear. Hear. 30, 234-237 (2009)] obtained using speech stimuli from a visually present talker heard via loudspeakers in a sound-attenuating chamber indicate little difference in loudness when listening with one or two ears (i.e., significantly reduced binaural loudness summation, BLS), which is known as "binaural loudness constancy." These data challenge current understanding drawn from laboratory measurements that indicate a tone presented binaurally is louder than the same tone presented monaurally. Twelve normal listeners were presented recorded spondees, monaurally and binaurally across a wide range of levels via earphones and a loudspeaker with and without visual cues. Statistical analyses of binaural-to-monaural ratios of magnitude estimates indicate that the amount of BLS is significantly less for speech presented via a loudspeaker with visual cues than for stimuli with any other combination of test parameters (i.e., speech presented via earphones or a loudspeaker without visual cues, and speech presented via earphones with visual cues). These results indicate that the loudness of a visually present talker in daily environments is little affected by switching between binaural and monaural listening. This supports the phenomenon of binaural loudness constancy and underscores the importance of ecological validity in loudness research.	\N	\N
22559380	Speech perception requires the integration of information from multiple phonetic and phonological dimensions. A sizable literature exists on the relationships between multiple phonetic dimensions and single phonological dimensions (e.g., spectral and temporal cues to stop consonant voicing). A much smaller body of work addresses relationships between phonological dimensions, and much of this has focused on sequences of phones. However, strong assumptions about the relevant set of acoustic cues and/or the (in)dependence between dimensions limit previous findings in important ways. Recent methodological developments in the general recognition theory framework enable tests of a number of these assumptions and provide a more complete model of distinct perceptual and decisional processes in speech sound identification. A hierarchical Bayesian Gaussian general recognition theory model was fit to data from two experiments investigating identification of English labial stop and fricative consonants in onset (syllable initial) and coda (syllable final) position. The results underscore the importance of distinguishing between conceptually distinct processing levels and indicate that, for individual subjects and at the group level, integration of phonological information is partially independent with respect to perception and that patterns of independence and interaction vary with syllable position.	\N	\N
22559460	Peruvian Spanish (PS) and Iberian Spanish (IS) learners were tested on their ability to categorically discriminate and identify Dutch vowels. It was predicted that the acoustic differences between the vowel productions of the two dialects, which compare differently to Dutch vowels, would manifest in differential L2 perception for listeners of these two dialects. The results show that although PS learners had higher general L2 proficiency, IS learners were more accurate at discriminating all five contrasts and at identifying six of the L2 Dutch vowels. These findings confirm that acoustic differences in native vowel production lead to differential L2 vowel perception.	\N	\N
22563091	Linguistic variables alone cannot fully account for bilingual listeners' perception of English-running speech. In the present study, the authors investigated how linguistic and attitudinal factors, in combination, affect bilingual processing of temporally degraded English passages in quiet and in noise. Thirty-six bilinguals with various linguistic and attitudinal characteristics participated in the study. Bilingual individuals completed questionnaires that assessed their language background, willingness to communicate (WTC), and self-perceived communication competency (SPCC) in English. Participants listened to English passage pairs from the Connected Speech Test, presented at 45 dB HL at 3 rates (unprocessed, expanded, compressed), in quiet and in noise. Language proficiency measures were the most significant linguistic variables, accounting for the largest amount of variance in performance across most conditions. Both WTC and SPCC were associated with performance and contributed to regression models. Subscales assessing listeners' WTC and SPCC in a group were more predictive of performance than communication in an interpersonal or public setting. Performance in noise was more difficult to predict than in quiet. Performance with compression was more difficult to predict than with expansion. To fully understand bilingual clients' perception of English speech, hearing professionals should consider their attitudinal characteristics in addition to language background.	\N	\N
22564903	To evaluate whether a hypothesis suggesting that apraxia of speech results from phonological overspecification could be relevant for childhood apraxia of speech (CAS). High-density EEG was recorded from 5 children with CAS and 5 matched controls, ages 5-8 years, with and without CAS, as they listened to randomized sequences of CV syllables in two oddball paradigms: phonemic (/ba/, /pa/) and allophonic (/pa/, /p(h)a/). In the phonemic contrast condition, mismatch negativity (MMN) responses to oddball sounds were observed for the typically developing (comparison) group but not the CAS group, although a component similar to an immature mismatch response was apparent. The allophonic contrast did not elicit MMN responses in the comparison group, but in the CAS group, an MMN-like response was observed. The authors propose that these preliminary findings are consistent with a view of CAS as a disorder that not only affects motor planning but also has a phonological component.	\N	\N
22565049	Primary facial nerve tumors (FNTs) present in varying ways. In this study, the authors present their institutional experience with the management of facial nerve tumors, including their recommendations for available therapies such as observation, microsurgical decompression or removal, and stereotactic radiation. They emphasize the auditory and facial nerve function outcomes. Retrospective case review. Tertiary referral center. Retrospective review of all cases of FNT seen at the authors' tertiary care academic medical center over a 10-year period (2002-2011). The clinical presentation, treatment modality, and outcome parameters of cochlear and facial nerve function were assessed. Twelve patients were identified. House-Brackmann grades on presentation were 4 grade I, 2 grade II, 2 grade III, 1 grade IV, and 3 grade V, with 2 grade V patients declining to grade VI shortly after presentation. Seven patients presented with serviceable hearing and 4 with nonserviceable hearing. Treatment options/arms included observation with serial clinicoradiological review (2 cases), stereotactic radiation with the CyberKnife (3 cases), wide fallopian canal decompression (3 cases), microsurgical excision and repair (3 cases), and biopsy followed by observation (1 case). At the end of the review period, facial nerve function was stable in 8 patients, improved in 3, and declined in 1, and none had documented worsening of hearing based on American Academy of Otolaryngology--Head and Neck Surgery Foundation classification. Management of FNT is largely based on the clinicoradiological picture. Each treatment arm is different, but overall auditory and facial function can be maintained.	\N	\N
22571290	Vocal emblems, such as shh and brr, are speech sounds that have linguistic and nonlinguistic features; thus, it is unclear how they are processed in the brain. Five adult dextral individuals with left-brain damage and moderate-severe Wernicke's aphasia, five adult dextral individuals with right-brain damage, and five Controls participated in two tasks: (1) matching vocal emblems to photographs ('picture task') and (2) matching vocal emblems to verbal translations ('phrase task'). Cross-group statistical analyses on items on which the Controls performed at ceiling revealed lower accuracy by the group with left-brain damage (than by Controls) on both tasks, and lower accuracy by the group with right-brain damage (than by Controls) on the picture task. Additionally, the group with left-brain damage performed significantly less accurately than the group with right-brain damage on the phrase task only. Findings suggest that comprehension of vocal emblems recruits more left- than right-hemisphere processing.	\N	\N
22584037	Music is an ancient and ubiquitous form of human expression. One important component for which music is sought after is its aesthetic value, whose appreciation has typically been associated with largely learned, culturally determined factors, such as education, exposure, and social pressure. However, neuroscientific evidence shows that the aesthetic response to music is often associated with automatic, physically- and biologically-grounded events, such as shivers, chills, increased heart rate, and motor synchronization, suggesting the existence of an underlying biological platform upon which contextual factors may act. Drawing on philosophical notions and neuroscientific evidence, I argue that, although there is no denying that social and cultural context play a substantial role in shaping the aesthetic response to music, these act upon largely universal, biological mechanisms involved with neural processing. I propose that the simultaneous presence of culturally-influenced and biologically-determined contributions to the aesthetic response to music epitomizes Baumgarten's equation of sensory perception with taste. Taking the argument one step further, I suggest that the heavily embodied aesthetic response to music bridges the cleavage between the two discrepant meanings-the one referring to sensory perception, the other referring to judgments of taste-traditionally attributed to the word "aesthetics" in the sciences and the humanities.	\N	\N
22588234	To identify whether speech recognition outcomes are influenced by the choice of ear for cochlear implantation in adults with bilateral hearing loss who use a hearing aid in 1 ear but have long-term auditory deprivation in the other. Retrospective matched cohort study. Speech recognition results were examined in 30 adults with monaural sound deprivation. Fifteen received the implant in the sound-deprived ear and 15 in the aided ear. Tertiary referral centers with active cochlear implant programs. Adults with bilateral hearing loss and a minimum of 15 years of monaural sound deprivation who received a cochlear implant after meeting the traditional implantation criteria of the referral centers. Cochlear implantation with devices approved by the U.S. Food and Drug Administration. Paired comparisons of postoperative monosyllabic word recognition scores obtained with the implant alone and in the usual listening condition (CI alone or bimodal). With the cochlear implant alone, individuals who received the implant in a sound-deprived ear obtained poorer scores than individuals who received the implant in the aided ear. There was no significant difference, however, in speech recognition results for the 2 groups when tested in their usual listening condition. In particular, poorer speech recognition scores were obtained with the cochlear implant alone by individuals using bimodal hearing. Similar clinical outcomes of cochlear implantation can be achieved by adults with a long-term monaural sound deprivation when comparing the usual listening condition, irrespective of whether the implant is in the sound-deprived or in the aided ear.	\N	\N
22588270	This study aimed to characterize horizontal plane sound localization in interfering noise at different signal-to-noise ratios (SNRs) and to compare performance across normal-hearing listeners and users of unilateral and bilateral cochlear implants (CIs). CI users report difficulties with listening in noisy environments. Although their difficulties with speech understanding have been investigated in several studies, the ability to localize sounds in background noise has not extensively been examined, despite the benefits of binaural hearing being greatest in noisy situations. Sound localization is a measure of binaural processing and is thus well suited to assessing the benefit of bilateral implantation. The results will inform clinicians and implant manufacturers how to focus their efforts to improve localization with CIs in noisy situations. Six normal-hearing listeners, four unilateral, and 10 bilateral CI users indicated the perceived location of sound sources using a light pointer method. Target sounds were noise pulses played from one of 11 loudspeakers placed between -80 and +80 degrees in the frontal horizontal plane in the free field. Localization was assessed in quiet and in diffuse background noise at SNRs between +10 and -7 dB. Speech reception thresholds were measured and their relation to the localization results examined. Localization performance declined with decreasing SNR: target sounds were perceived closer to the median plane and the standard deviation of responses increased. Localization performance across groups was compared using a measure of "Spatial Resolvability" (SR). This measure gives the angular separation between two sound sources that would enable an ideal observer to correctly distinguish them 69.1% of the time. For all participants SR increased with decreasing SNR, that is, at low SNRs the spatial separation between sound sources remained distinguishable only when it was larger. Normal-hearing participants performed best, with SR between 1.4 and 5.1 degrees in quiet. Bilateral CI users showed SR between 8.3 and 43.6 degrees in quiet, corresponding approximately to the spatial resolution of normal-hearing listeners at an SNR of -5 dB. Most bilateral CI users had lost the ability to correctly determine which side the sound came from at an SNR of -3 dB. Overall, the SNR had to be at least +7 dB to achieve localization performance near to that in quiet for all bilateral CI users. No significant correlation was found between spatial resolution and speech reception thresholds, but the speech processor sensitivity setting did significantly affect performance. Unilateral CI users showed the most severe localization problems, with only two of four participants being able to correctly determine which side sounds came from in quiet. This study is the first to examine sound localization with CIs at various SNRs and to compare it with normal hearing. The results confirm that localization with CIs is strongly disrupted in noisy situations. Bilateral CIs were shown to be clearly superior over unilateral CIs for localization in quiet and in noisy situations. With bilateral CIs, localization declined at moderately high absolute noise levels (>63 dB SPL), suggesting that an extension of the acoustic-dynamic range to higher levels would be beneficial. The absence of a relation between speech reception thresholds and spatial resolution highlights the need for additional clinical tests to assess the binaural benefit of a second implant.	\N	\N
22591493	Recent oddball studies showed that auditory change detection responses exist in the first 50 ms after sound onset, upstream of mismatch negativity (MMN). We examined if these early responses could be elicited by feature-specific changes, meaning changes in the value of one attribute of a stimulus, regardless of whether other attributes of the stimulus are changing or not. We used a multifeature paradigm with four types of deviants: frequency, duration, intensity, and interaural time difference. In the middle latency range, only frequency deviants led to an enhanced Nb response. All four feature changes generated significant MMNs. Our results indicate that human brain is capable of detecting a feature-specific change for frequency attributes in the middle latency. The different levels of information being encoded in two separate event-related potential time ranges support the notion of a hierarchical organization of auditory deviance detection.	\N	\N
22606932	We describe the audiometric results following surgery in a consecutive series of patients with a congenital ossicular middle ear disorder that was associated with a mobile stapes footplate. We performed a retrospective analysis of patient charts from a tertiary referral center. A total of 23 patients (23 ears) underwent exploratory tympanotomy and ossicular reconstruction between 1986 and 2001. The main outcome measure was the audiometric results. Overall, we observed a mean gain in air conduction pure tone average of 17 dB (from 47 dB to 30 dB), a sensorineural deterioration of 3 dB, and a mean postoperative air-bone gap of 19 dB (mean preoperative air-bone gap of 38 dB). The air-bone gap closure was 20 dB or less in 15 of the 23 cases (65%), in agreement with the few results reported in the literature. Moreover, the audiometric results remained stable. In the syndromic group, the mean gain in air conduction was only 13 dB, which was worse than that observed for the nonsyndromic ears. Surgery for congenital ossicular chain anomalies with a concomitant mobile stapes footplate provides positive audiometric outcomes. Most ears had some sensorineural impairment (10 to 20 dB), which influenced the final hearing level attained after surgery. Preoperative assessment is mandatory to search for syndromal diagnoses, which might be important for patient counseling and prognosis.	\N	\N
22609773	This study investigated the bandwidth of phase sensitivity. Subjects discriminated amplitude-modulated tones (AM), and quasi-frequency-modulated tones (QFM) in a two-interval, forced-choice task. An adaptive threshold procedure was used to estimate the modulation depth needed to discriminate the stimuli as a function of carrier and modulation frequency. Non-monotonicities in threshold-bandwidth functions were often observed at higher modulation frequencies. The results are discussed in terms of two potential cues: (1) waveform envelope, (2) cubic distortion products. In order to degrade the information obtained from auditory distortions, the phase for the carrier frequency was randomly sampled from a uniform distribution, which diminished the non-monotonicities with minimal effect at lower modulation frequencies. Model simulations demonstrated that phase randomization degrades distortion product cues with only a modest effect on temporal cues. Final results show that maximum bandwidths for phase sensitivity (BW(max)) were not proportional to carrier frequencies.	\N	\N
22615475	In this study, the authors evaluated the effect of frequency compression hearing aids on speech perception ability and the time course and magnitude of acclimatization-related changes. Participants included children ages 11-18 years. Speech perception ability was evaluated over well-controlled baseline, treatment, and withdrawal study phases. Study-worn hearing aids were individually fitted to all participants. The authors evaluated speech perception ability using outcomes of speech detection (/s/ and /[symbol in text]/ sounds), /s-[symbol in text]/ discrimination, and plural and consonant recognition. Indices of change were discussed on a case-by-case basis across all study phases. Significant treatment effects were measured for all cases, on at least one measure, with some listeners displaying significant acclimatization trends following a trial of frequency compression. Findings suggest that frequency compression provided varying outcomes, both in benefit and acclimatization, across listeners. For some, a period of acclimatization was necessary before change could be measured. For others, performance remained stable over the time course under evaluation, suggesting that some but not all children will experience improved speech recognition ability after a period of frequency compression hearing aid use.	\N	\N
22615939	In natural audio-visual environments, a change in depth is usually correlated with a change in loudness. In the present study, we investigated whether correlating changes in disparity and loudness would provide a functional advantage in binding disparity and sound amplitude in a visual search paradigm. To test this hypothesis, we used a method similar to that used by van der Burg et al. to show that non-spatial transient (square-wave) modulations of loudness can drastically improve spatial visual search for a correlated luminance modulation. We used dynamic random-dot stereogram displays to produce pure disparity modulations. Target and distractors were small disparity-defined squares (either 6 or 10 in total). Each square moved back and forth in depth in front of the background plane at different phases. The target's depth modulation was synchronized with an amplitude-modulated auditory tone. Visual and auditory modulations were always congruent (both sine-wave or square-wave). In a speeded search task, five observers were asked to identify the target as quickly as possible. Results show a significant improvement in visual search times in the square-wave condition compared to the sine condition, suggesting that transient auditory information can efficiently drive visual search in the disparity domain. In a second experiment, participants performed the same task in the absence of sound and showed a clear set-size effect in both modulation conditions. In a third experiment, we correlated the sound with a distractor instead of the target. This produced longer search times, indicating that the correlation is not easily ignored.	\N	\N
22616091	Sound localization in the horizontal (azimuth) plane relies mainly on interaural time differences (ITDs) and interaural level differences (ILDs). Both are distorted in listeners with acquired unilateral conductive hearing loss (UCHL), reducing their ability to localize sound. Several studies demonstrated that UCHL listeners had some ability to localize sound in azimuth. To test whether listeners with acquired UCHL use strongly perturbed binaural difference cues, we measured localization while they listened with a sound-attenuating earmuff over their impaired ear. We also tested the potential use of monaural pinna-induced spectral-shape cues for localization in azimuth and elevation, by filling the cavities of the pinna of their better-hearing ear with a mould. These conditions were tested while a bone-conduction device (BCD), fitted to all UCHL listeners in order to provide hearing from the impaired side, was turned off. We varied stimulus presentation levels to investigate whether UCHL listeners were using sound level as an azimuth cue. Furthermore, we examined whether horizontal sound-localization abilities improved when listeners used their BCD. Ten control listeners without hearing loss demonstrated a significant decrease in their localization abilities when they listened with a monaural plug and muff. In 4/13 UCHL listeners we observed good horizontal localization of 65 dB SPL broadband noises with their BCD turned off. Localization was strongly impaired when the impaired ear was covered with the muff. The mould in the good ear of listeners with UCHL deteriorated the localization of broadband sounds presented at 45 dB SPL. This demonstrates that they used pinna cues to localize sounds presented at low levels. Our data demonstrate that UCHL listeners have learned to adapt their localization strategies under a wide variety of hearing conditions and that sound-localization abilities improved with their BCD turned on.	\N	\N
22617829	Lateral prefrontal cortex and basal ganglia work together to mediate working memory and top-down regulation of cognition. This circuit regulates the balance and interactions between automatic and high-order control responses. Using ultra-high-field high-resolution functional magnetic resonance imaging (7T-fMRI), the present study examined the role of subcortical structures in cognitive control during language processing. Participants were asked to judge the grammaticality of unambiguous, ungrammatical and ambiguous sentences. Grammatical unambiguous sentences should elicit an automatic response, while ambiguous and ungrammatical sentences should conflict with the automatic response and, hence, require a high-order control response. Within the control response domain, ambiguity and ungrammaticality represent two different dimensions of conflict resolution, while for a temporarily ambiguous sentence a correct interpretation is available, that is not the case for ungrammatical sentences. Our results reveal an anterior-posterior axis in the dorsomedial striatum with more rostral regions supporting higher levels of cognitive processing. This functional architecture mirrors the rostrocaudal hierarchical organization evidenced within the lateral prefrontal cortex.	\N	\N
22621261	Categorical perception, an increased sensitivity to between- compared with within-category contrasts, is a stable property of native speech perception that emerges as language matures. Although recent research suggests that categorical responses to speech sounds can be found in left prefrontal as well as temporo-parietal areas, it is unclear how the neural system develops heightened sensitivity to between-category contrasts. In the current study, two groups of adult participants were trained to categorize speech sounds taken from a dental/retroflex/velar continuum according to two different boundary locations. Behavioral results suggest that for successful learners, categorization training led to increased discrimination accuracy for between-category contrasts with no concomitant increase for within-category contrasts. Neural responses to the learned category schemes were measured using a short-interval habituation design during fMRI scanning. Whereas both inferior frontal and temporal regions showed sensitivity to phonetic contrasts sampled from the continuum, only the bilateral middle frontal gyri exhibited a pattern consistent with encoding of the learned category scheme. Taken together, these results support a view in which top-down information about category membership may reshape perceptual sensitivities via attention or executive mechanisms in the frontal lobes.	\N	\N
22646315	The study investigated the effect of immediate feedback in training listeners to perceive subtle differences in voice quality, a perceptual skill that is important for speech-language pathologists. Sixty naive listeners were randomly assigned to a feedback group (Group F), a no feedback group (Group NF), and a no training group acting as a control group (Group C). The task was to evaluate the severity of a perceptual voice quality (breathiness) by using a reference-matching paradigm. All participants took part in three rating sessions (pre-training, 2 days after training and 1 week after training). Group F and Group NF participated in a training session immediately after the first rating session, where Group F practiced with immediate feedback given and Group NF practice with no immediate feedback given. The results showed that Group F and Group NF had significant improvement after training, but Group F did not retain the improvement in the third rating session. The use of a reference-matching training paradigm without giving frequent immediate feedback is suggested for auditory-perceptual voice evaluation training. The most effective frequency of immediate feedback is yet to be determined.	\N	\N
22648604	The "pip-and-pop effect" refers to the facilitation of search for a visual target (a horizontal or vertical bar whose color changes frequently) among multiple visual distractors (tilted bars also changing color unpredictably) by the presentation of a spatially uninformative auditory cue synchronized with the color change of the visual target. In the present study, the visual stimuli in the search display changed brightness instead of color, and the crossmodal congruency between the pitch of the auditory cue and the brightness of the visual target was manipulated. When cue presence and cue congruency were randomly varied between trials (Experiment 1), both congruent cues (low-frequency tones synchronized with dark target states or high-frequency tones synchronized with bright target states) and incongruent cues (the reversed mapping) facilitated visual search performance equally, relative to a no-cue baseline condition. However, when cue congruency was blocked and the participants were informed about the pitch-brightness mapping in the cue-present blocks (Experiment 2), performance was significantly enhanced when the cue and target were crossmodally congruent as compared to when they were incongruent. These results therefore suggest that the crossmodal congruency between auditory pitch and visual brightness can influence performance in the pip-and-pop task by means of top-down facilitation.	\N	\N
22659285	The health impacts of environmental noise are a growing concern amongst both the general public and policy-makers in Europe. Environmental noise - especially from road transportation - is widely accepted as an important environmental impact factor that can be taken as a start for the process of evaluating the impact of annoyance on the exposed urban population. Extensive urbanisation and the increase of road transport define the main driving forces for the environmental noise exposure of the population. In urban conditions, it is rather common, regarding road transportation noise, to hear from people that, especially, PTW (Powered Two Wheelers) are annoying, and many times are actually the most annoying environmental noise sources introducing a degradation of the urban environment. In this research, in Athens city centre, both scooters and motorbikes operation patterns are analysed, in the basis of their environmental impact through ad-hoc tests to establish if specific features of their emitted noise are annoying and affect the quality of life. It resulted that PTW are a relevant cause of specific environmental annoyance on pedestrians when low background noise levels and sparse traffic flow allow identifying the PTW. Based on the results of a measurement campaign, both L(max) and roughness indices are identified as characteristic noise signatures of the PTW. Results are compared to laboratory studies on annoyance found in literature and to a specific set of interviews with a large number of pedestrians in selected sites. Annoyance caused by scooters and motorbikes is analysed in the findings and conclusions.	\N	\N
22659582	How do perceivers apply knowledge to instances they have never experienced before? On one hand, listeners might use idealized representations that do not contain specific details. On the other, they might recognize and process information based on more detailed memory representations. The current study examined the latter possibility with respect to musical meter perception, previously thought to be computed based on highly-idealized (isochronous) internal representations. In six experiments, listeners heard sets of metrically-ambiguous melodies. Each melody was played in a simultaneous musical context with unambiguous metrical cues (3/4 or 6/8). Cross-melody similarity was manipulated by pairing certain cues-timbre (musical instrument) and motif content (2-6-note patterns)-with each meter, or distributing cues across meters. After multiple exposures, listeners heard each melody without context, and judged metrical continuations (all Experiments) or familiarity (Experiments 5-6). Responses were assessed for "metrical restoration"-the tendency to make metrical judgments that fit the melody's previously-heard metrical context. Cross-melody similarity affected the presence and degree of metrical restoration, and timbre affected familiarity. Results suggest that metrical processing may be calculated based on fairly detailed representations rather than idealized isochronous pulses, and is dissociated somewhat from familiarity judgments. Implications for theories of meter perception are discussed.	\N	\N
22666424	Sensory attenuation refers to the observation that self-generated stimuli are attenuated, both in terms of their phenomenology and their cortical response compared to the same stimuli when generated externally. Accordingly, it has been assumed that sensory attenuation might help individuals to determine whether a sensory event was caused by themselves or not. In the present study, we investigated whether this dependency is reciprocal, namely whether sensory attenuation is modulated by prior beliefs of authorship. Participants had to judge the loudness of auditory effects that they believed were either self-generated or triggered by another person. However, in reality, the sounds were always triggered by the participants' actions. Participants perceived the tones' loudness attenuated when they believed that the sounds were self-generated compared to when they believed that they were generated by another person. Sensory attenuation is considered to contribute to the emergence of people's belief of authorship. Our results suggest that sensory attenuation is also a consequence of prior belief about the causal link between an action and a sensory change in the environment.	\N	\N
22667466	Cochlear microphonic (CM) measurements may potentially become a supplementary approach to otoacoustic emission (OAE) measurements for assessing low-frequency cochlear functions in the clinic. The objective of this study was to investigate the measurement of CMs in subjects with high-frequency hearing loss. Currently, CMs can be measured using electrocochleography (ECochG or ECoG) techniques. Both CMs and OAEs are cochlear responses, while auditory brainstem responses (ABRs) are not. However, there are inherent limitations associated with OAE measurements such as acoustic noise, which can conceal low-frequency OAEs measured in the clinic. However, CM measurements may not have these limitations. CMs were measured in human subjects using an ear canal electrode. The CMs were compared between the high-frequency hearing loss group and the normal-hearing control group. Distortion product OAEs (DPOAEs) and audiogram were also measured. The DPOAE and audiogram measurements indicate that the subjects were correctly selected for the two groups. Low-frequency CM waveforms (CMWs) can be measured using ear canal electrodes in high-frequency hearing loss subjects. The difference in amplitudes of CMWs between the high-frequency hearing loss group and the normal-hearing group is insignificant at low frequencies but significant at high frequencies.	\N	\N
22670350	Quinn and Watt (2006 Perception 35 267-280) showed that the optimal tempi for pieces of music (ie the appropriate speed for a melody) vary from melody to melody. The current study tested if such tempi responses depend on previous stimulus presentations. To do this, we ran a many-participants single-presentation version of the Quinn and Watt experiment. 616 visitors to the Glasgow Science Centre participated. We found that the results substantially matched those obtained earlier, and demonstrate that participants' responses are essentially independent of previously presented stimuli.	\N	\N
22688920	Previous research suggests that young children have significant difficulty recognizing speech in the presence of background noise as compared with older children and adults. However, limited research exists that examines the developmental effects of speech recognition in noise in separate age groups of young children, especially in a classroom setting. The lack of research may relate to the limited number of tests with multiple, equally intelligible lists in noise that are also appropriate for young children. As a result, the goals of the present study include investigating (1) effects of age and (2) benefits of spatial separation of speech and noise sources on the speech recognition in noise performance of young children with normal-hearing sensitivity. A secondary goal of the study was to establish the validity and reliability of the Phrases in Noise Test (PINT) for assessing the 50% correct speech-in-noise threshold of young children. The investigators used a two-way repeated measures design to examine the main effects of age and spatial separation. Sixty-eight children in separate groups of 3-, 4-, 5-, and 6-year-olds and 17 adults completed two speech-recognition conditions with (1) speech and noise from the same loudspeaker at 0-degree azimuth (S0/N0) and (2) speech and noise from separate loudspeakers at 0- and 180-degree azimuth (S0/N180). Recruiting sites included local preschools and school districts for children and a university for adults. The results of this investigation suggest that younger children (<4 years of age) have significantly poorer speech-in-noise thresholds than older children and adults, and 4- and 5-year-old children also have significantly poorer performance than adults when speech and noise are presented from the same spatial location. All participants obtained significant spatial release from masking. On a parent and teacher screening questionnaire to assess educational risk, five of 12 children with at-risk behaviors had poor speech-in-noise thresholds relative to their peers. When two lists of the PINT are used, the test seems to be a valid and reliable measure for assessing young children's speech-in-noise thresholds. Young children exhibit significantly poorer speech recognition than do older children and adults in a classroom, especially when speech and noise are presented from the same location. Given the poor acoustics of typical classrooms, and the earlier age at which many children are educated, special modifications to classrooms may be necessary to improve listening through acoustic modifications or classroom amplification. A combination of a parent or teacher questionnaire and the PINT may be helpful in identifying children who are at risk for educational delays and listening difficulties in classrooms with typically poor acoustics.	\N	\N
22693344	Hearing and feeling both rely upon the transduction of physical events into frequency-based neural codes, suggesting that the auditory system may be intimately related to the somatosensory system. Here, we provide evidence that the neural substrates for audition and somatosensation are anatomically linked. Using diffusion tensor imaging with both deterministic and probabilistic tractography to measure white matter connectivity, we show that there are extensive ipsilateral connections between the primary auditory cortex and the primary and secondary somatosensory regions in the human cerebral cortex. We further show that these cross-modal connections are exaggerated between the auditory and secondary somatosensory cortex in the lesioned hemisphere of a patient (SR) with acquired auditory-tactile synesthesia, in whom sounds alone produce bodily sensations. These results provide an anatomical basis for multisensory interactions between audition and somatosensation and suggest that cross-talk between these regions may explain why some sounds, such as nails screeching down a chalkboard or an audible mosquito, can induce feelings of touch, especially on the contralesional body surface of patient SR.	\N	\N
22695875	The aim of this study is to compare the hearing thresholds of the diabetic patients with the age- and sex-matched normal control group regarding age, glucose level, duration and complications of diabetes with the degree of hearing impairment. Pure tone audiometry was performed in 58 patients with type 1 and 2 diabetes mellitus and compared with 58 age- and sex-matched controls. The patients were categorized into groups according to age, duration of diabetes, complications and control of diabetes. These observations were compared with those from the control subjects. 15-50 years age group with diabetes showed a significant high frequency hearing loss, as compared to the controls. Complicated and poorly controlled diabetics have significant degree of hearing loss in high frequencies as compared to those who were well controlled and uncomplicated. There was also a correlation between the level of hearing loss and duration of diabetes.	\N	\N
22710551	Superficial siderosis is a progressive disease of the central nervous system associated with chronic subarachnoid hemorrhage. Sensorineural hearing loss occurs early in the disease typically progressing to a profound hearing loss during several years and ultimately affecting 95% of patients. There are published reports of variable outcomes regarding auditory performance for cochlear implantation in cases of superficial siderosis: the objective of this article was to systematically review this evidence. A systematic search of NHS Evidence electronic journal databases AMED (1985 to present), BNI (1985 to present), CINAHL (1981 to present), EMBASE (1980 to present), HEALTH BUSINESS ELITE, HMIC, MEDLINE (1950 to present), and PsycINFO (1806 to present) was performed. Further research using personal communication, Google Scholar, hand searching Otology & Neurotology (2008-2011), and assessment of reference lists identified in other relevant articles yielded additional articles. A total of 24 articles were short-listed based on relevance; no studies were excluded on a basis of quality. Of these 24 articles, 11 were excluded. The 13 articles included in this review report 15 cases of cochlear implantation in superficial siderosis. Of these 15 individual cases, 7 (47%) showed clear sustained benefit from cochlear implantation, 6 showed limited/no benefit from the onset, and the remaining 2 patients' initial benefit was not maintained. Outcomes will depend on the site of lesion and the degree of cochlear nerve functionality, as well as ongoing neural deterioration. Comprehensive assessment of the auditory pathway including electrical auditory brainstem response and magnetic resonance imaging as well as pre/postimplantation counseling is indicated, but these preoperative measures are imperfect predictors of outcomes. There are indications that, where the underlying disease is stable, cochlear implant performance may be sustained, and where there is disease progression (specifically regarding involvement of auditory brainstem nuclei), cochlear implant performance may deteriorate. Further data are needed in this regard; however, results suggest that earlier implantation would provide benefit for a longer period and increase cost-effectiveness.	\N	\N
22712945	Frequency modulation detection limens (FMDLs) were measured for five hearing-impaired (HI) subjects for carrier frequencies f(c) = 1000, 4000, and 6000 Hz, using modulation frequencies f(m) = 2 and 10 Hz and levels of 20 dB sensation level and 90 dB SPL. FMDLs were smaller for f(m) = 10 than for f(m) = 2 Hz for the two higher f(c), but not for f(c) = 1000 Hz. FMDLs were also determined with additional random amplitude modulation (AM), to disrupt excitation-pattern cues. The disruptive effect was larger for f(m) = 10 than for f(m) = 2 Hz. The smallest disruption occurred for f(m) = 2 Hz and f(c) = 1000 Hz. AM detection thresholds for normal-hearing and HI subjects were measured for the same f(c) and f(m) values. Performance was better for the HI subjects for both f(m). AM detection was much better for f(m)  = 10 than for f(m) = 2 Hz. Additional tests showed that most HI subjects could discriminate temporal fine structure (TFS) at 800 Hz. The results are consistent with the idea that, for f(m) = 2 Hz and f(c) = 1000 Hz, frequency modulation (FM) detection was partly based on the use of TFS information. For higher carrier frequencies and for all carrier frequencies with f(m) = 10 Hz, FM detection was probably based on place cues.	\N	\N
22712949	The musical scale is a basis for melodies and can be a simple melody by itself. The present study investigated magnetoencephalographic (MEG) responses to omissions of one tone out of the C major scale. The tone preceding the omitted "target" tone was either prolonged or repeated. In another series, the tone after the target tone was repeated. In "normal" oddball experiments, the complete C major scale was presented more frequently than an incomplete scale lacking one tone, and in "reverse" oddball experiments, the roles were exchanged. In the normal oddball experiments, omission of any tone produced a response significantly different in amplitude from the standard response in the group of non-musicians, although the responses differed depending on the types of omission. The leading tone (B in the C major scale) was shown to elicit a large response when omitted and also when its presence was emphasized. The Reverse oddball experiments showed that repeated presentation of an incomplete scale lacking one tone temporarily reduced the influence of the complete scale but could not even temporarily replace it working as "standard." In addition, an auxiliary study was done to see possible influence of rhythmic variations.	\N	\N
22713383	We report a patient with non-fluent Primary Progressive Aphasia who was premorbidly literate in two alphabetic scripts, Hungarian (L1) and English (L2). Testing was performed over a two-year period to assess the impact of progressive illness on oral reading and repetition of single words. Results showed significant decline in oral reading in both languages, and an effect of language status in favour of oral reading in L1. Phonological complexity was a significant predictor of oral reading decline in both languages. Of interest, we observed an effect of language status on task performance whereby repetition was better in L2 than L1 but oral reading was better in L1 than L2. We conclude that language status has an effect on repetition and oral reading abilities for bilingual speakers with non-fluent Primary Progressive Aphasia.	\N	\N
22714710	It is clear that the ability to learn new speech contrasts changes over development, such that learning to categorize speech sounds as native speakers of a language do is more difficult in adulthood than it is earlier in development. There is also a wealth of data concerning changes in the perception of speech sounds during infancy, such that infants quite rapidly progress from language-general to more language-specific perceptual biases. It is often suggested that the perceptual narrowing observed during infancy plays a causal role in the loss of plasticity observed in adulthood, but the relationship between these two phenomena is complicated. Here I consider the relationship between changes in sensitivity to speech sound categorization over the first 2 years of life, when they appear to reorganize quite rapidly, to the "long tail" of development throughout childhood, in the context of understanding the sensitive period for speech perception.	\N	\N
22716266	This study aimed to discover whether general receptive vocabulary is qualitatively phenotypical in Down syndrome. Sixty-two participants with Down syndrome (M age=16.74 years, SD=3.28) were individually matched on general vocabulary raw total score with 62 participants with intellectual disability of undifferentiated etiology (M age=16.20 years, SD=3.08) and 62 typical children (M age=5.32 years, SD=0.82). Item analyses using the transformed item difficulties method to detect differential item functioning across groups showed that the groups' rank orders of item difficulty were highly similar. It was concluded that the general receptive vocabulary of older children and adolescents with Down syndrome is not qualitatively distinguished when its overall size is held constant. Methodological and theoretical implications of this finding are discussed.	\N	\N
22717687	To develop a predictive model of spatial release from masking (SRM) for cochlear implantees, and validate this model against data from the literature. To establish the spatial configurations for which the model predicts a large advantage of bilateral over unilateral implantation. To collect data to support these predictions and generate predictions of more typical advantages of bilateral implantation. The model initially assumed that bilateral cochlear implantees had equally effective implants on each side, with which they could perform optimal better-ear listening. Predictions were compared with measurements of SRM, using one and two implants with up to three interfering noises. The effect of relaxing the assumption of equally effective implants was explored. Novel measurements of SRM for eight unilateral implantees were collected, including measurements using speech and noise at azimuths of ± 60 degrees, and compared with prediction. A spatial map of bilateral implant benefit was generated for a situation with one interfering noise in anechoic conditions, and predictions of benefit were generated from binaural room impulse responses in a variety of real rooms. The model accurately predicted data from a previous study for multiple interfering noises in a variety of spatial configurations, even when implants were assumed to be equally effective (r = 0.97). It predicted that the maximum benefit of bilateral implantation was 18 dB. Predictions were little affected if the implants were not assumed to be equally effective. The new measurements supported the 18 dB advantage prediction. The spatial map of predicted benefit showed that, for a listener facing the target voice, bilateral implantees could enjoy an advantage of about 10 dB over unilateral implantees in a wide range of situations. Predictions based on real-room measurements with speech and noise at 1 m showed that large benefits can occur even in reverberant spaces. In optimal conditions, the benefit of bilateral implantation to speech intelligibility in noise can be much larger than has previously been reported. This benefit is thus considerably larger than reported benefits of summation or squelch and is robust in reverberation when the interfering source is close.	\N	\N
22721629	Understanding the temporal dynamics underlying cortical processing of auditory categories is complicated by difficulties in equating temporal and spectral features across stimulus classes. In the present magnetoencephalography (MEG) study, female voices and cat sounds were filtered so as to match in most of their acoustic properties, and the respective auditory evoked responses were investigated with a paradigm that allowed us to examine auditory cortical processing of two natural sound categories beyond the physical make-up of the stimuli. Three cat or human voice sounds were first presented to establish a categorical context. Subsequently, a probe sound that was congruent, incongruent, or ambiguous to this context was presented. As an index of a categorical mismatch, MEG responses to incongruent sounds were stronger than the responses to congruent sounds at ~250 ms in the right temporoparietal cortex, regardless of the sound category. Furthermore, probe sounds that could not be unambiguously attributed to any of the two categories ("cat" or "voice") evoked stronger responses after the voice than cat context at 200-250 ms, suggesting a stronger contextual effect for human voices. Our results suggest that categorical templates for human and animal vocalizations are established at ~250 ms in the right temporoparietal cortex, likely reflecting continuous online analysis of spectral stimulus features during auditory categorizing task.	\N	\N
22726605	In a recent study, we reported that the accurate perception of beat structure in music ('perception of musical meter') accounted for over 40% of the variance in single word reading in children with and without dyslexia (Huss et al., 2011). Performance in the musical task was most strongly associated with the auditory processing of rise time, even though beat structure was varied by manipulating the duration of the musical notes. Here we administered the same musical task a year later to 88 children with and without dyslexia, and used new auditory processing measures to provide a more comprehensive picture of the auditory correlates of the beat structure task. We also measured reading comprehension and nonword reading in addition to single word reading. One year later, the children with dyslexia performed more poorly in the musical task than younger children reading at the same level, indicating a severe perceptual deficit for musical beat patterns. They now also had significantly poorer perception of sound rise time than younger children. Longitudinal analyses showed that the musical beat structure task was a significant longitudinal predictor of development in reading, accounting for over half of the variance in reading comprehension along with a linguistic measure of phonological awareness. The non-linguistic musical beat structure task is an important independent longitudinal and concurrent predictor of variance in reading attainment by children. The different longitudinal versus concurrent associations between musical beat perception and auditory processing suggest that individual differences in the perception of rhythmic timing are an important shared neural basis for individual differences in children in linguistic and musical processing.	\N	\N
22732772	The purpose of this study was to determine how combinations of reverberation and noise, typical of environments in many elementary school classrooms, affect normal-hearing school-aged children's speech recognition in stationary and amplitude-modulated noise, and to compare their performance with that of normal-hearing young adults. In addition, the magnitude of release from masking in the modulated noise relative to that in stationary noise was compared across age groups in nonreverberant and reverberant listening conditions. Last, for all noise and reverberation combinations the degree of change in predicted performance at 70% correct was obtained for all age groups using a best-fit cubic polynomial. Bamford-Kowal-Bench sentences and noise were convolved with binaural room impulse responses representing nonreverberant and reverberant environments to create test materials representative of both audiology clinics and school classroom environments. Speech recognition of 48 school-aged children and 12 adults was measured in speech-shaped and amplitude-modulated speech-shaped noise, in the following three virtual listening environments: nonreverberant, reverberant at 2 m, and reverberant at 6 m. Speech recognition decreased in the reverberant conditions and with decreasing age. Release from masking in modulated noise relative to stationary noise decreased with age and was reduced by reverberation. In the nonreverberant condition, participants showed similar amounts of masking release across ages. The slopes of performance-intensity functions increased with age, with the exception of the nonreverberant modulated masker condition. The slopes were steeper in the stationary masker conditions, where they also decreased with reverberation and distance. In the presence of a modulated masker, the slopes did not differ between the two reverberant conditions. The results of this study reveal systematic developmental changes in speech recognition in noisy and reverberant environments for elementary-school-aged children. The overall pattern suggests that younger children require better acoustic conditions to achieve sentence recognition equivalent to their older peers and adults. In addition, this is the first study to report a reduction of masking release in children as a result of reverberation. Results support the importance of minimizing noise and reverberation in classrooms, and highlight the need to incorporate noise and reverberation into audiological speech-recognition testing to improve predictions of performance in the real world.	\N	\N
22743078	This work is a preliminary study that sought to investigate and develop a method for defining and evaluating "success" in paediatric cochlear implantation (PCI) and to apply a process by which a clinical team could optimally achieve this aim. A pilot group of 25 profoundly deaf children who received a unilateral cochlear implant from 1995 to 2008 was used to develop the process. The cases displayed features that are commonly encountered in PCI. Individual case records were examined retrospectively for adverse factors that might impact on the implantation outcome with particular reference to the probability and severity of impact of each factor. Case prognosis was then rated on a 1-4 basis (1: excellent, 2: good, 3: fair, 4: poor). The subsequent outcomes were assessed using standardised speech (GFW, DEAP), language (PLS-4; CELF) and vocabulary (PPVT; EVT) assessments. Auditory performance outcomes were assessed using a new Categories of Auditory Performance Index (CAPI) that incorporated criteria, testing and scoring aspects. Family issues were also evaluated. Case outcomes were rated 1-4 as above and the prognoses and outcomes were then compared. Accurate prognostication was seen in 14 cases, 5 had better outcomes than expected and 6 obtained poorer results. "Success", where the outcome equalled or exceeded the prognosis, occurred in 19 (76%) of cases. The successful group contained some "limited gains" cases where the results were nonetheless in line with expectations and parental satisfaction. The detrimental effect of delayed implantation was evident; Connexin 26 (GJB2) mutation had little influence. Poor general medical condition and adverse family situations commonly produced poorer outcomes. Success in PCI is achieved when the outcome matches or exceeds the pre-operative expectations of the well-counselled family, without adverse side effects. The assessments achieved a good success rate, but further research is required to clearly identify potential problems and a skilled team is needed to evaluate their risk to the PCI outcome. Unforseen events may also intervene. Currently, differing outcome evaluation techniques impede comparison of studies, particularly in the speech and hearing domains. Rationalisation of these is recommended to facilitate future research.	\N	\N
22744139	To determine if short-term computerized speech-in-noise training can produce significant improvements in speech-in-noise perception by cochlear implant (CI) recipients on standardized audiologic testing measures. Five adult postlingually deafened CI recipients participated in 4 speech-in-noise training sessions using the Seeing and Hearing Speech program (Sensimetrics; Malden, MA). Each participant completed lessons concentrating on consonant and vowel recognition at word, phrase, and sentence levels. Speech-in-noise abilities were assessed using the QuickSIN (Killion, Niquette, Gudmundsen, Revit, & Banerjee, 2004) and the Hearing in Noise Test (HINT ( Nilsson, Soli & Sullivan, 1994)). All listeners significantly improved key word identification on the HINT after training, albeit only at the most favorable signal-to-noise ratio (SNR). Listeners also showed a significant reduction in the degree of SNR loss on the QuickSIN after training. Short-term speech-in-noise training may improve speech-in-noise perception in postlingually deafened adult CI recipients.	\N	\N
22760769	Sound localization is a computational process accomplished along the auditory pathway. Once the acoustic information received at each ear is analyzed independently (monaural cues) and comparatively (binaural cues), those cues are integrated to generate a coherent spatial percept. Using adult ferrets trained by positive conditioning in a spatial task, we aimed to study the role of the auditory cortex in the ability to localize sounds under both normal hearing and monaurally occluded conditions, the latter of which requires a reinterpretation of the values of the localization cues. Sound localization deficits were found after lesion or inactivation of the different auditory cortical regions, thereby indicating their participation in spatial processing. The differential impairments found in the approach-to-target and in the head movement responses reveal the complex relationship between cortex and midbrain which are putatively responsible for the voluntary and reflexive aspects of localization behaviour respectively. Furthermore, every auditory cortical region contributes to the adaptation process that follows monaural occlusion, indicating the key role that the auditory cortex plays in experience-dependent plasticity. Also, the selective lesion of the descending projections from the auditory cortex to the inferior colliculus by chromophore-targeted laser photolysis has revealed the essential function that descending pathways play in learning-induced localization plasticity.	\N	\N
22772879	Synesthesia is an unusual condition in which stimulation of one sensory modality causes an experience in another sensory modality or when a sensation in one sensory modality causes another sensation within the same modality. We describe a previously unreported association of auditory-olfactory synesthesia coexisting with auditory-visual synesthesia. Given that many types of synesthesias involve vision, it is important that the clinician provide these patients with the necessary information and support that is available.	\N	\N
22773777	Many neurons adapt their spike output to accommodate the prevailing sensory environment. Although such adaptation is thought to improve coding of relevant stimulus features, the relationship between adaptation at the neural and behavioral levels remains to be established. Here we describe improved discrimination performance for an auditory spatial cue (interaural time differences, ITDs) following adaptation to stimulus statistics. Physiological recordings in the midbrain of anesthetized guinea pigs and measurement of discrimination performance in humans both demonstrate improved coding of the most prevalent ITDs in a distribution, but with highest accuracy maintained for ITDs corresponding to frontal locations, suggesting the existence of a fovea for auditory space. A biologically plausible model accounting for the physiological data suggests that neural tuning is stabilized by inhibition to maintain high discriminability for frontal locations. The data support the notion that adaptive coding in the midbrain is a key element of behaviorally efficient sound localization in dynamic acoustic environments.	\N	\N
22779451	Animals live in cluttered auditory environments, where sounds arrive at the two ears through several paths. Reflections make sound localization difficult, and it is thought that the auditory system deals with this issue by isolating the first wavefront and suppressing later signals. However, in many situations, reflections arrive too early to be suppressed, for example, reflections from the ground in small animals. This paper examines the implications of these early reflections on binaural cues to sound localization, using realistic models of reflecting surfaces and a spherical model of diffraction by the head. The fusion of direct and reflected signals at each ear results in interference patterns in binaural cues as a function of frequency. These cues are maximally modified at frequencies related to the delay between direct and reflected signals, and therefore to the spatial location of the sound source. Thus, natural binaural cues differ from anechoic cues. In particular, the range of interaural time differences is substantially larger than in anechoic environments. Reflections may potentially contribute binaural cues to distance and polar angle when the properties of the reflecting surface are known and stable, for example, for reflections on the ground.	\N	\N
22779484	Previous studies have shown a loss in the precision of horizontal localization responses of older hearing-impaired (HI) individuals, along with potentially poorer neural representations of sound-source location. These deficits could be the result or corollary of greater difficulties in discriminating spatial images, and the insensitivity to punctate sound sources. This hypothesis was tested in three headphone-presentation experiments varying interaural coherence (IC), the cue most associated with apparent auditory source width. First, thresholds for differences in IC were measured for a broad sampling of participants. Older HI participants were significantly worse at discriminating IC across reference values than younger normal-hearing participants. These results are consistent with senescent increases in temporal jitter. Performance decreased with age, a finding corroborated in a second discrimination experiment using a separate group of participants matched for hearing loss. This group also completed a third, visual experiment, with both a cross-mapping task where they drew the size of the sound they heard and the identification task where they chose the image that best corresponded to what they heard. The results from the visual tasks indicate that older HI individuals do not hear punctate images and are relatively insensitive to changes in width based on IC.	\N	\N
22783631	This study investigates the phonetic implementation of stress in American English compounds by measuring the interaction of stress cues with different intonation patterns. Participants in an experiment produced compounds and phrases such as greenhouse and green house in different prosodic positions and sentence types to elicit the contrast in a variety of intonational environments. Intonation patterns were labeled and carefully controlled for, and measurements of vowel duration, intensity (dB) and pitch (in semitones) were compared. The results of the experiment reveal clear patterns that distinguish compounds from phrases, and provide acoustic evidence of the characteristic prominence pattern for adjective + noun compounds. Intensity is a significant cue for compound stress in all but the rising intonation environments, such as questions. Duration differences are a reliable cue in exactly this intonational environment, and also in certain clause-final intonation patterns, which similarly contain a high boundary tone. Distinctive pitch patterns were also found. The results suggest that interactions with the intonational and prosodic environment determine which phonetic cues will signal the stress pattern of a compound in a given utterance.	\N	\N
22786953	Auditory spatial perception plays a critical role in day-to-day communication. For instance, listeners utilize acoustic spatial information to segregate individual talkers into distinct auditory "streams" to improve speech intelligibility. However, spatial localization is an exceedingly difficult task in everyday listening environments with numerous distracting echoes from nearby surfaces, such as walls. Listeners' brains overcome this unique challenge by relying on acoustic timing and, quite surprisingly, visual spatial information to suppress short-latency (1-10 ms) echoes through a process known as "the precedence effect" or "echo suppression." In the present study, we employed electroencephalography (EEG) to investigate the neural time course of echo suppression both with and without the aid of coincident visual stimulation in human listeners. We find that echo suppression is a multistage process initialized during the auditory N1 (70-100 ms) and followed by space-specific suppression mechanisms from 150 to 250 ms. Additionally, we find a robust correlate of listeners' spatial perception (i.e., suppressing or not suppressing the echo) over central electrode sites from 300 to 500 ms. Contrary to our hypothesis, vision's powerful contribution to echo suppression occurs late in processing (250-400 ms), suggesting that vision contributes primarily during late sensory or decision making processes. Together, our findings support growing evidence that echo suppression is a slow, progressive mechanism modifiable by visual influences during late sensory and decision making stages. Furthermore, our findings suggest that audiovisual interactions are not limited to early, sensory-level modulations but extend well into late stages of cortical processing.	\N	\N
22790547	Children and adolescents who live in situations of social vulnerability present a series of health problems. Nonetheless, affirmations that sensory and cognitive abnormalities are present are a matter of controversy. The aim of this study was to investigate aspects to auditory processing, through applying the brainstem auditory evoked potential (BAEP) and behavioral auditory processing tests to children living on the streets, and comparison with a control group. Cross-sectional study in the Laboratory of Auditory Processing, School of Medicine, Universidade de São Paulo. The auditory processing tests were applied to a group of 27 individuals, subdivided into 11 children (7 to 10 years old) and 16 adolescents (11 to 16 years old), of both sexes, in situations of social vulnerability, compared with an age-matched control group of 10 children and 11 adolescents without complaints. The BAEP test was also applied to investigate the integrity of the auditory pathway. For both children and adolescents, there were significant differences between the study and control groups in most of the tests applied, with significantly worse performance in the study group, except in the pediatric speech intelligibility test. Only one child had an abnormal result in the BAEP test. The results showed that the study group (children and adolescents) presented poor performance in the behavioral auditory processing tests, despite their unaltered auditory brainstem pathways, as shown by their normal results in the BAEP test.	\N	\N
22813575	To separate neural signals from noise, brain responses measured in neuroimaging are routinely averaged across space and time. However, such procedures may obscure some properties of neural activity. Recently, multi-voxel pattern analysis methods have demonstrated that patterns of activity across voxels contain valuable information that is concealed by spatial averaging. Here we show that temporal patterns of neural activity contain information that can discriminate different stimuli, even within brain regions that show no net activation to that stimulus class. Furthermore, we find that in many brain regions, responses to natural stimuli are highly context dependent. In such cases, prototypical event-related responses do not even exist for individual stimuli, so that averaging responses to the same stimulus within different contexts may worsen the effective signal-to-noise. As a result, analysis of the temporal structures of single events can reveal aspects of neural dynamics which cannot be detected using standard event-related averaging methods.	\N	\N
22821077	The decision about which location should be the goal of the next eye movement is known to be determined by the interaction between auditory and visual input. This interaction can be explained by the vector theory that states that each element (either visual or auditory) in a scene evokes a vector in the oculomotor system. These vectors determine the direction in which the eye movement is initiated. Because auditory input is lateralized and localizable in most studies, it is currently unclear how non-lateralized auditory input interacts with the vectors evoked by visual input. In the current study, we investigated the influence of a non-lateralized auditory non-target on saccade accuracy (saccade angle deviation from the target) and latency in a single-target condition in Experiment 1 and a double-target condition in Experiment 2. The visual targets in Experiment 2 were positioned in such a way that saccades on average landed in between the two targets (i.e., a global effect). There was no effect of the auditory input on saccade accuracy in the single-target condition, but auditory input did influence saccade accuracy in the double-target condition. In both experiments, saccade latency increased when auditory input accompanied the visual target(s). Together, these findings show that non-lateralized auditory input enhances all vectors evoked by visual input. The results will be discussed in terms of their possible neural substrates.	\N	\N
22834336	The coherency characteristics of the brain electrical activity were studied in two groups of subjects: 1) with high and 2) low indexes of "emotional ear" (an ability to successfully recognize emotions in the speech). Comparison of the coherency links between two groups of subjects permitted the authors to make a conclusion that the persons of the first group had a much lower coherency level, especially in the alpha- and gamma-rhythms. The subjects of the second group were characterized by the opposite tendency: an increase in coherent links on the majority of frequency bands.	\N	\N
22836173	Functional networks in the human brain give rise to complex cognitive and perceptual abilities. While the decrease of functional connectivity is linked to neurological and psychiatric disorders, less is known about the consequences of increased functional connectivity. One population that has exceptionally enhanced perceptual abilities is people with absolute pitch (AP) - an ability to categorize tones into pitch classes without reference. AP has been linked to exceptional talent as well as to psychiatric and neurological conditions. Here we show that AP possessors have increased functional activation during music listening, as well as increased degrees, clustering, and local efficiency of functional correlations, with the difference being highest around the left superior temporal gyrus. Our results provide the first evidence that increased functional connectivity in a small-world brain network is related to exceptional perceptual abilities in a healthy population.	\N	\N
22842471	Task-irrelevant perceptual learning (TIPL) refers to the phenomenon where the stimulus features of a subject's task are learned when they are consistently presented at times when behaviorally relevant events occur. In this article, we addressed two points concerning TIPL. First, we address the question, are all behaviorally relevant events equal in their impact on encoding processes? Second, we address the hypothesis that TIPL involves mechanisms of the alerting attentional system. Two experiments of fast-TIPL were conducted in which the attentional state of participants was manipulated by using an alerting cue (visual or auditory) that informed participants of the arrival of an upcoming target. Images were presented with task-related stimuli (cues, targets and distractors) and subjects were tested on their memory of those images. Results indicate that memory for target-paired images was enhanced and cue-paired images were suppressed relative to that of distractor-paired images. The alerting cue increased the ability to recall target-paired images presented after this cue, although this result depended on the proportion of cued trials in a session. These results demonstrate a complex interplay between task-elements and the encoding of stimuli paired with them where both enhancement and suppression of task-paired stimuli can be found depending whether those stimuli are paired with task-targets or cues.	\N	\N
22848464	When a second sound follows a long first sound, its location appears to be perceived away from the first one (the localization/lateralization aftereffect). This aftereffect has often been considered to reflect an efficient neural coding of sound locations in the auditory system. To understand determinants of the localization aftereffect, the current study examined whether it is induced by an interaural temporal difference (ITD) in the amplitude envelope of high frequency transposed tones (over 2 kHz), which is known to function as a sound localization cue. In Experiment 1, participants were required to adjust the position of a pointer to the perceived location of test stimuli before and after adaptation. Test and adapter stimuli were amplitude modulated (AM) sounds presented at high frequencies and their positional differences were manipulated solely by the envelope ITD. Results showed that the adapter's ITD systematically affected the perceived position of test sounds to the directions expected from the localization/lateralization aftereffect when the adapter was presented at ±600 µs ITD; a corresponding significant effect was not observed for a 0 µs ITD adapter. In Experiment 2, the observed adapter effect was confirmed using a forced-choice task. It was also found that adaptation to the AM sounds at high frequencies did not significantly change the perceived position of pure-tone test stimuli in the low frequency region (128 and 256 Hz). The findings in the current study indicate that ITD in the envelope at high frequencies induces the localization aftereffect. This suggests that ITD in the high frequency region is involved in adaptive plasticity of auditory localization processing.	\N	\N
22858614	The purpose of this evidence-based systematic review was to evaluate the efficacy of digital noise reduction and directional microphones for outcome measures of audibility, speech recognition, speech and language, and self- or parent-report in pediatric hearing aid users. The authors searched 26 databases for experimental studies published after 1980 addressing one or more clinical questions and meeting all inclusion criteria. The authors evaluated studies for methodological quality and reported or calculated p values and effect sizes when possible. A systematic search of the literature resulted in the inclusion of 4 digital noise reduction and 7 directional microphone studies (in 9 journal articles) that addressed speech recognition, speech and language, and/or self- or parent-report outcomes. No digital noise reduction or directional microphone studies addressed audibility outcomes. On the basis of a moderate level of evidence, digital noise reduction was not found to improve or degrade speech understanding. Additional research is needed before conclusions can be drawn regarding the impact of digital noise reduction on important speech, language, hearing, and satisfaction outcomes. Moderate evidence also indicates that directional microphones resulted in improved speech recognition in controlled optimal settings; however, additional research is needed to determine the effectiveness of directional microphones in actual everyday listening environments.	\N	\N
22859982	Pitch processing is a critical ability on which humans' tonal musical experience depends, and which is also of paramount importance for decoding prosody in speech. Congenital amusia refers to deficits in the ability to properly process musical pitch, and recent evidence has suggested that this musical pitch disorder may impact upon the processing of speech sounds. Here we present the first electrophysiological evidence demonstrating that individuals with amusia who speak Mandarin Chinese are impaired in classifying prosody as appropriate or inappropriate during a speech comprehension task. When presented with inappropriate prosody stimuli, control participants elicited a larger P600 and smaller N100 relative to the appropriate condition. In contrast, amusics did not show significant differences between the appropriate and inappropriate conditions in either the N100 or the P600 component. This provides further evidence that the pitch perception deficits associated with amusia may also affect intonation processing during speech comprehension in those who speak a tonal language such as Mandarin, and suggests music and language share some cognitive and neural resources.	\N	\N
22866760	Many studies have examined the processes involved in recognizing types of human action through sound, but little is known about whether the physical characteristics of an action (such as kinetic and kinematic parameters) can be perceived and imitated from sound. Twelve young healthy adults listened to recordings of footsteps on a gravel path taken from walks of different stride lengths (SL) and cadences. In 1 protocol, participants performed a real-time reenactment of the walking action depicted in a sound sample. Second, participants listened to 2 different sound samples and discriminated differences in SL. In a 2nd experiment, these procedures were repeated using synthesized sounds derived from the kinetic interactions between the foot and walking surface. A 3rd experiment examined the influence of altered cadence on participants' ability to discriminate changes in SL. Participants significantly adapted their own SL and cadence according to those depicted in both real and synthesized sounds (p < .01). However, although participants accurately discriminated between large changes in SL, these perceptions were heavily influenced by temporal factors, that is, when cadence changed between samples. These findings show that spatial attributes of action sounds can be both mimicked and discriminated, even when only basic kinetic interactions present within the action are specified.	\N	\N
22875083	The aim of the current study was to differentiate between neural activity that represents neural anomalies that are responsible for persistent developmental stuttering (PDS) from the activity that is a result of compensating for stuttering. This was done by investigating alterations to the intrinsic functional architecture of speech-language processes of patients with PDS before and after a short-term intervention. The resting-state functional connectivity (RSFC) and cortical thickness were examined before and after the intervention. The structural data were used to validate the functional results. Fifteen stuttering patients who received intervention (PDS+), 13 stuttering patients who did not receive intervention (PDS-), and 13 fluent controls participated. Before the intervention, both groups of PDS patients showed significant RSFC and cortical thickness reductions in the left pars-opercularis (PO) and RSFC increases in the cerebellum, as compared to fluent controls. The intervention was effective in reducing stuttering in PDS+ patients and lowering their RSFC in the cerebellum to the level of fluent controls. The intervention effect was specific to the PDS+ group (it was not evident in the PDS- group). The intervention did not change RSFC and cortical thickness in the left PO, which remained at its preintervention level. The results suggest that the left PO is a locus where the intrinsic functional architecture of speech-language processes is altered in PDS patients, suggesting an etiologic role of this region in PDS. The cerebellum showed intervention-induced neural reorganization, suggesting a compensatory response when stuttering occurs.	\N	\N
22889186	Two experiments are reported concerning the perception of ground extent to discover whether prior reports of anisotropy between frontal extents and extents in depth were consistent across different measures (visual matching and pantomime walking) and test environments (outdoor environments and virtual environments). In Experiment 1 it was found that depth extents of up to 7 m are indeed perceptually compressed relative to frontal extents in an outdoor environment, and that perceptual matching provided more precise estimates than did pantomime walking. In Experiment 2, similar anisotropies were found using similar tasks in a similar (but virtual) environment. In both experiments pantomime walking measures seemed to additionally compress the range of responses. Experiment 3 supported the hypothesis that range compression in walking measures of perceived distance might be due to proactive interference (memory contamination). It is concluded that walking measures are calibrated for perceived egocentric distance, but that pantomime walking measures may suffer range compression. Depth extents along the ground are perceptually compressed relative to frontal ground extents in a manner consistent with the angular scale expansion hypothesis.	\N	\N
22894208	Artificial bandwidth extension methods have been developed to improve the quality and intelligibility of narrowband telephone speech and to reduce the difference with wideband speech. Such methods have commonly been evaluated with objective measures or subjective listening-only tests, but conversational evaluations have been rare. This article presents a conversational evaluation of two methods for the artificial bandwidth extension of telephone speech. Bandwidth-extended narrowband speech is compared with narrowband and wideband speech in a test setting including a simulated telephone connection, realistic conversation tasks, and various background noise conditions. The responses of the subjects indicate that speech processed with one of the methods is preferred to narrowband speech in noise, but wideband speech is superior to both narrowband and bandwidth-extended speech. Bandwidth extension was found to be beneficial for telephone conversation in noisy listening conditions.	\N	\N
22894315	Studies of spoken-word recognition have revealed that competition from embedded words differs in strength as a function of where in the carrier word the embedded word is found and have further shown embedding patterns to be skewed such that embeddings in initial position in carriers outnumber embeddings in final position. Lexico-statistical analyses show that this skew is highly attenuated in Japanese, a noninflectional language. Comparison of the extent of the asymmetry in the three Germanic languages English, Dutch, and German allows the source to be traced to a combination of suffixal morphology and vowel reduction in unstressed syllables.	\N	\N
22897231	When asked how many animals of each kind Moses took on the Ark, most people respond with "two" despite the substituted name (Moses for Noah) in the question. Possible explanations for semantic illusions appear to be related to processing limitations such as those of working memory. Indeed, individual working memory capacity has an impact upon how sentences containing substitutions are processed. This experiment examined further the role of working memory in the occurrence of semantic illusions using a dual-task working memory load approach. Participants verified statements while engaging in either articulatory suppression or random number generation. Secondary task type had a significant effect on semantic illusion rate, but only when comparing the control condition to the two dual-task conditions. Furthermore, secondary task performance in the random number generation condition declined, suggesting a tradeoff between tasks. Response time analyses also showed a different pattern of processing across the conditions. The findings suggest that the phonological loop plays a role in representing semantic illusion sentences coherently and in monitoring for details, while the role of the central executive is to assist gist-processing of sentences. This usually efficient strategy leads to error in the case of semantic illusions.	\N	\N
22915198	Scalar Expectancy Theory (SET) has been the leading theory in timing research, and has also influenced research into human timing. However, other timing theories exist, such as Learning to Time (LeT). The double bisection task was designed to test the SET and LeT theories in pigeons. The purpose of this experiment was to verify whether similar results emerge from a human adaptation of the double bisection task. The results indicated that humans perform the double bisection task in the same way as pigeons do. However, the assumptions inherent in LeT cannot be applied to humans. Two other explanations are also assessed here.	\N	\N
22915276	A hearing screening among 14- to 15-year-old pupils was performed to estimate the number of hearing-impaired individuals in the adolescent population. A total of 1,298 pupils from 30 schools in Tyrol (Austria) participated in the screening. Hearing tests were performed in a silent room at the school. Sinus tones at frequencies 0.5/1/2/4/6 kHz and at levels of 25/20/20/20/20 dB HL, respectively, were delivered via headphones to either ear. Failure of screening was defined as not hearing one or more frequencies in one or both ears. The screening was failed by 16.3% of the pupils. There was a small but not significant difference between males and females (17.0 vs. 15.2%). Most of the pupils failed at only one frequency (9.6%). Failing at two or more frequencies in the same ear occurred in 3.9% of the pupils, thereof in 1.1% bilaterally. As the specificity of our screening is limited, false-positive results may result. Thus, the rate of hearing deficits in our sample is probably a bit lower than indicated by the figures above. Most of the adolescents who failed the screen failed at only one frequency. These subjects have a small elevation of their hearing threshold, not a hearing loss in the sense of a raised averaged threshold. A hearing loss in the latter sense is supposed to be present in only very few percent of adolescents, a bilateral hearing loss in perhaps less than 1%.	\N	\N
22918112	Current strategies for functional rehabilitation of microtia-atresia patients with bone-anchored implants or surgical atresia repair have been extended by the feasibility of active middle ear implants. The aim of the present research is to evaluate a new flowchart of the treatment of these patients that considers active middle ear implants. Congenital aural atresia and microtia. Bilateral cases are provided with a conductive hearing aid after birth and implanted with an active middle ear implant within the second year. Unilateral cases are provided with a conductive hearing aid and implanted with a middle ear or bone-conduction device in early childhood. Unilateral cases without amplification in the vulnerable time after birth are carefully selected for late implantation. At age 8 to 10, the auricular reconstruction is completed. Feasibility of implantation irrespective of age, functional gain in audiometry. The results of early implantation are as good as those previously published for adolescents. Mean reaction threshold with the Vibrant Soundbridge was 21 dB. Mean functional gain was 48 dB. The local tissues are unaltered and ready for auricular reconstruction. Active middle ear implants allow early and selective stimulation of the auditory pathway in children with congenital conductive hearing loss and are expected to lead to the normal development of the binaural hearing functions. To date, it is the only option if the stimulation is to be started at the age of 12 to 18 months. This was implemented into a new flowchart for aural atresia-microtia.	\N	\N
22921291	To use a randomized design to evaluate the effectiveness of voice training programs for telemarketers via multidimensional analysis. Forty-eight telemarketers were randomly assigned to two groups: voice training group (n=14) who underwent training over an 8-week period and a nontraining control group (n=34). Before and after training, recordings of the sustained vowel /ɛ/ and connected were collected for acoustic and perceptual analyses. Based on pre- and posttraining comparisons, the voice training group presented with a significant reduction in percent jitter (P=0.044). No other significant differences were observed, and inter-rater reliability varied from poor to fair. These findings suggest that voice training improved a single acoustic dimension, but do not change perceptual dimension of telemarketers' voices.	\N	\N
22921292	This study investigated whether listener's experience, presence/absence of vibrato, formant frequency difference, or onset delay affect the ability of experienced and inexperienced listeners to segregate complex vocal stimuli. Repeated measures factorial design. Two sets of stimuli were constructed: one with no vibrato and another with vibrato. For each set, each stimulus was synthesized at four pitches: A3, E4, B4, and F5. Stimuli were synthesized using formant patterns appropriate for the vowel |ɑ|. Frequencies for formants one through four were systematically varied from lower to higher in an attempt to simulate the acoustic results of corresponding changes in vocal tract length. Four formant patterns were synthesized (patterns A-D). Three pairs were created at each pitch, pairing the formants AB (mezzo-soprano/mezzo-soprano), CD (soprano/soprano), and AD (mezzo-soprano/soprano). Each of these three pairs was constructed in three separate conditions: simultaneous onset; the first voice in the pair with an onset delay of 100 milliseconds; and the second voice in the pair with an onset delay of 100 milliseconds. Using a scroll bar, listeners rated how difficult it was for them to hear each stimulus pair as two separate voices. The most difficult combinations to segregate were produced with no vibrato and used simultaneous onset. The easiest conditions to segregate were combinations including a "soprano-like" formant pattern (D) in the vibrato condition. Overall, listener's experience did not affect the perceived difficulty of segregation; however, in the presence of vibrato cues, inexperienced listeners did not use delay cues as an aid in segregation in the same manner as did experienced listeners. Once vibrato was removed from the experimental context, inexperienced listeners were able to use delay to aid in segregation in a similar manner to experienced listeners. Presence/absence of vibrato, formant pattern difference, and onset delay interact in a complex manner to affect the perceived difficulty of voice segregation.	\N	\N
22921368	In spite of its massively parallel architecture [1], the human brain is fundamentally limited if required to perform two tasks at the same time [2, 3]. This limitation can be studied with the psychological refractory period (PRP) paradigm, where two stimuli that require speeded responses occur in close succession [4]. Interference generally takes the form of a delay in the time to respond to the second stimulus [5]. Previous studies suggested that sensory decisions require the accumulation of sensory evidence [6, 7] and that the PRP reflects the inability to form more than one decision at a time [4, 8]. In the present study, we used a psychophysical reverse-correlation technique [9, 10] to measure the time-course of evidence accumulation during the PRP. We found that the accumulation of evidence could occur during the PRP albeit with a reduced efficiency, which implies that multiple decision processes can occur in parallel in the human brain. In addition to the reduced efficiency of evidence accumulation, our results uncover an additional delay in the routing of the decision to motor structures during the PRP, which implies that the process of sensory decision making is separable from the preparation of a motor response [11-13].	\N	\N
22921779	To evaluate the auditory outcomes of children implanted in an ear with eighth nerve hypoplasia or aplasia and to determine whether preoperative characteristics are predictive of auditory performance achieved. retrospective case review. tertiary care medical center. ten children implanted in an ear with eighth nerve hypoplasia or aplasia, as determined by high resolution magnetic resonance imaging. Neural response test measurements, detection and speech awareness thresholds, Meaningful Auditory Integration Scale scores, as well as speech perception level achieved. Post-implantation, three children demonstrated little to no detection of sound, three had improved detection and awareness of environmental sounds, one developed closed-set speech perception and spoken language, and three developed open-set speech perception and spoken language. No imaging findings appeared related to outcomes. Significantly better implant detection thresholds and Meaningful Auditory Integration Scale scores were found in children who had preoperative aided auditory detection (p's ≤ 0.02-0.05). Some children with eighth nerve hypoplasia or aplasia may derive significant benefit from a cochlear implant. In our study high resolution magnetic resonance imaging was more sensitive than high resolution computer tomography in detecting neural deficiency. However, no imaging findings were predictive of auditory performance level achieved post-implantation.	\N	\N
22928919	To investigate speech recognition performance in noise with bilateral open-fit hearing aids and as reference also with closed earmolds, in omnidirectional mode, directional mode, and directional mode in conjunction with noise reduction. A within-subject design with repeated measures across conditions was used. Speech recognition thresholds in noise were obtained for the different conditions. Twenty adults without prior experience with hearing aids. All had symmetric sensorineural mild hearing loss in the lower frequencies and moderate to severe hearing loss in the higher frequencies. Speech recognition performance in noise was not significantly better with an omnidirectional microphone compared to unaided, whereas performance was significantly better with a directional microphone (1.6 dB with open fitting and 4.4 dB with closed earmold) compared to unaided. With open fitting, no significant additional advantage was obtained by combining the directional microphone with a noise reduction algorithm, but with closed earmolds a significant additional advantage of 0.8 dB was obtained. The significant, though limited, advantage of directional microphones and the absence of additional significant improvement by a noise reduction algorithm should be considered when fitting open-fit hearing aids.	\N	\N
22928962	In synaesthetes, stimulation of one sensory pathway provokes a sensory experience (e.g. a colour concurrent) in a different sensory modality or sub-modality. Results of synaesthetic Stroop and priming tests indicate that the perception of a colour concurrent interferes with the processing of a veridical colour in synaesthetes. We here examined the congruency between a stimulus' colour and the colour concurrent both in grapheme-colour synaesthetes and in non-synaesthetes trained on grapheme-colour associations. Electrophysiological (electroencephalogram) and behavioural measurements were collected during a priming task that included grapheme-grapheme and grapheme-colour patch pairs. To investigate covert bidirectional synaesthesia, an additional inverted colour patch-grapheme condition was included. Both groups of participants showed longer reaction time and more negative-going N300 and N400 event-related potential (ERP) components on incongruent trials. Whereas ERP effects in the non-synaesthetes were largely confined to the late cognitive components N300, P300 and N400, the synaesthetes also showed congruency-dependent modulation of the early sensory component N170. Our results suggest that early cognitive processes distinguish cross-modal synaesthetic perceptions from acquired associations. The involvement of both early- and late-stage cognitive components in bidirectional synaesthesia possibly indicates similar feature-binding mechanisms during processing of opposite flow directions of information, namely grapheme-colour and colour-grapheme.	\N	\N
22937153	In everyday life, we need a capacity to flexibly shift attention between alternative sound sources. However, relatively little work has been done to elucidate the mechanisms of attention shifting in the auditory domain. Here, we used a mixed event-related/sparse-sampling fMRI approach to investigate this essential cognitive function. In each 10-sec trial, subjects were instructed to wait for an auditory "cue" signaling the location where a subsequent "target" sound was likely to be presented. The target was occasionally replaced by an unexpected "novel" sound in the uncued ear, to trigger involuntary attention shifting. To maximize the attention effects, cues, targets, and novels were embedded within dichotic 800-Hz vs. 1500-Hz pure-tone "standard" trains. The sound of clustered fMRI acquisition (starting at t = 7.82 sec) served as a controlled trial-end signal. Our approach revealed notable activation differences between the conditions. Cued voluntary attention shifting activated the superior intra--parietal sulcus (IPS), whereas novelty-triggered involuntary orienting activated the inferior IPS and certain subareas of the precuneus. Clearly more widespread activations were observed during voluntary than involuntary orienting in the premotor cortex, including the frontal eye fields. Moreover, we found -evidence for a frontoinsular-cingular attentional control network, consisting of the anterior insula, inferior frontal cortex, and medial frontal cortices, which were activated during both target discrimination and voluntary attention shifting. Finally, novels and targets activated much wider areas of superior temporal auditory cortices than shifting cues.	\N	\N
22938066	There are different reports of the usefulness of the Nasometer™ as a complement to listening, often as correlation calculations between listening and nasalance measurements. Differences between findings have been attributed to listener experience and types of speech stimuli. To compare nasalance scores from the Nasometer with perceptual assessments, for the same and different Swedish speech stimuli, using three groups of listeners with differing levels of experience in judging speech nasality. To compare nasalance scores and blinded listener ratings of randomized recordings using three groups of listeners and two groups of speakers. Speakers were either classified as having hypernasal speech or speech with typical speech resonance. Listeners were speech-language pathologists (SLPs) working predominantly with resonance disorders, other SLPs and untrained listeners. Correlations (r(s)) between hypernasality ratings and nasalance scores for each listener group and speech stimuli were calculated. For both groups of SLPs all correlations between perceptual ratings and nasalance scores were significant at p= 0.01. The correlations between the nasalance scores and ratings by listeners in the SLP groups were higher than those for the untrained listener group regardless of stimulus type. Post-hoc Mann-Whitney U-tests showed that the only difference that was significant was expert SLP group versus untrained listener group. Secondly, correlations between perceptual ratings and oral stimulus nasalance scores were higher when the perceptual ratings were based on spontaneous speech rather than on the oral stimulus. However, a Wilcoxon signed rank test showed that the difference was not significant. A third finding was that correlations between oral stimulus nasalance scores and perceptual scores were higher than those between mixed stimulus nasalance scores and perceptual scores. A Wilcoxon signed rank test showed that the difference was significant. The Nasometer might be useful for the SLP with limited experience in assessing resonance disorders in differentiating between hyper- and hyponasality. With listener reliability for ratings of hypernasality still being an issue, the use of a nasalance score as a complement to the perceptual evaluation will also aid the expert SLP. It will give an alternative way of quantifying speech resonance and might help in especially hard to judge cases.	\N	\N
22944369	Previous studies have demonstrated amygdala activation in response to fearful faces even if presented below the threshold of conscious visual perception. It has also been proposed that subcortical regions are selectively sensitive to low spatial frequency (LSF) information. However, chronic hyperarousal may reduce amygdala activation in panic disorder (PD). Our aim was to establish whether the amygdala is engaged by masked and LSF fearful faces in PD as compared to healthy subjects. Neutral faces were used as the mask stimulus. Thirteen PD patients (seven females, six males; mean age=29.1 (S.D: 5.9)) and 15 healthy volunteers (seven females, eight males; mean age=27.9 (S.D. 4.5)) underwent two passive viewing tasks during a 3T functional magnetic resonance imaging (fMRI) as follows: 1) presentation of faces with fearful versus neutral expressions (17ms) using a backward masking procedure and 2) presentation of the same faces whose spatial frequency contents had been manipulated by low-pass filtering. Level of awareness was confirmed by a forced choice fear-detection task. Whereas controls showed bilateral activation to fearful masked faces versus neutral faces, patients failed to show activation within the amygdala. LSF stimuli did not elicit amygdala response in either group, contrary to the view that LSF information plays a crucial role in the processing of facial expressions in the amygdala. Findings suggest maladaptive amygdala responses to potentially threatening visual stimuli in PD patients.	\N	\N
22962856	It has been suggested that high alexithymia scorers have an 'augmenter' profile which amplifies their physiological and subjective responses to highly arousing stimuli. The aim of this study was to test this theory using several physiological measures. Participants listened to musical excerpts either in a 'weak-to-strong' or a 'strong-to-weak' order of arousing levels of stimuli. The results show that alexithymia was associated with an augmenter profile for subjective reports for the most arousing stimulus and with stronger skin conductance level responses in the 'strong-to-weak' order. These results partially support the augmenter profile and reveal that alexithymia may be associated with higher anticipation for the most arousing excerpt.	\N	\N
22970141	Extensive research shows that inter-talker variability (i.e., changing the talker) affects recognition memory for speech signals. However, relatively little is known about the consequences of intra-talker variability (i.e. changes in speaking style within a talker) on the encoding of speech signals in memory. It is well established that speakers can modulate the characteristics of their own speech and produce a listener-oriented, intelligibility-enhancing speaking style in response to communication demands (e.g., when speaking to listeners with hearing impairment or non-native speakers of the language). Here we conducted two experiments to examine the role of speaking style variation in spoken language processing. First, we examined the extent to which clear speech provided benefits in challenging listening environments (i.e. speech-in-noise). Second, we compared recognition memory for sentences produced in conversational and clear speaking styles. In both experiments, semantically normal and anomalous sentences were included to investigate the role of higher-level linguistic information in the processing of speaking style variability. The results show that acoustic-phonetic modifications implemented in listener-oriented speech lead to improved speech recognition in challenging listening conditions and, crucially, to a substantial enhancement in recognition memory for sentences.	\N	\N
22978875	Simulated room impulse responses have been proven to be both useful and indispensable for comprehensive testing of acoustic signal processing algorithms while controlling parameters such as the reverberation time, room dimensions, and source-array distance. In this work, a method is proposed for simulating the room impulse responses between a sound source and the microphones positioned on a spherical array. The method takes into account specular reflections of the source by employing the well-known image method, and scattering from the rigid sphere by employing spherical harmonic decomposition. Pseudocode for the proposed method is provided, taking into account various optimizations to reduce the computational complexity. The magnitude and phase errors that result from the finite order spherical harmonic decomposition are analyzed and general guidelines for the order selection are provided. Three examples are presented: an analysis of a diffuse reverberant sound field, a study of binaural cues in the presence of reverberation, and an illustration of the algorithm's use as a mouth simulator.	\N	\N
22985274	Whether the mechanisms giving rise to pitch reflect spectral or temporal processing has long been debated. Generally, sounds having strong harmonic structures in their spectra have strong periodicities in their temporal structures. We found that when a wideband harmonic tone complex is passed through a noise vocoder, the resulting sound can have a harmonic structure with a large peak-to-valley ratio, but with little or no periodicity in the temporal structure. To test the role of harmonic structure in pitch perception for a nonhuman mammal, we measured behavioral responses to noise-vocoded tone complexes in chinchillas (Chinchilla laniger) using a stimulus generalization paradigm. Chinchillas discriminated either a harmonic tone complex or an iterated rippled noise from a 1-channel vocoded version of the tone complex. When tested with vocoded versions generated with 8, 16, 32, 64, and 128 channels, responses were similar to those of the 1-channel version. Behavioral responses could not be accounted for based on harmonic peak-to-valley ratio as the acoustic cue, but could be accounted for based on temporal properties of the autocorrelation functions such as periodicity strength or the height of the first peak. The results suggest that pitch perception does not arise through spectral processing in nonhuman mammals but rather through temporal processing. The conclusion that spectral processing contributes little to pitch in nonhuman mammals may reflect broader cochlear tuning than that described in humans.	\N	\N
22986018	Structural priming paradigms have been influential in shaping theories of adult sentence processing and theories of syntactic development. However, until recently there have been few attempts to provide an integrated account that explains both adult and developmental data. The aim of the present paper was to begin the process of integration by taking a developmental approach to structural priming. Using a dialog comprehension-to-production paradigm, we primed participants (3-4year olds, 5-6year olds and adults) with double object datives (Wendy gave Bob a dog) and prepositional datives (Wendy gave a dog to Bob). Half the participants heard the same verb in prime and target (e.g. gave-gave) and half heard a different verb (e.g. sent-gave). The results revealed substantial differences in the magnitude of priming across development. First, there was a small but significant abstract structural priming effect across all age groups, but this effect was larger in younger children than in older children and adults. Second, adding verb overlap between prime and target prompted a large, significant increase in the priming effect in adults (a lexical boost), a small, marginally significant increase in the older children and no increase in the youngest children. The results support the idea that abstract syntactic knowledge can develop independently of verb-specific frames. They also support the idea that different mechanisms may be needed to explain abstract structural priming and lexical priming, as predicted by the implicit learning account (Bock, K., & Griffin, Z. M. (2000). The persistence of structural priming: Transient activation or implicit learning? Journal of Experimental Psychology - General, 129(2), 177-192). Finally, the results illustrate the value of an integrative developmental approach to both theories of adult sentence processing and theories of syntax acquisition.	\N	\N
22989579	The perception of a melody is invariant to the absolute properties of its constituting notes, but depends on the relation between them-the melody's relative pitch profile. In fact, a melody's "Gestalt" is recognized regardless of the instrument or key used to play it. Pitch processing in general is assumed to occur at the level of the auditory cortex. However, it is unknown whether early auditory regions are able to encode pitch sequences integrated over time (i.e., melodies) and whether the resulting representations are invariant to specific keys. Here, we presented participants different melodies composed of the same 4 harmonic pitches during functional magnetic resonance imaging recordings. Additionally, we played the same melodies transposed in different keys and on different instruments. We found that melodies were invariantly represented by their blood oxygen level-dependent activation patterns in primary and secondary auditory cortices across instruments, and also across keys. Our findings extend common hierarchical models of auditory processing by showing that melodies are encoded independent of absolute pitch and based on their relative pitch profile as early as the primary auditory cortex.	\N	\N
22989871	The function of consciousness was explored in two contexts of audio-visual speech, cross-modal visual attention guidance and McGurk cross-modal integration. Experiments 1, 2, and 3 utilized a novel cueing paradigm in which two different flash suppressed lip-streams cooccured with speech sounds matching one of these streams. A visual target was then presented at either the audio-visually congruent or incongruent location. Target recognition differed for the congruent versus incongruent trials, and the nature of this difference depended on the probabilities of a target appearing at these respective locations. Thus, even though the lip-streams were never consciously perceived, they were nevertheless meaningfully integrated with the consciously perceived sounds, and participants learned to guide their attention according to statistical regularities between targets and these unconsciously perceived cross-modal cues. In Experiment 4, McGurk stimuli were presented in which the lip-streams were either flash suppressed (4a) or unsuppressed (4b), and the McGurk effect was found to vanish under conditions of flash suppression. Overall, these results suggest a simple yet fundamental principle regarding the function of consciousness in multisensory integration - cross-modal effects can occur in the absence of consciousness, but the influencing modality must be consciously perceived for its information to cross modalities.	\N	\N
22989933	Distraction is a strategy that is commonly used to cope with pain. Results concerning the efficacy of distraction from both experimental and clinical studies are variable, however, and indicate that its efficacy may depend on particular circumstances. Several models propose that distraction may be less effective for people who display a large attentional bias towards pain-related information. This hypothesis was tested in an experimental context with 53 pain-free volunteers. First, attentional bias towards cues signalling the occurrence of pain (electrocutaneous stimuli) and towards words describing the sensory experience of this painful stimulus was independently assessed by means of 2 behavioural paradigms (respectively, spatial cueing task and dot-probe task). This was followed by a subsequent distraction task during which the efficacy of distraction, by directing attention away from the electrocutaneous stimuli, was tested. In addition, state-trait anxiety, catastrophic thinking, and initial pain intensity were measured. Results indicated that people who display a large attentional bias towards predictive cues of pain or who initially experience the pain as more painful benefit less from distraction on a subsequent test. No effects were found between attentional bias towards pain words, state-trait anxiety, catastrophic thinking, and the efficacy of distraction. Current findings suggest that distraction should not be used as a 'one size fits all' method to control pain, but only under more specific conditions.	\N	\N
22992016	The present study showed that elevation of bone-conduction (BC) thresholds at low frequencies might be a characteristic audiometric finding in cases with otitis media with effusion (OME) with high pepsinogen (PG) concentrations. The objective of this study was to investigate whether there is any characteristic audiometric finding in adult cases with otitis media with high PG compared to those with low PG. Twenty-four adult patients with unilateral OME of undetermined etiology and high PG concentrations (> 500 ng/ml) in their middle ear effusions (high PG group) were selected. The air-conduction and BC thresholds of pure tone audiometry were compared between the affected and healthy ears. Results were compared to those in 23 patients with low PG concentrations (< 50 ng/ml; low PG group). The average BC difference in the threshold at 0.25 kHz between the affected ear and the healthy ear was significantly higher in the high PG group than in the low PG group, with a significantly higher proportion of patients in the high PG group having BC thresholds at 0.25 kHz in the affected ear that were ≥ 15 dB higher than in the healthy ear.	\N	\N
23000014	Music is a stimulus which may give rise to a wide range of emotional and cognitive responses. Therefore, brain reactivity to music has become a focus of interest in cognitive neuroscience. It is possible that individual preference moderates the effectof music on the brain. In the present study we examined whether there are common effects of listening to music even if each subject in a sample chooses their own piece of music. We invited 18 subjects to bring along their favorite relaxing music, and their favourite stimulating music. Additionally, a condition with tactile stimulation on the foot and a baseline condition (rest) without stimulation were used. The tactile stimulation was chosen to provide a simple, non-auditory condition which would be identical for all subjects. The electroencephalogram was recorded for each of the 3 conditions and during rest. We found responses in the alpha range mainly on parietal and occipital sites that were significant compared to baseline in 13 subjects during relaxing music, 15 subjects during activating music, and 16 subjects during tactile stimulation. Most subjects showed an alpha desynchronization in a lower alpha range followed by a synchronization in an upper frequency range. However, some subjects showed an increase in this area, whereas others showed a decrease only. In addition, many subjects showed reactivity in the beta range. Beta activity was especially increased while listening to activating music and during tactile stimulation in most subjects. We found interindividual differences in the response patterns even though the stimuli provoked comparable subjective emotions (relaxation, activation), and even if the stimulus was the same for all subjects (somatosensory stimulation). We suggest that brain responsivity to music should be examined individually by considering individual characteristics.	\N	\N
23009003	Cochlear Implant (CI) is the most advanced method of treatment in receptive type of deafness and profound hearing loss. Good functioning auditory organ plays a significant role not only in auditory perception but also in the process of phonation, giving the possibility of good realization of the process of verbal communication. The aim of the study is to assess the quality of voice and life in adults with pre- and postlingual deafness treated using cochlear implant. Twenty six patients with pre- (group I) and postlingual (group II) deafness deriving no benefit from hearing aids were included into the study. Voice quality was assessed using subjective and objective methods. The endoscopic (VLS) and stroboscopic (VLSS) examination of the larynx and the acoustic voice analysis were carried out. The quality of life was assessed using the Nijmegen Cochlear Implant Questionnaire (NCIQ). Examinations were conducted before implantation and 6 months after activation of speech processor. In the subjective and objective assessment of voice quality the improvement was registered in both groups. The effects were less spectacular in prelingual patients. In this group of patients the subjective assessment of voice quality and stroboscopic examination confirmed the hypofunctional type of dysphonia. In postlingual patients the hyperfunctional type of dysphonia was registered what was confirmed by the analysis of acoustic parameters of voice. The improvement of quality of life was observed in both groups of patients after implantation. The voice quality was improved after implantation in both analyzed groups. In patients with postlingual deafness values of parameters of voice quality assessment were closed to physiological. Results of the subjective assessment of voice quality were confirmed by objective examinations and the acoustic voice analysis. Rehabilitation with cochlear implant gave the opportunity for active participation in private and social life, improving the quality of life in patients with pre- and postlingual deafness.	\N	\N
23017812	Auditory impairments in schizophrenia have been demonstrated previously, especially for tasks requiring precise encoding of frequency, although it is unclear the extent to which they have difficulty using pitch information and other cues to segregate sounds. We determined the extent to which those with schizophrenia have difficulty using pitch information and other auditory cues to segregate sounds that are presented sequentially. Ten participants with schizophrenia and nine healthy/normal control participants completed a battery of tasks that tested for the ability to perform sequential auditory stream segregation using pitch, amplitude modulation, or inter-aural phase difference as cues to segregation. All three sequential segregation tasks showed reduced tendency for those with schizophrenia to perceive segregated sounds, compared to control participants. These findings extend prior research by demonstrating a general impairment on sequential sound segregation tasks in schizophrenia, and not just on tasks that require precise encoding of frequency. Together, the pattern of results provide evidence that auditory impairments in schizophrenia result from selective abnormalities in neural circuits that carry out specific computations necessary for stream segregation, as opposed to an impairment in processing specific cues.	\N	\N
23025161	We examined whether and how sounds influence visually induced illusory self-motion (vection). Visual stimuli were presented for 40 s. They were made radially, expanding or contracting visual motion field and luminance-defined gratings drifting in a vertical or horizontal direction. Auditory stimuli were presented with the visual stimuli in most conditions; we employed sounds that increased or decreased in intensity, or ascended or descended in frequency. As a result, the sound which increased in intensity facilitated forward vection, and the sound which ascended/descended in frequency facilitated upward/downward vection. The perceptual plausibility of the sound for the corresponding self-motion seemed an important factor of enhancing vection.	\N	\N
23025794	Preferences between low delays and phase-frequency responses of behind-the-ear, open-canal hearing aids were investigated with acoustic conditions deemed sensitive to delay effects by normal-hearing listeners. Hearing aids with the following selectable delay and phase response options were fitted at low insertion gain: (1) 1.4 ms delay, minimum phase; (2) 3.4 ms delay, minimum phase; and (3) 3.4 ms delay, linear phase. Blind paired comparisons were made between processing options and between each option and a muted hearing-aid output with two music stimuli. The three alternative forced choice responses were "Slightly prefer", "Prefer", or "Strongly prefer". Twelve hearing-impaired musicians. At the 3.4-ms delay, the minimum-phase response was significantly preferred to the linear-phase response for one music sample and vice-versa for the other sample with a sign test (p < 0.04) but not a Wilcoxon signed rank test that accounted for the low preference strength. Preferences between all other processing conditions were not significant. In acoustic conditions sensitive to delay effects, delays of 1.4 or 3.4 ms were either not detected or no less preferable than no delayed aided signal. It is unclear whether different phase-frequency responses may be preferred with different music stimuli.	\N	\N
23027674	To examine the hypothesis that infants receiving a degraded auditory signal have more difficulty segmenting words from fluent speech if familiarized with the words presented in both speech and sign compared to familiarization with the words presented in speech only. Experiment utilizing an infant-controlled visual preference procedure. Twenty 8.5-month-old normal-hearing infants completed testing. Infants were familiarized with repetitions of words in either the speech + sign (n = 10) or the speech only (n = 10) condition. Infants were then presented with four six-sentence passages using an infant-controlled visual preference procedure. Every sentence in two of the passages contained the words presented in the familiarization phase, whereas none of the sentences in the other two passages contained familiar words. Infants exposed to the speech + sign condition looked at familiar word passages for 15.3 seconds and at nonfamiliar word passages for 15.6 seconds, t (9) = -0.130, p = .45. Infants exposed to the speech only condition looked at familiar word passages for 20.9 seconds and to nonfamiliar word passages for 15.9 seconds. This difference was statistically significant, t (9) = 2.076, p = .03. Infants' ability to segment words from degraded speech is negatively affected when these words are initially presented in simultaneous speech and sign. The current study suggests that a decreased ability to segment words from fluent speech may contribute towards the poorer performance of pediatric cochlear implant recipients in total communication settings on a wide range of spoken language outcome measures.	\N	\N
23030713	The tip-of-the-tongue (TOT) state is a common experience, usually coupled with a frustrating feeling caused by the incapability of retrieving a familiar word. It is thought that TOTs occur when the semantic and syntactic information of the word is retrieved but not its phonology. This study aims to further understand the role of phonology in TOT resolution. Specifically, using a syllabic pseudohomophone priming paradigm, we aim to analyse the role of the phonological syllabic position (first vs. last) and the number of syllables in TOT states resolution. TOT was elicited by a picture naming task, after which a lexical decision task was presented. Here, first, last, or none of the phonological syllables of the target word were embedded in pseudohomophone primes. Results showed a significant syllabic pseudohomophone priming effect facilitating TOT resolution. The effect was stronger for four-syllable words, especially when the last syllable was used as prime. These results seem to reinforce the importance of phonology in TOT states resolution, particularly the role of the syllable as an important sublexical unit in speech processing.	\N	\N
23035086	Humans and other animals with foveate vision make saccadic eye movements to prioritize the visual analysis of behaviorally relevant information. Even before movement onset, visual processing is selectively enhanced at the target of a saccade, presumably gated by brain areas controlling eye movements. Here we assess concurrent changes in visual performance and perceived contrast before saccades, and show that saccade preparation enhances perception rapidly, altering early visual processing in a manner akin to increasing the physical contrast of the visual input. Observers compared orientation and contrast of a test stimulus, appearing briefly before a saccade, to a standard stimulus, presented previously during a fixation period. We found simultaneous progressive enhancement in both orientation discrimination performance and perceived contrast as time approached saccade onset. These effects were robust as early as 60 ms after the eye movement was cued, much faster than the voluntary deployment of covert attention (without eye movements), which takes ∼300 ms. Our results link the dynamics of saccade preparation, visual performance, and subjective experience and show that upcoming eye movements alter visual processing by increasing the signal strength.	\N	\N
23041297	Speech prosody conveys information about important aspects of communication: the meaning of the sentence and the emotional state or intention of the speaker. The present study addressed processing of emotional prosodic changes in natural speech stimuli in school-age children (mean age 10 years) by recording the electroencephalogram, facial electromyography, and behavioral responses. The stimulus was a semantically neutral Finnish word uttered with four different emotional connotations: neutral, commanding, sad, and scornful. In the behavioral sound-discrimination task the reaction times were fastest for the commanding stimulus and longest for the scornful stimulus, and faster for the neutral than for the sad stimulus. EEG and EMG responses were measured during non-attentive oddball paradigm. Prosodic changes elicited a negative-going, fronto-centrally distributed neural response peaking at about 500 ms from the onset of the stimulus, followed by a fronto-central positive deflection, peaking at about 740 ms. For the commanding stimulus also a rapid negative deflection peaking at about 290 ms from stimulus onset was elicited. No reliable stimulus type specific rapid facial reactions were found. The results show that prosodic changes in natural speech stimuli activate pre-attentive neural change-detection mechanisms in school-age children. However, the results do not support the suggestion of automaticity of emotion specific facial muscle responses to non-attended emotional speech stimuli in children.	\N	\N
23043968	The current study examined auditory processing deficits in dyslexia using a dichotic pitch stimulus and functional MRI. Cortical activation by the dichotic pitch task occurred in bilateral Heschl's gyri, right planum temporale, and right superior temporal sulcus. Adolescents with dyslexia, relative to age-matched controls, illustrated greater activity in left Heschl's gyrus for random noise, less activity in right Heschl's gyrus for all auditory conditions, and less activity in right superior temporal sulcus for a dichotic melody. Subsequent analyses showed that these group differences were attributable to dyslexic readers who performed poorly on the psychophysical task. Furthermore, behavioral performance on phonological reading was correlated to activity from dichotic conditions in right Heschl's gyrus and right superior temporal sulcus. It is postulated that these differences between reader groups is primarily due to a noise exclusion deficit shown previously in dyslexia.	\N	\N
23046141	Object-substitution masking (OSM) occurs when a mask, such as four dots that surround a brief target item, onsets simultaneously with the target and offsets a short time after the target, rather than simultaneously with it. OSM is a reduction in accuracy of reporting the target with the temporally trailing mask, compared with the simultaneously offsetting mask. It has been thought that OSM occurs only if attention cannot be rapidly focused, or prefocused, on the target location. One line of evidence for this is a reported interaction between target display set size and the duration of the trailing mask. We analyze the evidence for this interaction and suggest it occurs only as an artifact of data being compressed by a ceiling effect. We report six experiments that support this interpretation by showing that the interaction is always absent unless a ceiling effect is induced. We go on to analyze other evidence to support the notion that attention modulates OSM, and argue that in each case, the data either reflect a ceiling effect or can be explained in another way. Our data and our analyses of the existing literature have strong implications for how OSM should be conceptualized.	\N	\N
23046461	It has been repeatedly shown that the auditory N1 is enhanced for sounds presented at an attended time point. The present study investigated the underlying mechanisms using a temporal cuing paradigm. In each trial, an auditory cue indicated at which time point a second sound could be relevant for response selection. Crucially, in addition to temporal attention, two physical sound features with known effects on the sensory N1 were manipulated: location and intensity. Positive evidence for conjoint effects of attention and location or attention and intensity would corroborate the notion that the sensory N1 was modulated by temporal attention, thus supporting a gain mechanism. However, the N1 effect of temporal attention was not similarly lateralized as the sensory N1, and, moreover, it was independent of sound intensity. Thus, the present results do not provide compelling evidence that temporal attention involves an increase in sensory gain.	\N	\N
23047261	Acoustically evoked neural and hair cell potentials can be measured from the round window (RW) intraoperatively in the general population of cochlear implant recipients. Cochlear implant performance varies greatly among patients. Improved methods to assess and monitor functional hair cell and neural substrate before and during implantation could potentially aid in enhanced nontraumatic intracochlear electrode placement and subsequent improved outcomes. Subjects (1-80 yr) undergoing cochlear implantation were included. A monopolar probe was placed at the RW after surgical access was obtained. The cochlear microphonic (CM), summating potential (SP), compound action potential (CAP), and auditory nerve neurophonic (ANN) were recorded in response to tone bursts at frequencies of 0.25 to 4 kHz at various levels. Measurable hair cell/neural potentials were detected to 1 or more frequencies in 23 of 25 subjects. The greatest proportion and magnitude of cochlear responses were to low frequencies (<1,000 Hz). At these low frequencies, the ANN, when present, contributed to the ongoing response at the stimulus frequency. In many subjects, the ANN was small or absent, whereas hair cell responses remained. In cochlear implant recipients, acoustically evoked cochlear potentials are detectable even if hearing is extremely limited. Sensitive measures of cochlear and neural status can characterize the state of hair cell and neural function before implantation. Whether this information correlates with speech performance outcomes or can help in tailoring electrode type, placement or audiometric fitting, can be determined in future studies.	\N	\N
23049884	Accumulating evidence suggests that basic visual information processing is impaired in schizophrenia. However, deficits in peripheral vision remain largely unexplored. Here we hypothesized that sensory processing of information in the visual periphery would be impaired in schizophrenia patients and, as a result, crowding - the breakdown in target recognition that occurs in cluttered visual environments - would be stronger. Therefore, we assessed visual crowding in the peripheral vision of schizophrenia patients and healthy controls. Subjects were asked to identify a target letter that was surrounded by distracter letters of similar appearance. Targets and distracters were displayed at 8° and 10° of visual angle from the fixation point (eccentricity), and target-distracter spacing was 2°, 3°, 4°, 5°, 6°, 7° or 8° of visual angle. Eccentricity and target-distracter spacing were randomly varied. Accuracy was defined as the proportion of correctly identified targets. Critical spacing was defined as the spacing at which target identification accuracy began to deteriorate, and was assessed at viewing eccentricities of 8° and 10°. Schizophrenia patients were less accurate and showed a larger critical spacing than healthy individuals. These results indicate that crowding is stronger and sensory processing of information in the visual periphery is impaired in schizophrenia. This is in line with previous reports of preferential magnocellular dysfunction in schizophrenia. Thus, deficits in peripheral vision may account for perceptual alterations and contribute to cognitive dysfunction in schizophrenia.	\N	\N
23055485	Older adults frequently report they can hear what is said but cannot understand the meaning, especially in noise. This difficulty may arise from the inability to process rapidly changing elements of speech. Aging is accompanied by a general slowing of neural processing and decreased neural inhibition, both of which likely interfere with temporal processing in auditory and other sensory domains. Age-related reductions in inhibitory neurotransmitter levels and delayed neural recovery can contribute to decreases in the temporal precision of the auditory system. Decreased precision may lead to neural timing delays, reductions in neural response magnitude, and a disadvantage in processing the rapid acoustic changes in speech. The auditory brainstem response (ABR), a scalp-recorded electrical potential, is known for its ability to capture precise neural synchrony within subcortical auditory nuclei; therefore, we hypothesized that a loss of temporal precision results in subcortical timing delays and decreases in response consistency and magnitude. To assess this hypothesis, we recorded ABRs to the speech syllable /da/ in normal hearing younger (18-30 years old) and older (60-67 years old) adult humans. Older adults had delayed ABRs, especially in response to the rapidly changing formant transition, and greater response variability. We also found that older adults had decreased phase locking and smaller response magnitudes than younger adults. Together, our results support the theory that older adults have a loss of temporal precision in the subcortical encoding of sound, which may account, at least in part, for their difficulties with speech perception.	\N	\N
23057507	There is strong evidence of shared acoustic profiles common to the expression of emotions in music and speech, yet relatively limited understanding of the specific psychoacoustic features involved. This study combined a controlled experiment and computational modelling to investigate the perceptual codes associated with the expression of emotion in the acoustic domain. The empirical stage of the study provided continuous human ratings of emotions perceived in excerpts of film music and natural speech samples. The computational stage created a computer model that retrieves the relevant information from the acoustic stimuli and makes predictions about the emotional expressiveness of speech and music close to the responses of human subjects. We show that a significant part of the listeners' second-by-second reported emotions to music and speech prosody can be predicted from a set of seven psychoacoustic features: loudness, tempo/speech rate, melody/prosody contour, spectral centroid, spectral flux, sharpness, and roughness. The implications of these results are discussed in the context of cross-modal similarities in the communication of emotion in the acoustic domain.	\N	\N
23063935	Individuals who have been exposed to two different musical cultures (bimusicals) can be differentiated from those exposed to only one musical culture (monomusicals). Just as bilingual speakers handle the distinct language-syntactic rules of each of two languages, bimusical listeners handle two distinct musical-syntactic rules (e.g., tonal schemas) in each musical culture. This study sought to determine specific brain activities that contribute to differentiating two culture-specific tonal structures. We recorded magnetoencephalogram (MEG) responses of bimusical Japanese nonmusicians and amateur musicians as they monitored unfamiliar Western melodies and unfamiliar, but traditional, Japanese melodies, both of which contained tonal deviants (out-of-key tones). Previous studies with Western monomusicals have shown that tonal deviants elicit an early right anterior negativity (mERAN) originating in the inferior frontal cortex. In the present study, tonal deviants in both Western and Japanese melodies elicited mERANs with characteristics fitted by dipoles around the inferior frontal gyrus in the right hemisphere and the premotor cortex in the left hemisphere. Comparisons of the nature of mERAN activity to Western and Japanese melodies showed differences in the dipoles' locations but not in their peak latency or dipole strength. These results suggest that the differentiation between a tonal structure of one culture and that of another culture correlates with localization differences in brain subregions around the inferior frontal cortex and the premotor cortex.	\N	\N
23064383	1) Describe the association between hearing loss and dysfunction of each of the 5 vestibular end-organs--the horizontal, superior, and posterior semicircular canals; saccule; and utricle--in older individuals. 2) Evaluate whether hearing loss and vestibular end-organ deficits share any risk factors. Cross-sectional study. Academic medical center. Fifty-one individuals age 70 years or older. Audiometry, head-thrust dynamic visual acuity (htDVA), sound-evoked cervical vestibular-evoked myogenic potential (cVEMP), and tap-evoked ocular VEMP (oVEMP). Audiometric pure-tone averages (PTA), htDVA LogMAR scores as a measure of semicircular canal function in each canal plane, and cVEMP and oVEMP amplitudes as a measure of saccular and utricular function, respectively. We observed a significant correlation between hearing loss at high frequencies and reduced cVEMP amplitudes (or reduced saccular function; r = -0.37, p < 0.0001) in subjects age 70 years or older. In contrast, hearing loss was not associated with oVEMP amplitudes (or utricular function), or htDVA LogMAR scores (or semicircular canal function) in any of the canal planes. Age and noise exposure were significantly associated with measures of both cochlear and saccular dysfunction. The concomitant decline in the cochlear and saccular function associated with aging may reflect their common embryologic origin in the pars inferior of the labyrinth. Noise exposure seems to be related to both saccular and cochlear dysfunction. These findings suggest a potential benefit of screening individuals with presbycusis-particularly those with significant noise exposure history-for saccular dysfunction, which may contribute to fall risk in the elderly.	\N	\N
23067726	The ability to control external events through our own actions is a fundamental aspect of human experience. Both the subjective experience of agency, and its neural correlates, remain poorly understood. Previous studies show that the angular gyrus is activated when participants explicitly judge that they lack agency. In contrast, the positive sense of agency over external events is associated with distortions of time perception. Here, we show that the perceived interval between actions and a subsequent tone is shorter than the perceived interval between a physically comparable passive movement and a tone, replicating the 'intentional binding' effect reported previously. We considered this as a potential implicit marker of agency, and investigated its neural basis, by using parametric analyses to identify brain areas whose activation correlated more strongly with the perceived action-tone interval in the action condition, than in the passive condition. Small volume corrections were used to test specific hypotheses about the contribution of the angular gyrus, and of the supplementary motor area (SMA), based on previous literature. We found no correlation between angular gyrus and our temporal measure of sense of agency. In contrast, we found that a lateral, caudal region within the SMA proper was more strongly associated with the perceived action-tone interval than with perception of a control interval following a passive movement. We suggest that the supplementary motor complex contributes to the subjective experience of temporal flow that accompanies goal-directed voluntary actions.	\N	\N
23076114	Following prolonged exposure to adaptor sounds moving in a single direction, participants may perceive stationary-probe sounds as moving in the opposite direction [direction-selective auditory motion aftereffect (aMAE)] and be less sensitive to motion of any probe sounds that are actually moving (motion-sensitive aMAE). The neural mechanisms of aMAEs, and notably whether they are due to adaptation of direction-selective motion detectors, as found in vision, is presently unknown and would provide critical insight into auditory motion processing. We measured human behavioral responses and auditory evoked potentials to probe sounds following four types of moving-adaptor sounds: leftward and rightward unidirectional, bidirectional, and stationary. Behavioral data replicated both direction-selective and motion-sensitive aMAEs. Electrical neuroimaging analyses of auditory evoked potentials to stationary probes revealed no significant difference in either global field power (GFP) or scalp topography between leftward and rightward conditions, suggesting that aMAEs are not based on adaptation of direction-selective motion detectors. By contrast, the bidirectional and stationary conditions differed significantly in the stationary-probe GFP at 200 ms poststimulus onset without concomitant topographic modulation, indicative of a difference in the response strength between statistically indistinguishable intracranial generators. The magnitude of this GFP difference was positively correlated with the magnitude of the motion-sensitive aMAE, supporting the functional relevance of the neurophysiological measures. Electrical source estimations revealed that the GFP difference followed from a modulation of activity in predominantly right hemisphere frontal-temporal-parietal brain regions previously implicated in auditory motion processing. Our collective results suggest that auditory motion processing relies on motion-sensitive, but, in contrast to vision, non-direction-selective mechanisms.	\N	\N
23088548	This study investigates how newly learned words are integrated into the first-language lexicon using masked priming. Two lexical decision experiments are reported, with the aim of establishing whether newly learned words behave like real words in a masked form priming experiment. If they do, they should show a prime lexicality effect (PLE), in which less priming is obtained due to form similarity when the prime is a word. In the first experiment, subjects were taught the meanings of novel words that were neighbors of real words, but no PLE was observed; that is, equally strong form priming was obtained for both trained and untrained novel primes. In the second experiment, 4 training sessions were spread over 4 weeks, and under these conditions, a clear PLE was obtained in the final session. It is concluded that lexicalization requires multiple training sessions. Possible explanations of the PLE are discussed.	\N	\N
23088832	The neuroscience of tinnitus represents an ideal model to explore central issues in brain functioning such as the formation of auditory percepts, in addition to opening up new treatment avenues for the condition in the long-term. The present review discusses the origin and nature of tinnitus-related neural activity. First, we review evidence for the hypothesis that tinnitus is caused by the central nervous system changes induced by sensory deprivation, even when hearing loss is not visible in the audiogram. Second, we suggest that changes in neural activity in individual central structures may not be sufficient to underlie the tinnitus percept. Instead, we propose that tinnitus may arise from functional alterations at multiple levels which promote abnormal propagation of neural activity throughout the network involved in auditory perception. In this context, functional coupling within and between central auditory structures may be especially important to consider. Investigating how sensory deprivation affects functional coupling between areas, which might be reflected in changes in temporal coherence of intrinsic ongoing activity patterns, may give critical insights into the mechanisms of tinnitus.	\N	\N
23095305	To update a 15-year-old study of 800 postlinguistically deaf adult patients showing how duration of severe to profound hearing loss, age at cochlear implantation (CI), age at onset of severe to profound hearing loss, etiology and CI experience affected CI outcome. Retrospective multicenter study. Data from 2251 adult patients implanted since 2003 in 15 international centers were collected and speech scores in quiet were converted to percentile ranks to remove differences between centers. The negative effect of long duration of severe to profound hearing loss was less important in the new data than in 1996; the effects of age at CI and age at onset of severe to profound hearing loss were delayed until older ages; etiology had a smaller effect, and the effect of CI experience was greater with a steeper learning curve. Patients with longer durations of severe to profound hearing loss were less likely to improve with CI experience than patients with shorter duration of severe to profound hearing loss. The factors that were relevant in 1996 were still relevant in 2011, although their relative importance had changed. Relaxed patient selection criteria, improved clinical management of hearing loss, modifications of surgical practice, and improved devices may explain the differences.	\N	\N
23102807	Age-related hearing impairment (ARHI), or presbycusis, is a common condition of the elderly that results in significant communication difficulties in daily life. Clinically, it has been defined as a progressive loss of sensitivity to sound, starting at the high frequencies, inability to understand speech, lengthening of the minimum discernable temporal gap in sounds, and a decrease in the ability to filter out background noise. The causes of presbycusis are likely a combination of environmental and genetic factors. Previous research into the genetics of presbycusis has focused solely on hearing as measured by pure-tone thresholds. A few loci have been identified, based on a best ear pure-tone average phenotype, as having a likely role in susceptibility to this type of hearing loss; and GRM7 is the only gene that has achieved genome-wide significance. We examined the association of GRM7 variants identified from the previous study, which used an European cohort with Z-scores based on pure-tone thresholds, in a European-American population from Rochester, NY (N = 687), and used novel phenotypes of presbycusis. In the present study mixed modeling analyses were used to explore the relationship of GRM7 haplotype and SNP genotypes with various measures of auditory perception. Here we show that GRM7 alleles are associated primarily with peripheral measures of hearing loss, and particularly with speech detection in older adults.	\N	\N
23109085	People often fail to detect changes between successively presented tactile patterns, a phenomenon known as tactile change blindness. In this study, we investigated whether changes introduced to tactile patterns are detected better when a participant's attention is focused on the location where the change occurs. Across two experiments, participants (N = 55) were instructed to detect changes between two consecutively presented tactile patterns. In half of the trials, the stimulated body sites in the two patterns were identical. In the other half of the trials, one of the stimulated body locations differed between the two patterns. Endogenous (or voluntary) attention was manipulated by instructing participants which new bodily location was most likely to be stimulated. We found that changes at the attended location were detected more accurately than changes at bodily locations that were unattended. This finding demonstrates that attention can effectively modulate tactile change detection. We discuss the value of this experimental paradigm for investigating excessive attentional focus or hypervigilance to particular regions of the body in various clinical populations.	\N	\N
23116413	Aiming to further our understanding of fundamental mechanisms of auditory working memory (WM), the present study compared performance for three auditory materials (words, tones, timbres). In a forward recognition task (Experiment 1) participants indicated whether the order of the items in the second sequence was the same as in the first sequence. In a backward recognition task (Experiment 2) participants indicated whether the items of the second sequence were played in the correct backward order. In Experiment 3 participants performed an articulatory suppression task during the retention delay of the backward task. To investigate potential length effects the number of items per sequence was manipulated. Overall findings underline the benefit of a cross-material experimental approach and suggest that human auditory WM is not a unitary system. Whereas WM processes for timbres differed from those for tones and words, similarities and differences were observed for words and tones: Both types of stimuli appear to rely on rehearsal mechanisms, but might differ in the involved sensorimotor codes.	\N	\N
23117535	Noise sensitivity is considered to be a self-perceived indicator of vulnerability to stressors in general and not noise alone. Multiple chemical sensitivity (MCS) has to some extent been accompanied by noise sensitivity, indicating a moderate correspondence between them. The aim of this study is to investigate if the Weinstein's Noise Sensitivity Scale and Quick Environmental Exposure and Sensitivity Inventory's (QEESI) Chemical Intolerance Subscale can differentiate noise sensitivity and MCS as different entities, and if there are overlaps in the characteristics of noise sensitivity and MCS. In 2002, 327 individuals (166 men, 161 women; age range 45 - 66 years) from the Finnish Twin Cohort answered a questionnaire on noise-related and MCS items. Somatic, psychological, and lifestyle factors were obtained through earlier questionnaires for the same individuals. Both confirmatory and exploratory factor analyses (CFA and EFA) of the questionnaire items on the Weinstein's Noise Sensitivity Scale and QEESI's Chemical Intolerance Subscale indicated the presence of three factors - Noise Sensitivity, Chemical Sensitivity, and Ability to Concentrate factors - arising from the forming of two factors from the items of the Weinstein's scale. In the regression analyses, among all subjects, the Noise Sensitivity Factor was associated with neuroticism and smoking, and the Chemical Sensitivity Factor was associated with allergies and alcohol use. The study indicates that the Weinstein's Noise Sensitivity Scale and QEESI's Chemical Intolerance Subscale differentiate noise sensitivity and MCS as different entities.	\N	\N
23122629	To evaluate through a multidimensional protocol voice changes after voice therapy in patients with benign vocal fold lesions. 65 consecutive patients affected by benign vocal fold lesions were enrolled. Depending on videolaryngostroboscopy the patients were divided into 3 groups: 23 patients with Reinke's oedema, 22 patients with vocal fold cysts and 20 patients with gelatinous polyp. Each subject received 10 voice therapy sessions and was evaluated, before and after voice therapy, through a multidimensional protocol including videolaryngostroboscopy, perception, acoustics, aerodynamics and self-rating by the patient. Data were compared using Wilcoxon signed-rank test. Kruskal-Wallis test was used to analyse the mean variation difference between the three groups of patients. Mann-Whitney test was used for post hoc analysis. Only in 11 cases videolaryngostroboscopy revealed an improvement of the initial pathology. However a significant improvement was observed in perceptual, acoustic and self-assessment ratings in the 3 groups of patients. In particular the parameters of G, R and A of the GIRBAS scale, and the noise to harmonic ratio, Jitter and shimmer scores improved after rehabilitation. A significant improvement of all the parameters of Voice Handicap Index after rehabilitation treatment was found. No significant difference among the three groups of patients was visible, except for self-assessment ratings. Voice therapy may provide a significant improvement in perceptual, acoustic and self-assessed voice quality in patients with benign glottal lesions. Utilization of voice therapy may allow some patients to avoid surgical intervention.	\N	\N
23128585	Both the Stroop and the Simon paradigms are often used in research on cognitive control, however, there is evidence that dissociable control processes are involved in these tasks: While conflicts in the Stroop task may be resolved mainly by enhanced task-relevant stimulus processing, conflicts in the Simon task may be resolved rather by suppressing the influence of task-irrelevant information on response selection. In the present study, we show that these control mechanisms interact in different ways with the presentation of accessory stimuli. Accessory stimuli do not affect cognitive control in the Simon task, but they impair the efficiency of cross-trial control processes in the Stroop task. Our findings underline the importance of differentiating between different types of conflicts and mechanisms of cognitive control.	\N	\N
23135617	The purpose of this study was to examine differences between older and younger listeners in the ability to sequentially attend to and ignore words. Participants (n = 13 older adults and 13 younger adults) completed a temporally interleaved word recognition task. On each trial, 10 words were presented, and participants were instructed to repeat back every other word while ignoring the intervening words. Three variables were examined: (1) whether the word strings that were to be attended and to be ignored created syntactically correct sentences; (2) whether the to-be-attended and to-be-ignored words were presented from the same or from different spatial locations; and (3) whether the five target words in each trial (and the five distractor words in each trial) were spoken by a single talker or by five different talkers. In addition, digit-span forward and digit-span backward were measured and used as variables in correlation analyses. As a group, the younger participants outperformed the older listeners, particularly when the to-be-attended and to-be-ignored words were presented from the same spatial location (versus when they were presented with spatial separation). Compared with the younger participants, older listeners also made more error responses that were to-be-ignored words, although the proportion of errors that were not responses involving masking words did not significantly differ between groups. Scores on the digit-span-forward test (but not digit-span-backward scores or the degree of hearing loss) were associated with older individuals' performance on this temporally interleaved speech-recognition task. The overall pattern of results suggests that factors other than threshold elevation contribute to speech-understanding problems experienced by older listeners. However, although younger adults outperformed older listeners on this interleaved sentence task, older and younger adults benefited, to a similar extent, from spatial separation of the to-be-attended and to-be-ignored words, and from having a consistent target talker within a trial.	\N	\N
23138762	Posterior cortical atrophy (PCA) is typically considered to be a visual syndrome, primarily characterised by progressive impairment of visuoperceptual and visuospatial skills. However, patients commonly describe early difficulties with word retrieval. This paper details the first systematic analysis of linguistic function in PCA. Characterising and quantifying the aphasia associated with PCA is important for clarifying diagnostic and selection criteria for clinical and research studies. 15 patients with PCA, seven patients with logopenic/phonological aphasia (LPA) and 18 age matched healthy participants completed a detailed battery of linguistic tests evaluating auditory input processing, repetition and working memory, lexical and grammatical comprehension, single word retrieval and fluency, and spontaneous speech. Relative to healthy controls, PCA patients exhibited language impairments across all of the domains examined, but with anomia, reduced phonemic fluency and slowed speech rate the most prominent deficits. PCA performance most closely resembled that of LPA patients on tests of auditory input processing, repetition and digit span, but was relatively stronger on tasks of comprehension and spontaneous speech. The study demonstrates that in addition to the well reported degradation of vision, literacy and numeracy, PCA is characterised by progressive oral language dysfunction with prominent word retrieval difficulties. Overlap in the linguistic profiles of PCA and LPA, which are both most commonly caused by Alzheimer's disease, further emphasises the notion of a phenotypic continuum between typical and atypical manifestations of the disease. Clarifying the boundaries between Alzheimer's disease phenotypes has important implications for diagnosis, clinical trial recruitment and investigations into biological factors driving phenotypic heterogeneity in Alzheimer's disease. Rehabilitation strategies to ameliorate the phonological deficit in PCA are required.	\N	\N
23143506	This retrospective study aimed to evaluate the efficacy of the Esteem(®) middle ear implant in sensorineural hearing loss (SNHL) of different degree as well as to compare it with that obtained with conventional hearing aids. Fifteen out of 30 adults patients who received an Esteem(®) middle ear device for rehabilitation of sensorineural hearing loss met the primary eligibility criterion of prior, continuous use of conventional hearing aids. Study population included moderate-to-severe SNHL (8 patients) and severe-to-profound SNHL (7 patients). Audiometric measurements included free-field pure-tone and speech audiometry in Esteem(®)-aided, HA-aided, and baseline threshold. For speech audiometry, speech reception threshold (SRT) and word recognition score (WRS) were assessed. Subjective benefit was evaluated by Client Oriented Scale of Improvement (COSI) questionnaire. In all the subjects, SRT and WRS showed improvement both with conventional HA and Esteem(®) in respect to the unaided situation. Although not statistically significant, a slight prevalence of the Esteem(®) performances was recorded both audiometrically and as subjective satisfaction score. The Esteem(®) middle ear device demonstrated appreciable benefit for rehabilitation of SNHL of different degree, comparable to what can be achieved by conventional hearing aids. In addition, this rehabilitative process may enable also individuals presenting with severe-to-profound SNHL to achieve remarkable functional outcomes.	\N	\N
23145620	A modulation-based index is proposed for predicting speech intelligibility by cochlear implant (CI) listeners. The input to the proposed index are speech envelopes extracted using the individual CI user's daily strategy, and as such, this approach incorporates information about the number of active electrodes, shape of the compression function and electrical dynamic range. High correlation (r = 0.96) was achieved with the proposed index when evaluated with speech-reception thresholds (SRTs) obtained by CI users in steady and speech-masker conditions. This outcome suggests that the information contained in electrodograms seems to be sufficient for reliably predicting CI user's performance in noise. The proposed index can be used by clinicians to optimize the selection of fitting parameters of individual CI users for better performance in noise.	\N	\N
23150094	To report the results of cochlear implantation via the middle fossa approach in 4 patients, discuss the complications, and present a detailed description of the programming specifications in these cases. Retrospective case review. Tertiary-care referral center with a well-established cochlear implant program. Four patients with bilateral canal wall down mastoid cavities who underwent the middle fossa approach for cochlear implantation. Cochlear implantation and subsequent rehabilitation. A middle fossa approach with cochleostomy was successfully performed on the most superficial part of the apical turn in 4 patients. A Nucleus 24 cochlear implant system was used in 3 patients and a MED-EL Sonata Medium device in 1 patient. The single electrode array was inserted through a cochleostomy from the cochlear apex and occupied the apical, middle, and basal turns. Telemetry and intraoperative impedance recordings were performed at the end of surgery. A CT scan of the temporal bones was performed to document electrode insertion for all of the patients. Complications, hearing thresholds, and speech perception outcomes were evaluated. Neural response telemetry showed present responses in all but 1 patient, who demonstrated facial nerve stimulation during the test. Open-set speech perception varied from 30% to 100%, despite the frequency allocation order of the MAP. Cochlear implantation via the middle cranial fossa is a safe approach, although it is a challenging procedure, even for experienced surgeons.	\N	\N
23152235	This is an update of a Cochrane Review first published in The Cochrane Library in Issue 12, 2010.Tinnitus is described as the perception of sound or noise in the absence of real acoustic stimulation. Numerous management strategies have been tried for this potentially debilitating, heterogeneous symptom. External noise has been used as a management tool for tinnitus, in different capacities and with different philosophical intent, for over a century. To assess the effectiveness of sound-creating devices (including hearing aids) in the management of tinnitus in adults. Primary outcome measures were changes in the loudness or severity of tinnitus and/or impact on quality of life. Secondary outcome measures were change in pure-tone auditory thresholds and adverse effects of treatment. We searched the Cochrane ENT Group Trials Register; CENTRAL; PubMed; EMBASE; CINAHL; Web of Science; BIOSIS Previews; Cambridge Scientific Abstracts; ICTRP and additional sources for published and unpublished trials. The date of the most recent search was 8 February 2012. Prospective randomised controlled trials recruiting adults with persistent, distressing, subjective tinnitus of any aetiology in which the management strategy included maskers, noise-generating device and/or hearing aids, used either as the sole management tool or in combination with other strategies, including counselling. Two authors independently examined the 387 search results to identify studies for inclusion in the review, of which 33 were potentially relevant. The update searches in 2012 retrieved no further potentially relevant studies. Both authors extracted data independently. Six trials (553 participants) are included in this review. Studies were varied in design, with significant heterogeneity in the evaluation of subjective tinnitus perception, with different scores, scales, tests and questionnaires as well as variance in the outcome measures used to assess the improvement in tinnitus sensation/quality of life. This precluded meta-analysis of the data. There was no long-term follow-up. We assessed the risk of bias as medium in three and high in three studies. Following analysis of the data, no significant change was seen in the loudness of tinnitus or the overall severity of tinnitus following the use of sound therapy compared to other interventions such as patient education, 'relaxation techniques', 'tinnitus coping strategies', counselling, 'tinnitus retraining' and exposure to environmental sounds. No side effects or significant morbidity were reported from the use of sound-creating devices. The limited data from the included studies failed to show strong evidence of the efficacy of sound therapy in tinnitus management. The absence of conclusive evidence should not be interpreted as evidence of lack of effectiveness. The lack of quality research in this area, in addition to the common use of combined approaches (hearing therapy plus counselling) in the management of tinnitus are, in part, responsible for the lack of conclusive evidence. Other combined forms of management, such as tinnitus retraining therapy, have been subject to a Cochrane Review. Optimal management may involve multiple strategies.	\N	\N
23155729	Auditory stimuli are known to improve visual target recognition and detection when both are presented in the same spatial location. However, most studies have focused on crossmodal spatial congruency along the horizontal plane and the effects of audio-visual spatial congruency in depth (i.e., along the depth axis) are relatively less well understood. In the following experiments we presented a visual (face) or auditory (voice) target stimulus in a location on a spatial array which was either spatially congruent or incongruent in depth (i.e., positioned directly in front or behind) with a crossmodal stimulus. The participant's task was to determine whether a visual (experiments 1 and 3) or auditory (experiment 2) target was located in the foreground or background of this array. We found that both visual and auditory targets were less accurately located when crossmodal stimuli were presented from different, compared to congruent, locations in depth. Moreover, this effect was particularly found for visual targets located in the periphery, although spatial incongruency affected the location of auditory targets across both locations. The relative distance of the array to the observer did not seem to modulate this congruency effect (experiment 3). Our results add to the growing evidence for multisensory influences on search performance and extend these findings to the localisation of targets in the depth plane.	\N	\N
23160796	Small songbirds have a difficult analysis problem: their head is small compared to the wavelengths of sounds used for communication providing only small interaural time and level differences. Klump and Larsen (1992) measured the physical binaural cues in the European starling (Sturnus vulgaris) that allow the comparison of acoustical cues and perception. We determined the starling's minimum audible angle (MAA) in an operant Go/NoGo procedure for different spectral and temporal stimulus conditions. The MAA for broadband noise with closed-loop localization reached 17°, while the starling's MAA for open-loop localization of broadband noise reached 29°. No substantial difference between open-loop and closed-loop localization was found in 2 kHz pure tones. The closed-loop MAA improved from 26° to 19° with an increase in pure tone frequency from 1 to 4 kHz. This finding is in line with the physical cues available. While the starlings can only make use of interaural time difference cues at lower frequencies (e.g., 1 and 2 kHz), additional interaural level difference cues become available at higher frequencies (e.g., 4 kHz or higher, Klump and Larsen 1992). An improvement of the starling's MAA with an increasing number of standard stimulus presentations prior to the test stimulus has important implications for determining relative (MAA) localization thresholds.	\N	\N
23163413	Music performance requires control of two sequential structures: the ordering of pitches and the temporal intervals between successive pitches. Whether pitch and temporal structures are processed as separate or integrated features remains unclear. A repetition suppression paradigm compared neural and behavioral correlates of mapping pitch sequences and temporal sequences to motor movements in music performance. Fourteen pianists listened to and performed novel melodies on an MR-compatible piano keyboard during fMRI scanning. The pitch or temporal patterns in the melodies either changed or repeated (remained the same) across consecutive trials. We expected decreased neural response to the patterns (pitch or temporal) that repeated across trials relative to patterns that changed. Pitch and temporal accuracy were high, and pitch accuracy improved when either pitch or temporal sequences repeated over trials. Repetition of either pitch or temporal sequences was associated with linear BOLD decrease in frontal-parietal brain regions including dorsal and ventral premotor cortex, pre-SMA, and superior parietal cortex. Pitch sequence repetition (in contrast to temporal sequence repetition) was associated with linear BOLD decrease in the intraparietal sulcus (IPS) while pianists listened to melodies they were about to perform. Decreased BOLD response in IPS also predicted increase in pitch accuracy only when pitch sequences repeated. Thus, behavioral performance and neural response in sensorimotor mapping networks were sensitive to both pitch and temporal structure, suggesting that pitch and temporal structure are largely integrated in auditory-motor transformations. IPS may be involved in transforming pitch sequences into spatial coordinates for accurate piano performance.	\N	\N
23169193	An estimated 36 million US citizens have impaired hearing, but nearly half of them have never had a hearing test. As noted by a recent National Institutes of Health/National Institute on Deafness and Other Communication Disorders (NIH/NIDCD) Working Group, "In the United States (in contrast to many other nations) there are no readily accessible low cost hearing screening programs…" (Donahue et al, 2010, p. 2). Since 2004, telephone administered screening tests utilizing three-digit sequences presented in noise have been developed, validated, and implemented in seven countries. Each of these tests has been based on a test protocol conceived by Smits and colleagues in The Netherlands. Investigators from Communication Disorders Technology, Inc., Indiana University, and VU University Medical Center of Amsterdam agreed to collaborate in the development and validation of a screening test for hearing impairment suitable for delivery over the telephone, for use in the United States. This test, utilizing spoken three-digit sequences (triplets), was to be based on the design of Smits and his colleagues. A version of the digits-in-noise test was developed utilizing digit triplets spoken in Middle American dialect. The stimuli were individually adjusted to speech-to-noise ratio (SNR) values yielding 50% correct identification, on the basis of data collected from a group of 10 young adult listeners with normal hearing. A final set of 64 homogeneous stimuli were selected from an original 160 recorded triplets. Each test consisted of a series of 40 triplets drawn at random, presented in a noise background. The SNR threshold for 50% correct identification of the triplets was determined by a one-down, one-up adaptive procedure. The test was implemented by telephone, and administered to listeners with varying levels of hearing impairment. The listeners were then evaluated with pure-tone tests and other audiometric measures as clinically appropriate. Ninety participants included 72 who were volunteers from the regular client population at the Indiana University Hearing Clinic, and 18 who were recruited with a newspaper ad offering a free hearing test. Of the 90 participants, 49 were later determined to have mean pure-tone thresholds greater than 20 dB hearing level (HL). The primary data analyses were correlations between telephone test thresholds and other measures, including pure-tone thresholds and speech recognition tests, collected for the same participants. The correlation between the telephone test and pure-tone thresholds (r = 0.74) was within the range of correlations observed with successful telephone screening tests in use in other countries. Thresholds based on the average of only 21 trials (trials five through 25 of the 40-trial tracking history) yielded sensitivity and specificity values of 0.80 and 0.83, respectively, using pure-tone average((0.5, 1.0, 2.0 kHz)) >20 dB HL as the criterion measure. This US version of the digits-in-noise telephone screening test is sufficiently valid to be implemented for use by the general public. Its properties are quite similar to those telephone screening tests currently in use in most European countries. Telephone tests provide efficient, easy to use, and valid screening for functional hearing impairment. The results of this test are a reasonable basis for advising those who fail to seek a comprehensive hearing evaluation by an audiologist.	\N	\N
23169195	Speech recognition in noise testing has been conducted at least since the 1940s (Dickson et al, 1946). The ability to recognize speech in noise is a distinct function of the auditory system (Plomp, 1978). According to Kochkin (2002), difficulty recognizing speech in noise is the primary complaint of hearing aid users. However, speech recognition in noise testing has not found widespread use in the field of audiology (Mueller, 2003; Strom, 2003; Tannenbaum and Rosenfeld, 1996). The audiogram has been used as the "gold standard" for hearing ability. However, the audiogram is a poor indicator of speech recognition in noise ability. This study investigates the relationship between pure-tone thresholds, the articulation index, and the ability to recognize speech in quiet and in noise. Pure-tone thresholds were measured for audiometric frequencies 250-6000 Hz. Pure-tone threshold groups were created. These included a normal threshold group and slight, mild, severe, and profound high-frequency pure-tone threshold groups. Speech recognition thresholds in quiet and in noise were obtained using the Hearing in Noise Test (HINT) (Nilsson et al, 1994; Vermiglio, 2008). The articulation index was determined by using Pavlovic's method with pure-tone thresholds (Pavlovic, 1989, 1991). Two hundred seventy-eight participants were tested. All participants were native speakers of American English. Sixty-three of the original participants were removed in order to create groups of participants with normal low-frequency pure-tone thresholds and relatively symmetrical high-frequency pure-tone threshold groups. The final set of 215 participants had a mean age of 33 yr with a range of 17-59 yr. Pure-tone threshold data were collected using the Hughson-Weslake procedure. Speech recognition data were collected using a Windows-based HINT software system. Statistical analyses were conducted using descriptive, correlational, and multivariate analysis of covariance (MANCOVA) statistics. The MANCOVA analysis (where the effect of age was statistically removed) indicated that there were no significant differences in HINT performances between groups of participants with normal audiograms and those groups with slight, mild, moderate, or severe high-frequency hearing losses. With all of the data combined across groups, correlational analyses revealed significant correlations between pure-tone averages and speech recognition in quiet performance. Nonsignificant or significant but weak correlations were found between pure-tone averages and HINT thresholds. The ability to recognize speech in steady-state noise cannot be predicted from the audiogram. A new classification scheme of hearing impairment based on the audiogram and the speech reception in noise thresholds, as measured with the HINT, may be useful for the characterization of the hearing ability in the global sense. This classification scheme is consistent with Plomp's two aspects of hearing ability (Plomp, 1978).	\N	\N
23173635	A 42-year-old man suffered damage to the left supra-sylvian areas due to a stroke and presented with verbal short-term memory (STM) deficits. He occasionally could not recall even a single syllable that he had heard one second before. A study of mismatch negativity using magnetoencephalography suggested that the duration of auditory sensory (echoic) memory traces was reduced on the affected side of the brain. His maximum digit span was four with auditory presentation (equivalent to the 1st percentile for normal subjects), whereas it was up to six with visual presentation (almost within the normal range). He simply showed partial recall in the digit span task, and there was no self correction or incorrect reproduction. From these findings, reduced echoic memory was thought to have affected his verbal short-term retention. Thus, the impairment of verbal short-term memory observed in this patient was "pure auditory" unlike previously reported patients with deficits of the phonological short-term store (STS), which is the next higher-order memory system. We report this case to present physiological and behavioral data suggesting impaired short-term storage of verbal information, and to demonstrate the influence of deterioration of echoic memory on verbal STM.	\N	\N
23177349	This research investigates how early learning about native language sound structure affects how infants associate sounds with meanings during word learning. Infants (19-month-olds) were presented with bisyllabic labels with high or low phonotactic probability (i.e., sequences of frequent or infrequent phonemes in English). The labels were produced with the predominant English trochaic (strong/weak) stress pattern or the less common iambic (weak/strong) pattern. Using the habituation-based Switch Task to test label learning, we found that infants readily learned high probability trochaic labels. However, they failed to learn low probability labels, regardless of stress, and failed to learn iambic labels, regardless of phonotactics. Thus, infants required support from both common phoneme sequences and a common stress pattern to map the labels to objects. These findings demonstrate that early word learning is shaped by prior knowledge of native language phonological regularities and provide support for the role of statistical learning in language acquisition.	\N	\N
23177756	A plethora of investigations have studied the acoustic characteristics of vibrato such as the rate, extent, onset (time from initiation of phonation until the first peak of vibrato), and periodicity. Despite extensive research, the degree to which various parameters of vibrato contribute to its acceptability remain unclear. The present study sought to determine the psychoacoustical relationship of mean fundamental frequency (f(0)), modulation frequency (f(f0m)), modulation depth (d(f0m)), and intensity to the appropriateness or inappropriateness of vibrato. Phonation samples of eight voice majors singing at low, middle, and high pitches were obtained. A high fidelity vocoder (STRAIGHT; Kawahara, 1997) was used to resynthesize these vowels with systematic manipulations of f(f0m) and d(f0m) of the f(0) contours resulting in a total of 600 stimuli (8 singers×3 pitches×5 f(f0m) levels×5 d(f0m) levels). Nine listeners (four experts and five students) evaluated these stimuli for appropriateness of vibrato at two different presentation levels (70 and 90 dB sound pressure level). Statistical analyses of the perceptual data suggest that appropriateness of vibrato tends to increase with mean f(0) and decrease with d(f0m.) Appropriateness of vibrato is greatest for f(f0m) value of 6 Hz, but decreases both above and below this frequency. perceived appropriateness of vibrato results from an interaction of mean f(0), f(f0m), and d(f0m) of the vowel waveform.	\N	\N
23202431	The investigation of brain activity using naturalistic, ecologically-valid stimuli is becoming an important challenge for neuroscience research. Several approaches have been proposed, primarily relying on data-driven methods (e.g. independent component analysis, ICA). However, data-driven methods often require some post-hoc interpretation of the imaging results to draw inferences about the underlying sensory, motor or cognitive functions. Here, we propose using a biologically-plausible computational model to extract (multi-)sensory stimulus statistics that can be used for standard hypothesis-driven analyses (general linear model, GLM). We ran two separate fMRI experiments, which both involved subjects watching an episode of a TV-series. In Exp 1, we manipulated the presentation by switching on-and-off color, motion and/or sound at variable intervals, whereas in Exp 2, the video was played in the original version, with all the consequent continuous changes of the different sensory features intact. Both for vision and audition, we extracted stimulus statistics corresponding to spatial and temporal discontinuities of low-level features, as well as a combined measure related to the overall stimulus saliency. Results showed that activity in occipital visual cortex and the superior temporal auditory cortex co-varied with changes of low-level features. Visual saliency was found to further boost activity in extra-striate visual cortex plus posterior parietal cortex, while auditory saliency was found to enhance activity in the superior temporal cortex. Data-driven ICA analyses of the same datasets also identified "sensory" networks comprising visual and auditory areas, but without providing specific information about the possible underlying processes, e.g., these processes could relate to modality, stimulus features and/or saliency. We conclude that the combination of computational modeling and GLM enables the tracking of the impact of bottom-up signals on brain activity during viewing of complex and dynamic multisensory stimuli, beyond the capability of purely data-driven approaches.	\N	\N
23205712	To estimate the prevalence of severe and profound hearing loss in a clinical population and to report the audiological and hearing-aid characteristics for this group, as well as outcome measures from use of hearing aids. A retrospective observational study initially, followed by a postal Glasgow health status inventory (GHSI) to establish the patients functional outcomes. A clinical database of 32 781 cases was interrogated from which 2199 cases of severe /profound hearing loss were identified. From these, an adult sample stratified in terms of age and gender of n = 302 was contacted. An estimated 6.7% of the local clinical population and 0.7% of the general population were found to have hearing > 70 dB averaged over 0.5, 1, and 2 kHz. Most patients were fitted with bilateral hearing aids, using a non-linear prescription, and as a group they reported a high level of social support. This study has estimated the prevalence of severe and profound hearing loss as 6.7% of the clinical population, and 0.7% of the general population. This is consistent with previous work, although it probably underestimates the prevalence. Further work is indicated to strengthen the estimate.	\N	\N
23207574	Synchronizing movements with auditory beats, compared to visual flashes, yields divergent activation in timing-related brain areas as well as more stable tapping synchronization. The differences in timing-related brain activation could reflect differences in tapping synchronization stability, rather than differences between modality (i.e., audio-motor vs. visuo-motor integration). In the current fMRI study, participants synchronized their finger taps with four types of visual and auditory pacing sequences: flashes and a moving bar, as well as beeps and a frequency-modulated 'siren'. Behavioral tapping results showed that visuo-motor synchronization improved with moving targets, whereas audio-motor synchronization degraded with frequency-modulated sirens. Consequently, a modality difference in synchronization occurred between the discrete beeps and flashes, but not between the novel continuous siren and moving bar. Imaging results showed that activation in the putamen, a key timing area, paralleled the behavioral results: putamen activation was highest for beeps, intermediate for the continuous siren and moving bar, and was lowest for the flashes. Putamen activation differed between modalities for beeps and flashes, but not for the novel moving bar and siren. By dissociating synchronization performance from modality, we show that activation in the basal ganglia is associated with sensorimotor synchronization stability rather than modality-specificity in this task. Synchronization stability is apparently contingent upon the modality's processing affinity: discrete auditory and moving visual signals are modality appropriate, and can be encoded reliably for integration with the motor system.	\N	\N
23216089	Results for speech recognition in noise tests when using a new research coding strategy designed to introduce the virtual channel effect provided no advantage over MP3(000™). Although statistically significant smaller just noticeable differences (JNDs) were obtained, the findings for pitch ranking proved to have little clinical impact. The aim of this study was to explore whether modifications to MP3000 by including sequential virtual channel stimulation would lead to further improvements in hearing, particularly for speech recognition in background noise and in competing-talker conditions, and to compare results for pitch perception and melody recognition, as well as informally collect subjective impressions on strategy preference. Nine experienced cochlear implant subjects were recruited for the prospective study. Two variants of the experimental strategy were compared to MP3000. The study design was a single-blinded ABCCBA cross-over trial paradigm with 3 weeks of take-home experience for each user condition. Comparing results of pitch-ranking, a significantly reduced JND was identified. No significant effect of coding strategy on speech understanding in noise or competing-talker materials was found. Melody recognition skills were the same under all user conditions.	\N	\N
23218176	The use of the stapes coupling technique, employed in the Vibrant Soundbridge system, is technically less demanding than the vibroplasty technique, and is more likely to generate a positive outcome without significantly changing residual hearing or resulting in medical or surgical complication. We report a patient with repeated left ossiculoplasty failure, who was successfully implanted with a Vibrant Soundbridge. We believe that the stapes coupling technique can provide natural stimulation to the inner ear, resulting in a better perceived sound quality.	\N	\N
23219981	Prior work with Wright and others demonstrated that rhesus monkeys recognized the relative relationships of notes in common melodies. As an extension of tests of pattern similarities, tamarins were habituated to 3-sound unit patterns in an AAB or ABB form that were human phonemes, piano notes, or monkey calls. The subjects were tested with novel sounds in each category constructed either to match the prior pattern or to violate the prior habituated pattern. The monkeys attended significantly more to a violation of their habituated pattern to a new pattern when human phonemes were used, and there was a trend difference in attention toward pattern violations with melodies. Monkey call patterns generated a variety of behavioral responses, were less likely to show habituation, and did not generate a strong attention reaction to changes in the patterns. Monkeys can extract abstract rules and patterns from auditory stimuli but the stimuli, by their nature, may generate competing responses which block processing of abstract regularities.	\N	\N
23220120	Normal-hearing listeners can perceptually segregate concurrent sound sources, but listeners with significant hearing loss or who wear a cochlear implant (CI) lag behind in this ability. Perceptual grouping mechanisms are essential to segregate concurrent sound sources and affect comodulation masking release (CMR). Thus, CMR measurements in CI users could shed light on segregation cues needed for forming and grouping of auditory objects. CMR illustrates the fact that detection of a target sound embedded in a fluctuating masker is improved by the addition of masker energy remote from the target frequency, provided the envelope fluctuations across masker components are coherent. We modified such a CMR experiment to electrically-induced hearing using direct stimulation and measured the effect in 21 CI users. Cluster analysis of our data revealed two groups: one showed no or only small CMR of 0.1 dB ± 2.7 (N = 14) and a second group achieved a CMR of 10.7 dB ± 3.2 (N = 7), a value that is close to the enhancement observed in a comparable acoustic experiment in normal-hearing listeners (12.9 dB ± 2.6, N = 6). Interestingly, we observed that CMR in CI users may relate to hearing etiology and duration of hearing loss pre-implantation. Our study demonstrates for the first time that a substantial minority of cochlear-implant listeners (about a third) can show significant CMR. This outcome motivates the development of physiologically inspired multi-band gain control and/or different coding strategies for these groups in order to better preserve coherent modulation and thus to take advantage of the individual remaining capabilities to analyze spectro-temporal patterns.	\N	\N
23224782	Past research has identified an event-related potential (ERP) marker for vocal emotional encoding and has highlighted vocal-processing differences between male and female listeners. We further investigated this ERP vocal-encoding effect in order to determine whether it predicts voice-related changes in listeners' memory for verbal interaction content. Additionally, we explored whether sex differences in vocal processing would affect such changes. To these ends, we presented participants with a series of neutral words spoken with a neutral or a sad voice. The participants subsequently encountered these words, together with new words, in a visual word recognition test. In addition to making old/new decisions, the participants rated the emotional valence of each test word. During the encoding of spoken words, sad voices elicited a greater P200 in the ERP than did neutral voices. While the P200 effect was unrelated to a subsequent recognition advantage for test words previously heard with a neutral as compared to a sad voice, the P200 did significantly predict differences between these words in a concurrent late positive ERP component. Additionally, the P200 effect predicted voice-related changes in word valence. As compared to words studied with a neutral voice, words studied with a sad voice were rated more negatively, and this rating difference was larger, the larger the P200 encoding effect was. While some of these results were comparable in male and female participants, the latter group showed a stronger P200 encoding effect and qualitatively different ERP responses during word retrieval. Estrogen measurements suggested the possibility that these sex differences have a genetic basis.	\N	\N
23231206	Earlier work using sine-wave and noise-vocoded signals suggests that dynamic spectral structure plays a greater role in speech recognition for children than adults [Nittrouer and Lowenstein. (2010). J. Acoust. Soc. Am. 127, 1624-1635], but questions arise concerning whether outcomes can be compared because sine waves and wide noise bands are different in nature. The current study addressed that question using narrow noise bands for both signals, and applying a difference ratio to index the contribution made by dynamic spectral structure. Results replicated earlier findings, supporting the idea that dynamic spectral structure plays a critical role in speech recognition, especially for children.	\N	\N
23241225	According to classical theories, automatic processes operate independently of attention. Recent evidence, however, shows that masked visuomotor priming, an example of an automatic process, depends on attention to visual form versus semantics. In a continuation of this approach, we probed feature-specific attention within the perceptual domain and tested in two event-related potential (ERP) studies whether masked visuomotor priming in a shape decision task specifically depends on attentional sensitization of visual pathways for shape in contrast to color. Prior to the masked priming procedure, a shape or a color decision task served to induce corresponding task sets. ERP analyses revealed visuomotor priming effects over the occipitoparietal scalp only after the shape, but not after the color induction task. Thus, top-down control coordinates automatic processing streams in congruency with higher-level goals even at a fine-grained level.	\N	\N
23246616	Speech recognition in a multi-talker situation poses high demands on attentional and other central resources. This study examines the relationship between age, cognition and speech recognition in tasks that require selective or divided attention in a multi-talker setting. Two groups of normal-hearing adults (one younger and one older group) were asked to repeat utterances from either one or two concurrent speakers. Cognitive abilities were then inspected by neuropsychological tests. Speech recognition scores approached its ceiling and did not significantly differ between age groups for tasks that demanded selective attention. However, when divided attention was required, performance in older listeners was reduced as compared to the younger group. When selective attention was required, speech recognition was strongly related to working memory skills, as determined by a regression model. In comparison, speech recognition for tests requiring divided attention could be more strongly determined by neuropsychological probes of fluid intelligence. The findings of this study indicate that - apart from hearing impairment - cognitive aspects account for the typical difficulties of older listeners in a multi-speaker setting. Our results are discussed in the context of evidence showing that frontal lobe functions in terms of working memory and fluid intelligence generally decline with age.	\N	\N
23269517	The most prominent models of numerical representation posit that numerical symbols are converted into a single internal, abstract representation prior to estimation and comparison processing. Here, we (1) provide a mathematical analysis of the predictions of the abstract-representation hypothesis, assuming the validity of the analog-representation hypothesis, (2) run a simulation to assess the patterns of data that result from our mathematical analysis, and (3) conduct two experiments to test the predictions of our model, using relative frequencies as inputs. We assess relative frequencies in a typical numerical distance task, whereby participants are presented with two relative frequencies and asked to identify the one that represents the larger quantity. Our data reveal that relative frequencies' numerical representations (1) are analog and (2) are scale-specific (i.e., nonabstract).	\N	\N
23275409	In this study, the authors explored whether French-learning infants use nonadjacent phonotactic regularities in their native language, which they learn between the ages of 7 and 10 months, to segment words from fluent speech. Two groups of 20 French-learning infants were tested using the head-turn preference procedure at 10 and 13 months of age. In Experiment 1, infants were familiarized with 2 passages: 1 containing a target word with a frequent nonadjacent phonotactic structure and the other containing a target word with an infrequent nonadjacent phonotactic structure in French. During the test phase, infants were presented with 4 word lists: 2 containing the target words presented during familiarization and 2 other control words with the same phonotactic structure. In Experiment 2, the authors retested infants' ability to segment words with the infrequent phonotactic structure. Ten- and 13-month-olds were able to segment words with the frequent phonotactic structure, but it is only by 13 months, and only under the circumstances of Experiment 2, that infants could segment words with the infrequent phonotactic structure. These results provide new evidence showing that infant word segmentation is influenced by prior nonadjacent phonotactic knowledge.	\N	\N
23275416	In this article, the authors describe the development of a new instrument, the Test of Child Speechreading (ToCS), which was specifically designed for use with deaf and hearing children. Speechreading is a skill that is required for deaf children to access the language of the hearing community. ToCS is a deaf-friendly, computer-based test that measures child speechreading (silent lipreading) at 3 psycholinguistic levels: (a) Words, (b) Sentences, and (c) Short Stories. The aims of the study were to standardize the ToCS with deaf and hearing children and to investigate the effects of hearing status, age, and linguistic complexity on speechreading ability. Eighty-six severely and profoundly deaf children and 91 hearing children participated. All children were between the ages of 5 and 14 years. The deaf children were from a range of language and communication backgrounds, and their preferred mode of communication varied. Speechreading skills significantly improved with age for both groups of children. There was no effect of hearing status on speechreading ability, and children from both groups showed similar performance across all subtests of the ToCS. The ToCS is a valid and reliable assessment of speechreading ability in school-age children that can be used to measure individual differences in performance in speechreading ability.	\N	\N
23275425	In this study, the authors aimed to investigate how differences in language ability relate to differences in processing talker information in the native language and an unfamiliar language by comparing performance for different ages and for groups with impaired language. Three groups of native English listeners with typical language development (TLD; ages 7-9, ages 10-12, adults) and 2 groups with specific language impairment (SLI; ages 7-9, ages 10-12) participated in the study. Listeners heard pairs of words in both English and German (unfamiliar language) and were asked to determine whether the words were produced by the same or different talkers. In English, talker discrimination improved with age. In German, performance improved with age for the school-age children but was worse for adult listeners. No differences were found between TLD and SLI children. These results show that as listeners' language skills develop, there is a trade-off between more general perceptual abilities useful for processing talker information in any language and those that are relevant to their everyday language experiences and, thus, tied to the phonology. The lack of differences between the children with and without language impairments suggests that general auditory processing may be intact in at least some children with SLI.	\N	\N
23275583	This study was designed to evaluate the effect of a pinna compensation (PC) algorithm on localization performance in the horizontal plane and speech intelligibility in noise. Nine and 18 experienced hearing aid users with bilaterally symmetrical sensorineural hearing loss participated in the localization study and the speech-in-noise study, respectively. Performance was evaluated unaided, aided with a behind-the-ear (BTE) hearing aid with an omnidirectional microphone (Omni), and aided with the same hearing aid with the PC algorithm (Omni+PC). Localization performance was measured using 12 loudspeakers spaced 30° apart on a horizontal plane. Speech-in-noise performance was measured with speech presented from 0° or 180°. A single-blinded, repeated measures design was used. Significant improvement in localization accuracy was found when comparing the Omni+PC condition to the Omni condition. Also, the Omni+PC condition improved the signal-to-noise ratio by 2.4 dB when compared to the Omni condition when speech was presented from the front in a diffuse noise background. Use of the PC algorithm improved localization on the horizontal plane and speech-in-noise performance. These results support use of the PC algorithm in BTE hearing aid fittings.	\N	\N
23276111	Recent research on eye movements during scene viewing has primarily focused on where the eyes fixate. But eye fixations also differ in their durations. Here we investigated whether fixation durations in scene viewing are under the direct and immediate control of the current visual input. Subjects freely viewed photographs of scenes in preparation for a later memory test while their eye movements were recorded. Using a novel scene degradation paradigm based on a saccade-contingent display change method, scenes were reduced in luminance during saccades ending in critical fixations. Results from two experiments showed that the durations of the critical fixations were immediately affected by scene luminance, with a monotonic relationship between luminance reduction and fixation duration. The results are the first to demonstrate that fixation durations in scene viewing are immediately influenced by the ease of processing of the image currently in view. These results are consistent with the CRISP (a timer-Controlled Random-Walk with Inhibition for Saccade Planning) computational model of saccade generation in scenes, proposing that difficulty in moment-by-moment visual and cognitive processing of the scene modulates fixation durations.	\N	\N
23281939	Recent human behavioral studies have shown semantic and/or lexical processing for stimuli presented below the auditory perception threshold. Here, we investigated electroencephalographic responses to words, pseudo-words and complex sounds, in conditions where phonological and lexical categorizations were behaviorally successful (categorized stimuli) or unsuccessful (uncategorized stimuli). Data showed a greater decrease in low-beta power at left-hemisphere temporal electrodes for categorized non-lexical sounds (complex sounds and pseudo-words) than for categorized lexical sounds (words), consistent with the signature of a failure in lexical access. Similar differences between lexical and non-lexical sounds were observed for uncategorized stimuli, although these stimuli did not yield evoked potentials or theta activity. The results of the present study suggest that behaviorally uncategorized stimuli were processed at the lexical level, and provide evidence of the neural bases of the results observed in previous behavioral studies investigating auditory perception in the absence of stimulus awareness.	\N	\N
23285949	To study the long-term rehabilitation effects for treating tinnitus by tinnitus masking combined with counseling. Complete the tinnitus handicap inventory(THI) for participants before treatment and after six months, 1 year, 2 years, 3 years. Eighty-six tinnitus patients participated. Nine participants and sixteen, twenty-six, sixteen participants drop-up during the follow up after half-year, 1 year, 2 years, 3 years separately. The percentage of participants whose THI score decreased more than or equal to 20 are 66%, 56%, 40%, 48% after half year, 1 year, 2 years, 3 years respectively. The tinnitus related handicap improved by tinnitus masking combined with counseling after 1 year. The drop-out rate was increase after follow-up 1 year. The long-term rehabilitation effects for tinnitus treatment is still needed.	\N	\N
23288656	Three experiments investigated whether extrinsic vowel normalization takes place largely at a categorical or a precategorical level of processing. Traditional vowel normalization effects in categorization were replicated in Experiment 1: Vowels taken from an [I]-[ε] continuum were more often interpreted as /I/ (which has a low first formant, F(1)) when the vowels were heard in contexts that had a raised F(1) than when the contexts had a lowered F(1). This was established with contexts that consisted of only two syllables. These short contexts were necessary for Experiment 2, a discrimination task that encouraged listeners to focus on the perceptual properties of vowels at a precategorical level. Vowel normalization was again found: Ambiguous vowels were more easily discriminated from an endpoint [ε] than from an endpoint [I] in a high-F(1) context, whereas the opposite was true in a low-F(1) context. Experiment 3 measured discriminability between pairs of steps along the [I]-[ε] continuum. Contextual influences were again found, but without discrimination peaks, contrary to what was predicted from the same participants' categorization behavior. Extrinsic vowel normalization therefore appears to be a process that takes place at least in part at a precategorical processing level.	\N	\N
23294198	Thirteen (5.4%) of patients with idiopathic sudden sensorineural hearing loss (ISSNHL) had benign paroxysmal positional vertigo (BPPV). Most of the patients showed profound hearing loss and had BPPV of the lateral canal. BPPV in patients with ISSNHL may have no influence on hearing recovery. BPPV occurs in 8.6-12.7% of patients with ISSNHL; however, the role of BPPV in hearing recovery remains controversial. Therefore, we investigated hearing outcomes in the patients, including the distribution of initial hearing threshold, the type of canal involved, and the number of repositioning maneuvers performed. Of 241 patients with ISSNHL who presented to a dizziness clinic between March 2008 and May 2012, 13 with both ISSNHL and BPPV were recruited for this study. The patients were evaluated for their initial hearing threshold, type of canal involved, response to repositioning maneuvers, and hearing outcome. Age- and hearing threshold-matched patients with ISSNHL but without BPPV were randomly sampled and included for a hearing outcome comparison. Of 13 patients with ISSNHL and BPPV, 11 showed profound hearing loss. The lateral canal was involved in 11 patients, including 3 who had multi-canal involvement. Ten patients underwent a single repositioning maneuver. Those patients did not display a significant difference in hearing recovery compared with those patients having ISSNHL only.	\N	\N
23294284	Following cochlear implantation, hearing-impaired listeners must adapt to speech as heard through their prosthesis. Visual speech information (VSI; the lip and facial movements of speech) is typically available in everyday conversation. Here, we investigate whether learning to understand a popular auditory simulation of speech as transduced by a cochlear implant (noise-vocoded [NV] speech) is enhanced by the provision of VSI. Experiment 1 demonstrates that provision of VSI concurrently with a clear auditory form of an utterance as feedback after each NV utterance during training does not enhance learning over clear auditory feedback alone, suggesting that VSI does not play a special role in retuning of perceptual representations of speech. Experiment 2 demonstrates that provision of VSI concurrently with NV speech (a simulation of typical real-world experience) facilitates perceptual learning of NV speech, but only when an NV-only repetition of each utterance is presented after the composite NV/VSI form during training. Experiment 3 shows that this more efficient learning of NV speech is probably due to the additional listening effort required to comprehend the utterance when clear feedback is never provided and is not specifically due to the provision of VSI. Our results suggest that rehabilitation after cochlear implantation does not necessarily require naturalistic audiovisual input, but may be most effective when (a) training utterances are relatively intelligible (approximately 85% of words reported correctly during effortful listening), and (b) the individual has the opportunity to map what they know of an utterance's linguistic content onto the degraded form.	\N	\N
23294551	The aim of the present study was to examine patterns of neural activity in response to variations in scale notes and alterations from a scale note to a non-scale note. Event-related potentials (ERPs) were recorded in response to scale and non-scale violin notes using an odd-ball mismatch negativity (MMN) paradigm. Standard stimuli were set to the scale note A4 (440 Hz). Deviant stimuli included two scale notes (scale-B, B4 = 494 Hz; scale-C, C5 = 523 Hz) and a non-scale note halfway between them (non-scale, B4+42¢ = 506 Hz). MMN amplitude elicited by the non-scale was significantly larger than that elicited by the scale-B and scale-C, which did not differ significantly from one another. The current results suggest that the human brain may possess pre-attentive mechanisms for extracting relational aspects among sounds of the musical scale. The results indicate that non-scale notes may be processed in a different way even in the pre-attentive stage than scale notes.	\N	\N
23296187	Sounds can modulate visual perception as well as neural activity in retinotopic cortex. Most studies in this context investigated how sounds change neural amplitude and oscillatory phase reset in visual cortex. However, recent studies in macaque monkeys show that congruence of audio-visual stimuli also modulates the amount of stimulus information carried by spiking activity of primary auditory and visual neurons. Here, we used naturalistic video stimuli and recorded the spatial patterns of functional MRI signals in human retinotopic cortex to test whether the discriminability of such patterns varied with the presence and congruence of co-occurring sounds. We found that incongruent sounds significantly impaired stimulus decoding from area V2 and there was a similar trend for V3. This effect was associated with reduced inter-trial reliability of patterns (i.e. higher levels of noise), but was not accompanied by any detectable modulation of overall signal amplitude. We conclude that sounds modulate naturalistic stimulus encoding in early human retinotopic cortex without affecting overall signal amplitude. Subthreshold modulation, oscillatory phase reset and dynamic attentional modulation are candidate neural and cognitive mechanisms mediating these effects.	\N	\N
23297908	The relative contributions of within-channel and across-channel processes to perceptual comodulation masking release (CMR) were investigated in the framework of an auditory processing model. A generalized version of the computational auditory signal processing and perception model [CASP; Jepsen et al., J. Acoust. Soc. Am. 124, 422-438 (2008)] was used and extended by an across-channel modulation processing stage according to Piechowiak et al. [J. Acoust. Soc. Am. 121, 2111-2126 (2007)]. Five experimental paradigms were considered: CMR with a broadband noise masker as a function of the masker spectrum level; CMR with four widely spaced flanking bands (FBs) varying in overall level; CMR with one FB varying in frequency and level relative to the on-frequency band (OFB); CMR with one FB varying in frequency; and CMR as a function of the number of FBs. The predictions suggest that at least three different mechanisms contribute to overall CMR in the considered conditions: (1) a within-channel process based on changes in the envelope characteristic due to the addition of the signal to the masker; (2) a within-channel process based on nonlinear peripheral processing of the OFB's envelope caused by the FB(s); and (3) an across-channel process that is robust across presentation levels but relatively small (2-5 dB).	\N	\N
23297915	This study used the same methodology in Wong [J. Speech Lang. Hear. Res. 55, 1423-1437 (2012b)] to examine the perceived accuracy of monosyllabic Mandarin tones produced by 4- and 5-year-old Mandarin-speaking children growing up in Taiwan and combined the findings with those of 3-year-olds reported in Wong [J. Speech Lang. Hear. Res. 55, 1423-1437 (2012b)] to track the development of monosyllabic tone production in preschool children. Tone productions of adults and children were collected in a picture naming task and low-pass filtered to remove lexical information and reserve tone information. Five native-speakers categorized the target tones in the filtered productions. Children's tone accuracy was compared to adults' to determine mastery and developmental changes. The results showed that preschool children in Taiwan have not fully mastered the production of monosyllabic Mandarin tones. None of the tones produced by the children in the three age groups reached adult-like accuracy. Little developmental change was found in children's tone accuracy during the preschool years. A similar order of accuracy of the tones was observed across the three age groups and the order appeared to follow the order of articulatory complexity in producing the tones. The findings suggest a protracted course of development in children's acquisition of Mandarin tones and that tone development may be constrained by physiological factors.	\N	\N
23299125	Phantom electrode (PE) stimulation consists of out-of-phase stimulation of two electrodes. When presented at the apex of the electrode array, phantom stimulation is known to produce a lower pitch sensation than monopolar (MP) stimulation on the most apical electrode. The ratio of the current between the primary electrode (PEL) and the compensating electrode (CEL) is represented by the coefficient σ, which ranges from 0 (monopolar) to 1 (full bipolar). The exact mechanism by which PE stimulation produces a lower pitch sensation is unclear. In the present study, unmasked and masked thresholds were obtained using a forward masking paradigm to estimate the spread of current for MP and PE stimulation. Masked thresholds were measured for two phantom electrode configurations (1) PEL = 4, CEL = 5 (lower pitch phantom) and (2) PEL = 4, CEL = 3 (higher pitch phantom). The unmasked thresholds were subtracted from the masked thresholds to obtain masking patterns which were normalized to their peak. The masking patterns reveal (1) differences in the spread of excitation that are consistent with the direction of pitch shift produced by PE stimulation, and (2) narrower spread of electrical excitation for PE stimulation relative to MP stimulation.	\N	\N
23301659	The last decade has offered a multitude of instant fit coupling systems to be fitted with behind-the-ear (BTE) hearing aids. The impact of these designs on the reliability of real ear measurements (REMs) has not been reported. The purpose of this study was to obtain REM reliability data for instant fit coupling systems. REM reliability data was obtained for four different instant-fit coupling systems and for standard size 13 tubing and custom earmolds. REMs were performed for all five coupling systems two times and by two examiners. Ten normal-hearing individuals (20 ears) served as participants. The REM test-retest reliability is high for the four instant fit coupling systems as well as for the custom earmolds. The REM inter-examiner reliability is high for three of the four instant fit coupling systems. Carrying out REMs with instant fit coupling systems appears to be fundamentally no different than performing REMs with conventional hearing aids. For either, care should be taken in probe tube placement in terms of insertion depth and maintaining the probe tube placement, and other best practices regarding test environment and test setup should be observed.	\N	\N
23308266	Computational and experimental research has revealed that auditory sensory predictions are derived from regularities of the current environment by using internal generative models. However, so far, what has not been addressed is how the auditory system handles situations giving rise to redundant or even contradictory predictions derived from different sources of information. To this end, we measured error signals in the event-related brain potentials (ERPs) in response to violations of auditory predictions. Sounds could be predicted on the basis of overall probability, i.e., one sound was presented frequently and another sound rarely. Furthermore, each sound was predicted by an informative visual cue. Participants' task was to use the cue and to discriminate the two sounds as fast as possible. Violations of the probability based prediction (i.e., a rare sound) as well as violations of the visual-auditory prediction (i.e., an incongruent sound) elicited error signals in the ERPs (Mismatch Negativity [MMN] and Incongruency Response [IR]). Particular error signals were observed even in case the overall probability and the visual symbol predicted different sounds. That is, the auditory system concurrently maintains and tests contradictory predictions. Moreover, if the same sound was predicted, we observed an additive error signal (scalp potential and primary current density) equaling the sum of the specific error signals. Thus, the auditory system maintains and tolerates functionally independently represented redundant and contradictory predictions. We argue that the auditory system exploits all currently active regularities in order to optimally prepare for future events.	\N	\N
23317386	Non-word repetition (NWR) tasks have been found to correlate with language skills and to discriminate between groups of typically developing (TD) children and children with specific language impairment (SLI) across languages. The main aim was to develop an easily-administered NWR screening test that could discriminate between Slovak-speaking TD children and children with SLI. The second aim was to establish if the novel scoring methods for NWR tasks were equally effective at differentiating between the TD versus SLI groups. As Slovak vowels are not reduced in unstressed syllables, it was also sought to establish whether scoring vowels (in addition to the consonants usually assessed in English language tests) would be informative. The paper evaluated the performance of a new NWR task for Slovak-speaking children. Study 1 compared the performance of 60 TD children in three age groups: 3-year-olds (N = 20), 4-your-olds (N = 20) and 5-year-olds (N = 20). Five types of scoring methods were examined: whole-item, number of syllables, syllable structure, consonants, and vowels. Study 2 compared performance on the NWR task administered in Study 1 across three groups of child participants: an SLI group (N = 16), a TD age-matched group (N = 16), and a TD language-matched group (N = 14). Study 1 found an age effect in the TD sample for three out of five of the scoring methods tested (number of syllables, syllable structure, and consonants). Study 2 showed that all five of the scoring methods discriminated between: (1) the group of children with SLI and the TD language-matched (TDLM) sample and (2) the group of children with SLI and the TD age-matched (TDAM) group. The novel NWR tool reliably differentiated between children with SLI and TD children. Scoring cut-off points which demonstrated high rates of success at verifying true-positives (93.75%) and true-negatives (100%) are provided. The most informative scoring methods for Slavic languages (whole-item scoring and vowels correct) are identified and discussed.	\N	\N
23333667	Spontaneous beat gestures are an integral part of the paralinguistic context during face-to-face conversations. Here we investigated the time course of beat-speech integration in speech perception by measuring ERPs evoked by words pronounced with or without an accompanying beat gesture, while participants watched a spoken discourse. Words accompanied by beats elicited a positive shift in ERPs at an early sensory stage (before 100 ms) and at a later time window coinciding with the auditory component P2. The same word tokens produced no ERP differences when participants listened to the discourse without view of the speaker. We conclude that beat gestures are integrated with speech early on in time and modulate sensory/phonological levels of processing. The present results support the possible role of beats as a highlighter, helping the listener to direct the focus of attention to important information and modulate the parsing of the speech stream.	\N	\N
23333869	The present study investigates the status of rhythmic irregularities occurring in natural speech and the importance of rhythmic alternations in cognitive processing. Previous studies showed the relevance of rhythm for language processing, but there has been only little research using the method of event-related potentials to investigate this phenomenon in a natural metrical context. To this end, an experiment was conducted in which the so-called Rhythm Rule (alternation of stressed and unstressed syllables) was either met or violated by stress clashes or stress lapses which are known to occur in German. The comparison of rhythmic well-formed conditions with the conditions including rhythmic irregularities revealed biphasic EEG-patterns for rhythmically marked structures, i.e., stress clashes and lapses. The present results show that irregular but possible rhythmic variants are costly in language processing, reflected by an early negativity and an N400 in contrast to the well-formed control conditions. Supposedly, the early negativity reflects error detection in rhythmical structure and supports the view that the brain is sensitive to subtle violations of rhythmical structure. A late positive component reflects the evaluation process related to the task requirements. The study shows that subtle rhythmical deviations from the Rhythm Rule are perceived and treated differently from well-formed structures during processing, even if the deviation in question is permitted and can therefore occur in language production.	\N	\N
23335579	Recent work suggests that people predict how objects interact in a manner consistent with Newtonian physics, but with additional uncertainty. However, the sources of uncertainty have not been examined. In this study, we measure perceptual noise in initial conditions and stochasticity in the physical model used to make predictions. Participants predicted the trajectory of a moving object through occluded motion and bounces, and we compared their behavior to an ideal observer model. We found that human judgments cannot be captured by simple heuristics and must incorporate noisy dynamics. Moreover, these judgments are biased consistently with a prior expectation on object destinations, suggesting that people use simple expectations about outcomes to compensate for uncertainty about their physical models.	\N	\N
23337441	Here, we explore the sensitivity of different awareness scales in revealing conscious reports on visual emotion perception. Participants were exposed to a backward masking task involving fearful faces and asked to rate their conscious awareness in perceiving emotion in facial expression using three different subjective measures: confidence ratings (CRs), with the conventional taxonomy of certainty, the perceptual awareness scale (PAS), through which participants categorize "raw" visual experience, and post-decision wagering (PDW), which involves economic categorization. Our results show that the CR measure was the most exhaustive and the most graded. In contrast, the PAS and PDW measures suggested instead that consciousness of emotional stimuli is dichotomous. Possible explanations of the inconsistency were discussed. Finally, our results also indicate that PDW biases awareness ratings by enhancing first-order accuracy of emotion perception. This effect was possibly a result of higher motivation induced by monetary incentives.	\N	\N
23338560	Our study estimates detection thresholds for tones of different durations and frequencies in Great Tits (Parus major) with operant procedures. We employ signals covering the duration and frequency range of communication signals of this species (40-1,010 ms; 2, 4, 6.3 kHz), and we measure threshold level-duration (TLD) function (relating threshold level to signal duration) in silence as well as under behaviorally relevant environmental noise conditions (urban noise, woodland noise). Detection thresholds decreased with increasing signal duration. Thresholds at any given duration were a function of signal frequency and were elevated in background noise, but the shape of Great Tit TLD functions was independent of signal frequency and background condition. To enable comparisons of our Great Tit data to those from other species, TLD functions were first fitted with a traditional leaky-integrator model. We then applied a probabilistic model to interpret the trade-off between signal amplitude and duration at threshold. Great Tit TLD functions exhibit features that are similar across species. The current results, however, cannot explain why Great Tits in noisy urban environments produce shorter song elements or faster songs than those in quieter woodland environments, as detection thresholds are lower for longer elements also under noisy conditions.	\N	\N
23342146	This study investigated a theoretically challenging dissociation between good production and poor perception of tones among neurologically unimpaired native speakers of Cantonese. The dissociation is referred to as the near-merger phenomenon in sociolinguistic studies of sound change. In a passive oddball paradigm, lexical and nonlexical syllables of the T1/T6 and T4/T6 contrasts were presented to elicit the mismatch negativity (MMN) and P3a from two groups of participants, those who could produce and distinguish all tones in the language (Control) and those who could produce all tones but specifically failed to distinguish between T4 and T6 in perception (Dissociation). The presence of MMN to T1/T6 and null response to T4/T6 of lexical syllables in the dissociation group confirmed the near-merger phenomenon. The observation that the control participants exhibited a statistically reliable MMN to lexical syllables of T1/T6, weaker responses to nonlexical syllables of T1/T6 and lexical syllables of T4/T6, and finally null response to nonlexical syllables of T4/T6, suggests the involvement of top-down processing in speech perception. Furthermore, the stronger P3a response of the control group, compared with the dissociation group in the same experimental conditions, may be taken to indicate higher cognitive capability in attention switching, auditory attention or memory in the control participants. This cognitive difference, together with our speculation that constant top-down predictions without complete bottom-up analysis of acoustic signals in speech recognition may reduce one's sensitivity to small acoustic contrasts, account for the occurrence of dissociation in some individuals but not others.	\N	\N
23354998	Complex sounds vary along a number of acoustic dimensions. These dimensions may exhibit correlations that are familiar to listeners due to their frequent occurrence in natural sounds-namely, speech. However, the precise mechanisms that enable the integration of these dimensions are not well understood. In this study, we examined the categorization of novel auditory stimuli that differed in the correlations of their acoustic dimensions, using decision bound theory. Decision bound theory assumes that stimuli are categorized on the basis of either a single dimension (rule based) or the combination of more than one dimension (information integration) and provides tools for assessing successful integration across multiple acoustic dimensions. In two experiments, we manipulated the stimulus distributions such that in Experiment 1, optimal categorization could be accomplished by either a rule-based or an information integration strategy, while in Experiment 2, optimal categorization was possible only by using an information integration strategy. In both experiments, the pattern of results demonstrated that unidimensional strategies were strongly preferred. Listeners focused on the acoustic dimension most closely related to pitch, suggesting that pitch-based categorization was given preference over timbre-based categorization. Importantly, in Experiment 2, listeners also relied on a two-dimensional information integration strategy, if there was immediate feedback. Furthermore, this strategy was used more often for distributions defined by a negative spectral correlation between stimulus dimensions, as compared with distributions with a positive correlation. These results suggest that prior experience with such correlations might shape short-term auditory category learning.	\N	\N
23357804	Frequency-lowering signal processing in hearing aids has re-emerged as an option to improve audibility of the high frequencies by expanding the input bandwidth. Few studies have investigated the usefulness of the scheme as an option for bimodal users (i.e., combined use of a cochlear implant and a contralateral hearing aid). In this study, that question was posed. The purposes of this study were (1) to determine if frequency compression was a better bimodal option than conventional amplification and (2) to determine the impact of a frequency-compression hearing aid on speech recognition abilities. There were two separate experiments in this study. The first experiment investigated the contribution of a frequency-compression hearing aid to contralateral cochlear implant (CI) performance for localization and speech perception in noise. The second experiment assessed monaural consonant and vowel perception in quiet using the frequency-compression and conventional hearing aid without the use of a contralateral CI or hearing aid. Ten subjects fitted with a cochlear implant and hearing aid participated in the first experiment. Seventeen adult subjects with a cochlear implant and hearing aid or two hearing aids participated in the second experiment. To be included, subjects had to have a history of postlingual deafness, a moderate or moderate-to-severe hearing loss, and have not worn this type of frequency-lowering hearing aid previously. In the first experiment, performance using the frequency-compression and conventional hearing aids was assessed on tests of sound localization, speech perception in a background of noise, and two self-report questionnaires. In the second experiment, consonant and vowel perception in quiet was assessed monaurally for the two conditions. In both experiments, subjects alternated daily between a frequency-compression and conventional hearing aid for 2 mo. The parameters of frequency compression were set individually for each subject, and audibility was measured for the frequency compression and conventional hearing aid programs by comparing estimations of the Speech Intelligibility Index (SII) using a modified algorithm (Bentler et al, 2011). In both experiments, the outcome measures were administered following the hearing aid fitting to assess performance at baseline and after 2 mo of use. For this group of subjects, the results revealed no significant difference between the frequency-compression and conventional hearing aid on tests of localization and consonant recognition. Spondee-in-noise and vowel perception scores were significantly higher with the conventional hearing aid compared to the frequency-compression hearing aid after 2 mo of use. These results suggest that, for the subjects in this study, frequency compression is not a better bimodal option than conventional amplification. In addition, speech perception may be negatively influenced by frequency compression because formant frequencies are too severely compressed and can no longer be distinguished.	\N	\N
23357807	Johnson and Dillon (2011) provided a model-based comparison of current generic hearing aid prescriptive methods for adults with hearing loss based on the attributes of speech intelligibility, loudness, and bandwidth. This study compared the National Acoustic Laboratories-Non-linear 2 (NAL-NL2) and Cambridge Method for Loudness Equalization 2-High-Frequency (CAM2) prescriptive methods using adult participants with less high-frequency hearing loss than Johnson and Dillon (2011). Of study interest was quantification of prescribed audibility, speech intelligibility, and loudness. The preferences of participants for either NAL-NL2 or CAM2 and preferred deviations from prescribed settings are also reported. Using a single-blind, counter-balanced, randomized design, preference judgments for the prescriptive methods with regard to sound quality of speech and music stimuli were obtained. Preferred gain adjustments from the prescription within the 4-10 kHz frequency range were also obtained from each participant. Speech intelligibility and loudness model calculations were completed on the prescribed and adjusted amplification. Fourteen male Veterans, whose average age was 65 yr and whose hearing sensitivity averaged normal to borderline normal through 1000 Hz sloping to a moderately severe sensorineural loss, served as participants. Following a brief listening time (~10 min), typical of an initial fitting visit, the participants made paired comparison of sound quality between the NAL-NL2 and CAM2 prescriptive settings. Participants were also asked to modify each prescription in the range of 4-10 kHz using an overall gain control and make subsequent comparisons of sound quality preference between prescriptive and adjusted settings. Participant preferences were examined with respect to quantitative analysis of loudness modeling, speech intelligibility modeling, and measured high-frequency bandwidth audibility. Consistent with the lack of difference in predicted speech intelligibility between the two prescriptions, sound quality preferences on the basis of clarity were split across participants while some participants did not have a discernable preference. Considering sound quality judgments of pleasantness, the majority of participants preferred the sound quality of the NAL-NL2 (8 of 14) prescription instead of the CAM2 prescription (2 of 14). Four of the 14 participants showed no preference on the basis of pleasantness for either prescription. Individual subject preferences were supported by loudness modeling that indicated NAL-NL2 was the softer of the two prescriptions and CAM2 was the louder. CAM2 did provide more audibility to the higher frequencies (5-8 kHz) than NAL-NL2. Participants turned the 4-10 kHz gain recommendation of CAM2 lower, on average, by a significant amount of 4 dB when making adjustments while no significant adjustment was made to the initial NAL-NL2 recommendation. NAL-NL2 prescribed gains were more often preferred at the initial fitting by the majority of participating veterans. For those patients with preference for a louder fitting than NAL-NL2, CAM2 is a good alternative. When the participant adjustment from the prescription between 4 and 10 kHz exceeded 4 dB from either NAL-NL2 (2 of 14) or CAM2 (11 of 14), the participants demonstrated a later preference for that adjustment 69% of the time. These findings are viewed as limited evidence that some individuals may have a preference for high-frequency gain that differs from the starting prescription.	\N	\N
23363117	Recently introduced hearing devices allow dynamic-range compression to be coordinated at the two ears through a wireless link. This study investigates how linking compression across the ears might improve speech intelligibility in the presence of a spatially separated steady noise. An analysis of the compressors' behavior shows how linked compression can preserve interaural level differences (ILDs) and, compared to compression operating independently at each ear, improve the long-term apparent speech-to-noise ratio (SNR) at the ear with the better SNR. Speech intelligibility for normal-hearing listeners was significantly better with linked than with unlinked compression. The performance with linked compression was similar to that without any compression. The benefit of linked over unlinked compression was the same for binaural listening and for monaural listening to the ear with the better SNR, indicating that the benefit was due to changes to the signal at this ear and not to the preservation of ILDs. Differences in performance across experimental conditions were qualitatively consistent with changes in apparent SNR at the better ear. Predictions made using a speech intelligibility model suggest that linked compression could potentially provide a user of bilateral hearing aids with an improvement in intelligibility of up to approximately ten percentage points.	\N	\N
23374605	To date, the nature of the phonological deficit in developmental dyslexia is still debated. We concur with possible impairments in the representations of the universal phonological constraints that universally govern how phonemes co-occur as a source of this deficit. We were interested in whether-and how-dyslexic children have sensitivity to sonority-related markedness constraints. We tested 10 French dyslexic children compared with 20 typically developing chronological age-matched and reading level-matched controls. All were tested with two aurally administered syllable counting tasks that manipulated well-formedness of unattested consonant clusters, as determined by universal phonological sonority-related markedness constraints (onset clusters in Experiment 1; intervocalic clusters in Experiment 2). Surprisingly, dyslexic children's response patterns were similar to those in both control groups; as universal phonological sonority-related markedness increased, dyslexic children increasingly perceptually confused and phonologically repaired clusters with an illusory epenthetic vowel (e.g., /ʁəbal/). Although dyslexic children were systematically slower, like both control groups, they were influenced by universal sonority-related markedness constraints and hierarchically ranked constraints specific to French over evident acoustic-phonetic contrasts or sonority-unrelated cues. Our results are counterintuitive but innovative and compete to question an impaired universal phonological grammar because dyslexic children were found to have normal universal phonological constraints and were skilled to restore phonotactically legal syllable structures with a language-specific illusory epenthetic vowel (i.e., /ə/-like vowel). We discuss them regarding active phonological decoding and recoding processes within the framework of the optimality theory.	\N	\N
23384511	We tested whether incoming sounds are processed differently depending on how the preceding sound sequence has been interpreted by the brain. Sequences of a regularly repeating three-tone pattern, the perceived organization of which spontaneously switched back and forth between two alternative interpretations, were delivered to listeners. Occasionally, a regular tone was exchanged for a slightly or moderately lower one (deviants). The electroencephalogram (EEG) was recorded while listeners continuously marked their perception of the sound sequence. We found that for both the regular and the deviant tones, the early exogenous P1 and N1 amplitudes varied together with the perceived sound organization. Percept-dependent effects on the late endogenous N2 and P3a amplitudes were only found for deviant tones. These results suggest that the perceived sound organization affects sound processing both by modulating what information is extracted from incoming sounds as well as by influencing how deviant sound events are evaluated for further processing.	\N	\N
23384530	Prosodic aspects of speech such as pitch, duration and amplitude constitute nonverbal cues that supplement or modify the meaning of the spoken word, to provide valuable clues as to a speakers' state of mind. It can thus indicate what emotion a person is feeling (emotional prosody), or their attitude towards an event, person or object (attitudinal prosody). Whilst the study of emotional prosody has gathered pace, attitudinal prosody now deserves equal attention. In social cognition, understanding attitudinal prosody is important in its own right, since it can convey powerful constructs such as confidence, persuasion, sarcasm and superiority. In this review, it is examined what prosody is, how it conveys attitudes, and which attitudes prosody can convey. The review finishes by considering the neuroanatomy associated with attitudinal prosody, and put forward the hypothesis that this cognition is mediated by the right cerebral hemisphere, particularly posterior superior lateral temporal cortex, with an additional role for the basal ganglia, and limbic regions such as the medial prefrontal cortex and amygdala. It is suggested that further exploration of its functional neuroanatomy is greatly needed, since it could provide valuable clues about the value of current prosody nomenclature and its separability from other types of prosody at the behavioural level.	\N	\N
23386124	The sight of a speaker's facial movements during the perception of a spoken message can benefit speech processing through online predictive mechanisms. Recent evidence suggests that these predictive mechanisms can operate across sensory modalities, that is, vision and audition. However, to date, behavioral and electrophysiological demonstrations of cross-modal prediction in speech have considered only the speaker's native language. Here, we address a question of current debate, namely whether the level of representation involved in cross-modal prediction is phonological or pre-phonological. We do this by testing participants in an unfamiliar language. If cross-modal prediction is predominantly based on phonological representations tuned to the phonemic categories of the native language of the listener, then it should be more effective in the listener's native language than in an unfamiliar one. We tested Spanish and English native speakers in an audiovisual matching paradigm that allowed us to evaluate visual-to-auditory prediction, using sentences in the participant's native language and in an unfamiliar language. The benefits of cross-modal prediction were only seen in the native language, regardless of the particular language or participant's linguistic background. This pattern of results implies that cross-modal visual-to-auditory prediction during speech processing makes strong use of phonological representations, rather than low-level spatiotemporal correlations across facial movements and sounds.	\N	\N
23387878	Velopharyngeal incompetence is a contributing factor to speech disorders and implies the presence of hypernasality, inappropriate nasal escape, and decreased air pressure during speech. One prosthetic treatment is a rehabilitative procedure employing a palatal lift prosthesis (PLP), which reduces hypernasality by approximating the incompetent soft palate to the posterior pharyngeal wall and consists of two parts, the anterior denture base and the palatal lifting plate, which are connected with steel wires; however, it seems difficult to reproduce the mobility of the soft palate in speaking, and it is therefore likely that the palatal lifting plate stimulates or oppresses the tissue of the soft palate and hinders rather than assists articulatory function. To avoid these disturbances we devised an adjustable PLP with a flexible conjunction between the denture base and the palatal lifting plate to obtain the optimal vertical lifting angle. The palatal plate was adapted to conform in a passive manner to the soft palate with light-cured resin. The designed PLP simplified the procedure and reduced the number of adjustments and visits.	\N	\N
23389426	The human visual attention system is geared toward detecting the most salient and relevant events in an overwhelming stream of information. There has been great interest in measuring how many visual events can be processed at a time, and most of the work has suggested that the limit is three to four. However, attention to a visual stimulus can also be driven by a synchronous auditory event. The present work indicates that a fundamentally different limit applies to audiovisual processing, such that at most only a single audiovisual event can be processed at a time. This limited capacity is not due to a limitation in visual selection; participants were able to process about four visual objects simultaneously. Instead, we propose that audiovisual orienting is subject to a fundamentally different capacity limit than pure visual selection is.	\N	\N
23395711	In the current ERP study, an active oddball task was carried out, testing pure tones and auditory, visual and audiovisual syllables. For pure tones, an MMN, an N2b, and a P3 were found, confirming traditional findings. Auditory syllables evoked an N2 and a P3. We found that the amplitude of the P3 depended on the distance between standard and deviant. A smaller distance required more attention, which was reflected in a larger amplitude. An analysis of audiovisual material, after correction for visual activity, showed that McGurk type stimuli evoked brain responses that differed from both the standard and the congruent deviants. Finally, we found that congruent audiovisual stimuli elicited an N2 with a shorter latency and a P3 with a smaller amplitude than auditory stimuli. The current ERP study, thus, shows that for audiovisual processing the whole is more than the sum of its parts.	\N	\N
23395774	This paper examines the judgment of segmented temporal intervals, using short tone sequences as a convenient test case. In four experiments, we investigate how the relative lengths, arrangement, and pitches of the tones in a sequence affect judgments of sequence duration, and ask whether the data can be described by a simple weighted sum of segments model. The model incorporates three basic assumptions: (i) the judgment of each segment is a negatively accelerated function of its duration, (ii) the judgment of the overall interval is produced by summing the judgments of each segment, and (iii) more recent segments are weighted more heavily. We also assume that higher-pitched tones are judged to last longer. Empirically, sequences with equal-sized segments were consistently judged longer than those with accelerating or decelerating structures. Furthermore, temporal structure interacted with duration, such that accelerating sequences were judged longer than decelerating ones at short durations but the effect reversed at longer durations. These effects were modulated by the number of tones in the sequence, the rate of acceleration/deceleration, and whether the sequence had ascending or descending pitch, and were well-described by the weighted sum model. The data provide strong constraints on theories of temporal judgment, and the weighted sum of segments model offers a useful basis for future theoretical and empirical investigation.	\N	\N
23397035	We used a face-gender repetition priming paradigm to precisely map the spatial frequencies (SFs) that influence observers' responses under different prime awareness conditions. A visible prime condition was set up by presenting the stimulus sequence mask-blank-prime-blank-mask-target and an invisible prime condition by switching the order of the masks and the blanks (see also Dehaene et al., 2001). The prime faces (~4.6° × 3.1°) were randomly filtered trial-by-trial according to the SF bubbles technique (Willenbockel, Fiset et al., 2010). Classification vectors, derived by summing the SF filters from each trial weighted by observers' transformed response times, revealed that SFs around 12 cycles per face width modulated responses in both prime awareness conditions. The significant SFs closely matched those optimal for accurate performance in a direct face-gender classification paradigm. Surprisingly, the significant SFs facilitated observers' responses in the visible prime condition, whereas they slowed responses in the invisible prime condition. Our findings suggest that SF tuning per se remains robust under different prime awareness conditions but that diagnostic visual cues might be utilized in a qualitatively different fashion as a function of awareness.	\N	\N
23400826	In two experiments, we used an interruption-and-recall (IAR) task to explore listeners' ability to monitor the capacity of working memory as new information arrived in real time. In this task, listeners heard recorded word lists with instructions to interrupt the input at the maximum point that would still allow for perfect recall. Experiment 1 demonstrated that the most commonly selected segment size closely matched participants' memory span, as measured in a baseline span test. Experiment 2 showed that reducing the sound level of presented word lists to a suprathreshold but effortful listening level disrupted the accuracy of matching selected segment sizes with participants' memory spans. The results are discussed in terms of whether online capacity monitoring may be subsumed under other, already enumerated working memory executive functions (inhibition, set shifting, and memory updating).	\N	\N
23403808	The objective of this study was to examine the role of the acoustic stapedius reflex in the protection of speech recognition from the upward spread of masking arising from low-frequency background noise. Speech recognition scores were measured for nine control participants (19-34 years) and six patients with transected stapedius tendons poststapedotomy (39-57 years) as a function of the amplitude of a low-frequency masker, presented at nominal signal to noise ratios of +5 dB, -5 dB, and -15 dB. All participants had pure-tone hearing thresholds in the normal range. Continuous high-pass noise was present in all conditions to avoid ceiling effects; this reduced performance in quiet to approximately 85% for all participants. Scores were measured for soft and loud nonsense syllables (average third octave band levels of 35 and 65 dB SPL), so that a comparison of the low-frequency noise masking functions at the two levels would provide information about the effects of the reflex on speech intelligibility in noise. A third group of nine control participants (19-22 years) listened in the presence of a low-frequency masker gated to come on 1 sec before stimulus onset, to reduce the likelihood of reflex adaptation. The Speech-Intelligibility Index was used to quantify the amount of speech information available in each condition. Patients with transected tendons performed more poorly than control participants as a function of Speech-Intelligibility Index in all conditions, even at levels that were too soft for reflex activation. This could be because of postsurgical differences in sensitivity, the more advanced age of poststapedotomy group, or differences in medial olivocochlear inhibition. For loud speech, patient performance fell nearly linearly with increases in the low-frequency masker, but control participants' performance declined little as the signal to noise ratio declined from +5 to -5 dB, and then fell rapidly as the ratio declined to -15 dB. This plateau in the masking function did not occur for the patients. Masking functions obtained with the gated low-frequency masker were either highly similar or poorer to those obtained with a continuous masker, suggesting that the use of a continuous low frequency masker did not result in significant reflex adaptation. The stapedius reflex appears to offer some protection from the upward spread of masking of speech by background low-frequency noise at moderate levels, but not at high levels.	\N	\N
23406991	Around 10% of people experience subjective tinnitus (the perception of sound, only audible to the patient, in the absence of an external auditory stimulus).(1-3) It may be associated with hearing loss, anxiety, depression, sleep disturbance, concentration problems or reduced quality of life; for around 0.5% it is extremely disturbing.(1-4) Risk factors include aging, significant noise exposure, drug therapy (e.g. aminoglycosides, NSAIDs, diuretics), or disorders of the outer, middle or inner ear or auditory nerve (e.g. ear wax, infections, vestibular schwannoma, otosclerosis).(1,2,4) It may be due to excessive spontaneous activity in the auditory system and brain; if the signal (normally suppressed by the subconscious) becomes noticed it becomes more intrusive and annoying in a vicious cycle.(5) Here, we discuss symptomatic drug and non-drug treatments for subjective tinnitus in adults. We do not cover treatment of underlying causes of tinnitus.	\N	\N
23408389	Coding for the degree of disorder in a temporally unfolding sensory input allows for optimized encoding of these inputs via information compression and predictive processing. Prior neuroimaging work has examined sensitivity to statistical regularities within single sensory modalities and has associated this function with the hippocampus, anterior cingulate, and lateral temporal cortex. Here we investigated to what extent sensitivity to input disorder, quantified by Markov entropy, is subserved by modality-general or modality-specific neural systems when participants are not required to monitor the input. Participants were presented with rapid (3.3 Hz) auditory and visual series varying over four levels of entropy, while monitoring an infrequently changing fixation cross. For visual series, sensitivity to the magnitude of disorder was found in early visual cortex, the anterior cingulate, and the intraparietal sulcus. For auditory series, sensitivity was found in inferior frontal, lateral temporal, and supplementary motor regions implicated in speech perception and sequencing. Ventral premotor and central cingulate cortices were identified as possible candidates for modality-general uncertainty processing, exhibiting marginal sensitivity to disorder in both modalities. The right temporal pole differentiated the highest and lowest levels of disorder in both modalities, but did not show general sensitivity to the parametric manipulation of disorder. Our results indicate that neural sensitivity to input disorder relies largely on modality-specific systems embedded in extended sensory cortices, though uncertainty-related processing in frontal regions may be driven by both input modalities.	\N	\N
23413000	In the present experiments, participants had to verify properties of concepts but, depending on the trial condition, concept-property pairs were presented via headphones or on the screen. The results showed that participants took longer and were less accurate at verifying conceptual properties when the channel used to present the CONCEPT-property pair and the type of property matched in sensory modality (e.g., LEMON-yellow on screen; BLENDER-loud in headphones) compared to when properties and channel did not match (e.g., LEMON-yellow in headphones; BLENDER-loud on screen). Such interference is consistent with theories of embodied cognition holding that knowledge is grounded in modality-specific systems (Barsalou in Behav Brain Sci 22:577-660, 1999). When the resources of one modality are burdened during the task, processing costs are incurred in a conceptual task (Vermeulen et al. in Cognition 109:287-294, 2008).	\N	\N
23425567	Previous studies on the role of vowel harmony in word segmentation are based on artificial languages where harmonic cues reliably signal word boundaries. In this corpus study run on the data available at CHILDES, we investigated whether natural languages provide a learner with reliable segmentation cues similar to the ones created artificially. We observed that in harmonic languages (child-directed speech to thirty-five Turkish and three Hungarian children), but not in non-harmonic ones (child-directed speech to one Farsi and four Polish children), harmonic vowel sequences are more likely to appear within words, and non-harmonic ones mostly appear across word boundaries, suggesting that natural harmonic languages provide a learner with regular cues that could potentially be used for word segmentation along with other cues.	\N	\N
23432759	The time frame for infants' acquisition of language constancy was probed, using the phonetic variation in a rarely heard accent (South African English) or a frequently heard accent (American English). A total of 156 Australian infants were tested. Six-month-olds looked longer to Australian English than less commonly heard South African accent, but at 9 months, showed similar looking times. With the more frequently heard American accent, 3-month-olds looked longer to Australian and American English, whereas 6-month-olds looked equally. Together these results imply that in the 1st year, differential attention to native versus nonnative accents decreases as infants develop a sense of language constancy for the common native language. However, experience with the nonnative accent can expedite this process.	\N	\N
23433243	Patients with alien hand syndrome (AHS) experience making apparently deliberate and purposeful movements with their hand against their will. However, the mechanisms contributing to these involuntary actions remain poorly understood. Here, we describe two experimental investigations in a patient with corticobasal syndrome (CBS) with alien hand behaviour in her right hand. First, we show that responses with the alien hand are made significantly more quickly to images of objects which afford an action with that hand compared to objects which afford an action with the unaffected hand. This finding suggests that involuntary grasping behaviours in AHS might be due to exaggerated, automatic motor activation evoked by objects which afford actions with that limb. Second, using a backwards masked priming task, we found normal automatic inhibition of primed responses in the patient's unaffected hand, but importantly there was no evidence of such suppression in the alien limb. Taken together, these findings suggest that grasping behaviours in AHS may result from exaggerated object affordance effects, which might potentially arise from disrupted inhibition of automatically evoked responses.	\N	\N
23440517	Users of bilateral cochlear implants (CIs) experience difficulties localizing sounds in reverberant rooms, even in rooms where normal-hearing listeners would hardly notice the reverberation. We measured the localization ability of seven bilateral CI users listening with their own devices in anechoic space and in a simulated reverberant room. To determine factors affecting performance in reverberant space we measured the sensitivity to interaural time differences (ITDs), interaural level differences (ILDs), and forward masking in the same participants using direct computer control of the electric stimulation in their CIs. Localization performance, quantified by the coefficient of determination r(2) and the root mean squared error, was significantly worse in the reverberant room than in anechoic conditions. Localization performance in the anechoic room, expressed as r(2), was best predicted by subject's sensitivity to ILDs. However, the decrease in localization performance caused by reverberation was better predicted by the sensitivity to envelope ITDs measured on single electrode pairs, with a correlation coefficient of 0.92. The CI users who were highly sensitive to envelope ITDs also better maintained their localization ability in reverberant space. Results in the forward masking task added only marginally to the predictions of localization performance in both environments. The results indicate that envelope ITDs provided by CI processors support localization in reverberant space. Thus, methods that improve perceptual access to envelope ITDs could help improve localization with bilateral CIs in everyday listening situations.	\N	\N
23440859	Children with reading disability and normal reading development were compared in their ability to discriminate native (English) and novel language (Mandarin) from nonlinguistic sounds. Children's preference for native versus novel language sounds and for disyllables containing dominant trochaic versus non-dominant iambic stress patterns was also assessed. Participants included second and third grade monolingual native English speakers with reading disability (N = 18) and normal reading development (N = 18). Children selected from pairs of novel, native, and nonlinguistic sounds that was more like language. Both groups discriminated disyllabic linguistic sounds (native and novel) from nonlinguistic sounds. Both groups showed preference for the dominant English trochaic stress pattern over the non-dominant iambic stress pattern. Implications for development of prosodic sensitivity in relation to reading skills and future research are discussed.	\N	\N
23442569	The relative impact of early intervention approach on speech perception and language skills was examined in these 3 well-matched groups of children using cochlear implants. Eight children from an auditory verbal intervention program were identified. From a pediatric database, researchers blind to the outcome data, identified 23 children from auditory oral programs and 8 children from bilingual-bicultural programs with the same inclusion criteria and equivalent demographic factors. All child participants were male, had congenital profound hearing loss (pure tone average >80 dBHL), no additional disabilities, were within the normal IQ range, were monolingual English speakers, had no unusual findings on computed tomography/magnetic resonance imaging, and received hearing aids and cochlear implants at a similar age and before 4 years of age. Open-set speech perception (consonant-nucleus-consonant [CNC] words and Bamford-Kowal-Bench [BKB] sentences) and the Peabody Picture Vocabulary Test (PPVT) were administered. The mean age at cochlear implant was 1.7 years (range, 0.8-3.9; SD, 0.7), mean test age was 5.4 years (range, 2.5-10.1; SD, 1.7), and mean device experience was 3.7 years (range, 0.7-7.9; SD, 1.8). Results indicate mean CNC scores of 60%, 43%, and 24% and BKB scores of 77%, 77%, and 56% for the auditory-verbal (AV), aural-oral (AO), and bilingual-bicultural (BB) groups, respectively. The mean PPVT delay was 13, 19, and 26 months for AV, AO, and BB groups, respectively. Despite equivalent child demographic characteristics at the outset of this study, by 3 years postimplant, there were significant differences in AV, AO, and BB groups. Results support consistent emphasis on oral/aural input to achieve optimum spoken communication outcomes for children using cochlear implants.	\N	\N
23445327	Metabolic syndrome is a risk factor for age-related hearing impairment (ARHI). There are metabolic differences between abdominal adipose tissue present in subcutaneous and visceral areas. In this study, we investigated the association between abdominal fat composition, measured by computerized tomography (CT), and hearing thresholds. We recruited 662 adults aged 40-82 years with normal or symmetrical sensorineural hearing loss who underwent fat measurement by CT. Linear regression models were used to address the association between risk factors, including abdominal fat composition, and average hearing levels at low and high frequencies. After adjusting for age, systemic disease and other variables, a positive association between visceral adipose tissue (VAT) area and average hearing threshold was observed in women. In men, there was no significant association between abdominal fat composition and hearing threshold. Our findings show an association between VAT and hearing impairment in women. A reduction in visceral adiposity may help to prevent hearing loss in women.	\N	\N
23446225	The aim of this study was to assess the benefit of having preserved acoustic hearing in the implanted ear for speech recognition in complex listening environments. The present study included a within-subjects, repeated-measures design including 21 English-speaking and 17 Polish-speaking cochlear implant (CI) recipients with preserved acoustic hearing in the implanted ear. The patients were implanted with electrodes that varied in insertion depth from 10 to 31 mm. Mean preoperative low-frequency thresholds (average of 125, 250, and 500 Hz) in the implanted ear were 39.3 and 23.4 dB HL for the English- and Polish-speaking participants, respectively. In one condition, speech perception was assessed in an eight-loudspeaker environment in which the speech signals were presented from one loudspeaker and restaurant noise was presented from all loudspeakers. In another condition, the signals were presented in a simulation of a reverberant environment with a reverberation time of 0.6 sec. The response measures included speech reception thresholds (SRTs) and percent correct sentence understanding for two test conditions: CI plus low-frequency hearing in the contralateral ear (bimodal condition) and CI plus low-frequency hearing in both ears (best-aided condition). A subset of six English-speaking listeners were also assessed on measures of interaural time difference thresholds for a 250-Hz signal. Small, but significant, improvements in performance (1.7-2.1 dB and 6-10 percentage points) were found for the best-aided condition versus the bimodal condition. Postoperative thresholds in the implanted ear were correlated with the degree of electric and acoustic stimulation (EAS) benefit for speech recognition in diffuse noise. There was no reliable relationship among measures of audiometric threshold in the implanted ear nor elevation in threshold after surgery and improvement in speech understanding in reverberation. There was a significant correlation between interaural time difference threshold at 250 Hz and EAS-related benefit for the adaptive speech reception threshold. The findings of this study suggest that (1) preserved low-frequency hearing improves speech understanding for CI recipients, (2) testing in complex listening environments, in which binaural timing cues differ for signal and noise, may best demonstrate the value of having two ears with low-frequency acoustic hearing, and (3) preservation of binaural timing cues, although poorer than observed for individuals with normal hearing, is possible after unilateral cochlear implantation with hearing preservation and is associated with EAS benefit. The results of this study demonstrate significant communicative benefit for hearing preservation in the implanted ear and provide support for the expansion of CI criteria to include individuals with low-frequency thresholds in even the normal to near-normal range.	\N	\N
23446226	Understanding speech in acoustically degraded environments can place significant cognitive demands on school-age children who are developing the cognitive and linguistic skills needed to support this process. Previous studies suggest the speech understanding, word learning, and academic performance can be negatively impacted by background noise, but the effect of limited audibility on cognitive processes in children has not been directly studied. The aim of the present study was to evaluate the impact of limited audibility on speech understanding and working memory tasks in school-age children with normal hearing. Seventeen children with normal hearing between 6 and 12 years of age participated in the present study. Repetition of nonword consonant-vowel-consonant stimuli was measured under conditions with combinations of two different signal to noise ratios (SNRs; 3 and 9 dB) and two low-pass filter settings (3.2 and 5.6 kHz). Verbal processing time was calculated based on the time from the onset of the stimulus to the onset of the child's response. Monosyllabic word repetition and recall were also measured in conditions with a full bandwidth and 5.6 kHz low-pass cutoff. Nonword repetition scores decreased as audibility decreased. Verbal processing time increased as audibility decreased, consistent with predictions based on increased listening effort. Although monosyllabic word repetition did not vary between the full bandwidth and 5.6 kHz low-pass filter condition, recall was significantly poorer in the condition with limited bandwidth (low pass at 5.6 kHz). Age and expressive language scores predicted performance on word recall tasks, but did not predict nonword repetition accuracy or verbal processing time. Decreased audibility was associated with reduced accuracy for nonword repetition and increased verbal processing time in children with normal hearing. Deficits in free recall were observed even under conditions where word repetition was not affected. The negative effects of reduced audibility may occur even under conditions where speech repetition is not impacted. Limited stimulus audibility may result in greater cognitive effort for verbal rehearsal in working memory and may limit the availability of cognitive resources to allocate to working memory and other processes.	\N	\N
23464029	Aided consonant and vowel identification was measured in 13 listeners with high-frequency sloping hearing losses. To investigate the influence of compression-channel analysis bandwidth on identification performance independent of the number of channels, performance was compared for three 17-channel compression systems that differed only in terms of their channel bandwidths. One compressor had narrow channels, one had widely overlapping channels, and the third had level-dependent channels. Measurements were done in quiet, in speech-shaped noise, and in a three-talker background. The results showed no effect of channel bandwidth, neither on consonant nor on vowel identification scores. This suggests that channel bandwidth per se has little influence on speech intelligibility when individually prescribed, frequency-varying compressive gain is provided.	\N	\N
23466188	It is well established that individuals with schizophrenia demonstrate alterations in auditory perception beginning at the very earliest stages of information processing. However, it is not clear how these impairments in basic information processing translate into high-order cognitive deficits. Auditory scene analysis allows listeners to group auditory information into meaningful objects, and as such provides an important link between low-level auditory processing and higher cognitive abilities. In the present study we investigated whether low-level impairments in the processing of binaural temporal information impact upon auditory scene analysis ability. Binaural temporal processing ability was investigated in 19 individuals with schizophrenia and 19 matched controls. Individuals with schizophrenia showed impaired binaural temporal processing ability on an inter-aural time difference (ITD) discrimination task. In addition, patients demonstrated impairment in two measures of auditory scene analysis. Specifically, patients had reduced ability to use binaural temporal cues to extract signal from noise in a masking level difference paradigm, and to separate the location of a source sound in the presence of an echo in the precedence effect paradigm. These findings demonstrate that individuals with schizophrenia have impairments in the accuracy with which simple binaural temporal information is encoded in the auditory system, and furthermore, this impairment has functional consequences in terms of the use of these cues to extract information in complex auditory environments.	\N	\N
23467261	We tested whether congenital amusics, who exhibit pitch perception deficits, nevertheless adjust the pitch of their voice in response to a sudden pitch shift applied to vocal feedback. Nine amusics and matched controls imitated their own previously-recorded speech or singing, while the online feedback they received was shifted mid-utterance by 25 or 200 cents. While a few amusics failed to show pitch-shift effects, a majority showed a pitch-shift response and nearly half showed a normal response to both large and small shifts, with similar magnitudes and response times as controls. The size and presence of the shift response to small shifts were significantly predicted by participants' vocal pitch matching accuracy, rather than their ability to perceive small pitch changes. The observed dissociation between the ability to consciously perceive small pitch changes and to produce and monitor vocal pitch provides evidence for a dual-route model of pitch processing in the brain.	\N	\N
23472959	The more a novel word conforms to the phonotactics of the language, the more wordlike it is and the easier it is to learn. It is unknown to what extent children with hearing loss (CHL) take advantage of phonotactic cues to support word learning. This study investigated whether CHL had similar sensitivities to wordlikeness during a word-learning task as children with normal hearing (CNH). Sixteen CHL and 24 CNH participated in a novel word-learning task. Novel words varied by English wordlikeness. Recall was tested using a forced-choice identification task wherein foils for each trial related semantically, lexically or not at all. Receptive vocabulary and working memory were also assessed. All children were able to identify high wordlike novel words more accurately than low wordlike novel words. The number of errors on identification of words that were moderate in wordlikeness was inversely correlated to vocabulary size (not working memory) and CHL had smaller vocabularies than CNH. When in error, CHL were more likely than CNH to select a semantically related foil. Although they are sensitive to extremes in wordlikeness, compared with their peers with normal hearing, CHL present with subtle differences in word learning. Clinical implications for exploiting wordlikeness in service of word learning assessment and intervention are presented.	\N	\N
23473799	The Attention Network Test (ANT) assesses the networks of attention (alerting, orienting, and executive control). The utility of measuring attention network performances with the repeated administration of the ANT in clinical populations has not yet been explored. In the present study, we administered a variant of the ANT (ANT-I) to 11 multiple sclerosis (MS) patients and 11 controls over six monthly sessions to examine the stability, isolability, robustness, and reliability of the ANT-I. Participants responded through button presses to indicate the direction of a target arrow presented either above or below a fixation cross. The target was accompanied by distracting arrows, pointing either in the same or opposite direction of the target arrow. Target arrows were preceded in some trials by alerting auditory signals and/or by uninformative visual cues. Network scores were calculated using orthogonal subtractions of performance under selected conditions. The MS patients were slower than the controls, though group differences in network performance were rare. Even after five test sessions, the network scores remained stable, despite some practice effects that were the largest under conditions that tested the executive network. The reliabilities of the orienting and executive network effects were good in both groups and increased across sessions, especially with the MS patients. The alerting network was the least reliable, especially for MS patients, but it also became more reliable across sessions. The results suggest that the ANT-I can be used to measure the integrity of attention networks for MS patients in applications that require repeated testing.	\N	\N
23479475	The human visual system possesses the remarkable ability to pick out salient objects in images. Even more impressive is its ability to do the very same in the presence of disturbances. In particular, the ability persists despite the presence of noise, poor weather, and other impediments to perfect vision. Meanwhile, noise can significantly degrade the accuracy of automated computational saliency detection algorithms. In this article, we set out to remedy this shortcoming. Existing computational saliency models generally assume that the given image is clean, and a fundamental and explicit treatment of saliency in noisy images is missing from the literature. Here we propose a novel and statistically sound method for estimating saliency based on a nonparametric regression framework and investigate the stability of saliency models for noisy images and analyze how state-of-the-art computational models respond to noisy visual stimuli. The proposed model of saliency at a pixel of interest is a data-dependent weighted average of dissimilarities between a center patch around that pixel and other patches. To further enhance the degree of accuracy in predicting the human fixations and of stability to noise, we incorporate a global and multiscale approach by extending the local analysis window to the entire input image, even further to multiple scaled copies of the image. Our method consistently outperforms six other state-of-the-art models (Bruce & Tsotsos, 2009; Garcia-Diaz, Fdez-Vidal, Pardo, & Dosil, 2012; Goferman, Zelnik-Manor, & Tal, 2010; Hou & Zhang, 2007; Seo & Milanfar, 2009; Zhang, Tong, & Marks, 2008) for both noise-free and noisy cases.	\N	\N
23479544	The NIH Toolbox project has assembled measurement tools to assess a wide range of human perception and ability across the lifespan. As part of this initiative, a small but comprehensive battery of auditory tests has been assembled. The main tool of this battery, pure-tone thresholds, measures the ability of people to hear at specific frequencies. Pure-tone thresholds have long been considered the "gold standard" of auditory testing, and are normally obtained in a clinical setting by highly trained audiologists. For the purposes of the Toolbox project, an automated procedure (NIH Toolbox Threshold Hearing Test) was developed that allows nonspecialists to administer the test reliably. Three supplemental auditory tests are also included in the Toolbox auditory test battery: assessment of middle-ear function (tympanometry), speech perception in noise (the NIH Toolbox Words-in-Noise Test), and self-assessment of hearing impairment (the NIH Toolbox Hearing Handicap Inventory Ages 18-64 and the NIH Toolbox Hearing Handicap Inventory Ages 64+). Tympanometry can help differentiate conductive from sensorineural pathology. The NIH Toolbox Words-in-Noise Test measures a listener's ability to perceive words in noisy situations. This ability is not necessarily predicted by a person's pure-tone thresholds; some people with normal hearing have difficulty extracting meaning from speech sounds heard in a noisy context. The NIH Toolbox Hearing Handicap Inventory focuses on how a person's perceived hearing status affects daily life. The test was constructed to include emotional and social/situational subscales, with specific questions about how hearing impairment may affect one's emotional state or limit participation in specific activities. The 4 auditory tests included in the Toolbox auditory test battery cover a range of auditory abilities and provide a snapshot of a participant's auditory capacity.	\N	\N
23483527	We used the visual world paradigm to examine interlingual lexical competition when Dutch-English bilinguals listened to low-constraining sentences in their nonnative (L2; Experiment 1) and native (L1; Experiment 2) languages. Additionally, we investigated the influence of the degree of cross-lingual phonological similarity. When listening in L2, participants fixated more on competitor pictures of which the onset of the name was phonologically related to the onset of the name of the target in the nontarget language (e.g., fles, "bottle", given target flower) than on phonologically unrelated distractor pictures. Even when they listened in L1, this effect was also observed when the onsets of the names of the target picture (in L1) and the competitor picture (in L2) were phonologically very similar. These findings provide evidence for interlingual competition during the comprehension of spoken sentences, both in L2 and in L1.	\N	\N
23485447	With an incidence of 1:29 000 among Caucasians, Friedreich's ataxia (FRDA) is the most common inherited ataxia, leading to both sensory and motor degeneration. Despite many FRDA patients exhibiting normal or near normal sound detection thresholds, many individuals show abnormal neural conduction along their central auditory pathways. Electrophysiological testing can show abnormal or absent cochlear nerve and auditory brainstem recordings in the presence of normal pre-neural cochlear function (otoacoustic emissions or cochlear microphonics). This pattern of normal pre-neural cochlear function and disrupted neural conduction has been termed auditory neuropathy spectrum disorder (ANSD). Studies of FRDA patients with ANSD have shown that they exhibit severe deficits in temporal processing, impaired frequency discrimination, and deficits in speech perception. Rehabilitation of these auditory percept deficits remains difficult, as hearing aids may amplify sounds without adding clarity to the temporally disrupted or distorted signal that FRDA patients with ANSD may receive. There is limited data on the best intervention for patients with FRDA with ANSD, although personal radio aids (FM systems) have been shown to be beneficial. We report a case, where cochlear implantation has led to a dramatic improvement in speech perception in an individual with FRDA and ANSD. The majority of the literature on ANSD treatment has focused on paediatric patients with the 'dyssynchrony' type of ANSD, rather than the true neuropathy type underlying the hearing loss in FRDA patients.	\N	\N
23497238	Auditory feedback is important for accurate control of voice fundamental frequency (F(0)). The purpose of this study was to address whether task instructions could influence the compensatory responding and sensorimotor adaptation that has been previously found when participants are presented with a series of frequency-altered feedback (FAF) trials. Trained singers and musically untrained participants (nonsingers) were informed that their auditory feedback would be manipulated in pitch while they sang the target vowel [/α /]. Participants were instructed to either 'compensate' for, or 'ignore' the changes in auditory feedback. Whole utterance auditory feedback manipulations were either gradually presented ('ramp') in -2 cent increments down to -100 cents (1 semitone) or were suddenly ('constant') shifted down by 1 semitone. Results indicated that singers and nonsingers could not suppress their compensatory responses to FAF, nor could they reduce the sensorimotor adaptation observed during both the ramp and constant FAF trials. Compared to previous research, these data suggest that musical training is effective in suppressing compensatory responses only when FAF occurs after vocal onset (500-2500 ms). Moreover, our data suggest that compensation and adaptation are automatic and are influenced little by conscious control.	\N	\N
23506084	Although adults rapidly adjust to accented speakers' pronunciation of words, young children appear to struggle when confronted with unfamiliar variants of their native language (e.g., American English-learning 15-month-olds cannot recognize familiar words spoken in Jamaican English; Best et al., 2009). It is currently unclear, however, why this is the case, or how infants overcome this apparent inability. Here, we begin to address these crucial questions. Experiments 1 and 2 confirm with a new population that infants are initially unable to recognize familiar words produced in unfamiliar accents. That is, Canadian English-learning infants cannot recognize familiar words spoken in Australian English until they near their second birthday. However, Experiments 3 and 4 show that this early inability to recognize accented words can readily be overcome when infants are exposed to a story read in the unfamiliar accent prior to test. Importantly, this adaptation only occurs when the story is highly familiar, consistent with the idea that top-down lexical feedback may enable the adaptation process. We conclude that infants, like adults, have the cognitive capacity to rapidly deduce the mapping between their own and an unfamiliar variant of their native language. Thus, the essential machinery underlying spoken language communication is in place much earlier than previous studies have suggested.	\N	\N
23507048	Event related potentials (ERP) associated with early sensory information processing have been proposed as possible vulnerability markers for psychosis. Compared to other ERPs reported in schizophrenia research, like Mismatch Negativity (MMN), little is known about P3a, an ERP related to novelty detection. The aim of this study was to analyze the MMN-P3a complex in 20 antipsychotic naïve first-episode psychosis patients (FEP), 23 antipsychotic naïve individuals at clinical high-risk for psychosis (CHR) and 24 healthy controls. The MMN-P3a amplitudes and latencies were obtained during a passive auditory mismatch frequency deviant ERP paradigm and analyzed in frontal and central scalp regions. There were no significant differences in MMN amplitude between groups. There was a significant group difference in P3a due to reduced amplitude (F[2,64] = 3.7, p = 0.03) in both CHR and FEP groups (Mean difference (MD) = 0.39, p = 0.04 and MD = 0.49, p = 0.02, respectively) compared to the control group and this effect was most prominent on the right side (Group × laterality effect: MD = 0.57, p < 0.01 and MD = 0.58, p < 0.01, respectively). No significant differences were observed for MMN or P3a latencies between groups. Although a P3a decrement in chronic schizophrenia and FEP has been previously reported, our results suggest that this novelty detection impairment is present even in pre-psychosis stages in antipsychotic naïve subjects. This study supports the evidence that P3a could represent a neurophysiological vulnerability marker for the development of psychosis.	\N	\N
23510647	Rehabilitation success in cochlear implant patients is influenced by many factors. Influence of different etiologies of deafness on rehabilitation outcome is assessed. Retrospective survey of patients. University hospital. Secondary referral center. One hundred and sixty-three between 1996 and 2008 implanted children (0-18 years, mean 5.17 years). Evaluation of patients' data: origin of deafness, hearing and speech test results. Access Data Base; Wilcoxon and t-test. Mean follow-up: 65.4 months. Etiology of deafness in children found in 104 cases: 69 (51.9%) suffered from hereditary hearing loss. All children showed improvement in their auditory performance, children with connexin-26 mutation performed significantly best, Usher and CHARGE-syndrome children significantly worst. Post-meningitic and post-septic children developed slower but reached same levels later. Primary cause of deafness, among other factors, has a considerable impact on outcome of rehabilitation. This offers possibilities to influence the outcome by etiology-adjusted therapy modules.	\N	\N
23517653	Numerous cortical disorders affect language. We explore the connection between the observed language behavior and the underlying substrates by adopting a neurocomputational approach. To represent the observed trajectories of the discourse in patients with disorganized speech and in healthy participants, we design a graphical representation for the discourse as a trajectory that allows us to visualize and measure the degree of order in the discourse as a function of the disorder of the trajectories. Our work assumes that many of the properties of language production and comprehension can be understood in terms of the dynamics of modular networks of neural associative memories. Based upon this assumption, we connect three theoretical and empirical domains: (1) neural models of language processing and production, (2) statistical methods used in the construction of functional brain images, and (3) corpus linguistic tools, such as Latent Semantic Analysis (henceforth LSA), that are used to discover the topic organization of language. We show how the neurocomputational models intertwine with LSA and the mathematical basis of functional neuroimaging. Within this framework we describe the properties of a context-dependent neural model, based on matrix associative memories, that performs goal-oriented linguistic behavior. We link these matrix associative memory models with the mathematics that underlie functional neuroimaging techniques and present the "functional brain images" emerging from the model. This provides us with a completely "transparent box" with which to analyze the implication of some statistical images. Finally, we use these models to explore the possibility that functional synaptic disconnection can lead to an increase in connectivity between the representations of concepts that could explain some of the alterations in discourse displayed by patients with schizophrenia.	\N	\N
23522843	Aging usually affects the ability to focus attention on a given task and to ignore distractors. However, aging is also associated with increased between-subject variability, and it is unclear in which features of processing older high-performing and low-performing human beings may differ in goal-directed behavior. To study involuntary shifts in attention to task-irrelevant deviant stimuli and subsequent reorientation, we used an auditory distraction task and analyzed event-related potential measures (mismatch negativity), P3a and reorienting negativity) of 35 younger, 32 older high-performing, and 32 older low-performing participants. Although both high and low performing elderly individuals showed a delayed reorienting to the primary stimulus feature, relative to young participants, poor performance of the elderly participants in processing of deviant stimuli was associated with strong involuntary attention capture by task-irrelevant features. In contrast, high performance of the elderly group was associated with intensified attentional shifting toward the target features. Thus, it appears that performance deficits in aging are due to higher distractibility in combination with deficits in the orienting-reorienting mechanisms.	\N	\N
23526255	In this study, we present the normative values of the adaptation of the International Affective Digitized Sounds (IADS-2; Bradley & Lang, 2007a) for European Portuguese (EP). The IADS-2 is a standardized database of 167 naturally occurring sounds that is widely used in the study of emotions. The sounds were rated by 300 college students who were native speakers of EP, in the three affective dimensions of valence, arousal, and dominance, by using the Self-Assessment Manikin (SAM). The aims of this adaptation were threefold: (1) to provide researchers with standardized and normatively rated affective sounds to be used with an EP population; (2) to investigate sex and cultural differences in the ratings of affective dimensions of auditory stimuli between EP and the American (Bradley & Lang, 2007a) and Spanish (Fernández-Abascal et al., Psicothema 20:104-113 2008; Redondo, Fraga, Padrón, & Piñeiro, Behavior Research Methods 40:784-790 2008) standardizations; and (3) to promote research on auditory affective processing in Portugal. Our results indicated that the IADS-2 is a valid and useful database of digitized sounds for the study of emotions in a Portuguese context, allowing for comparisons of its results with those of other international studies that have used the same database for stimulus selection. The normative values of the EP adaptation of the IADS-2 database can be downloaded along with the online version of this article.	\N	\N
23528307	KCNA10 is a voltage gated potassium channel that is expressed in the inner ear. The localization and function of KCNA10 was studied in a mutant mouse, B6-Kcna10(TM45), in which the single protein coding exon of Kcna10 was replaced with a beta-galactosidase reporter cassette. Under the regulatory control of the endogenous Kcna10 promoter and enhancers, beta-galactosidase was expressed in hair cells of the vestibular organs and the organ of Corti. KCNA10 expression develops in opposite tonotopic gradients in the inner and outer hair cells. Kcna10(TM45) homozygotes display only a mild elevation in pure tone hearing thresholds as measured by auditory brainstem response (ABR), while heterozygotes are normal. However, Kcna10(TM45) homozygotes have absent vestibular evoked potentials (VsEPs) or elevated VsEP thresholds with prolonged peak latencies, indicating significant vestibular dysfunction despite the lack of any overt imbalance behaviors. Our results suggest that Kcna10 is expressed primarily in hair cells of the inner ear, with little evidence of expression in other organs. The Kcna10(TM45) targeted allele may be a model of human nonsyndromic vestibulopathy.	\N	\N
23534195	The author investigated the longitudinal relations between theory of mind (ToM) understanding and perceptions of self and social conversations in 17 school-aged children (12 girls, 5 boys, age 8-12 years). ToM was assessed at Time 1 (T1; M age = 8 years 5 months, SD = 8.7 months, and perceptions of self and conversational experiences assessed two years later at Time 2 (T2; M age = 10 years 4 months, SD = 7.9 months. Most importantly, longitudinal findings showed that children who scored relatively high on ToM at T1 reported relatively lower perceptions of self-worth and higher number of mental states verbs in their perceptions of peer and family conversations at T2. Significant negative longitudinal associations were found between children's number of siblings and their perceptions of self-worth (T1) and number of cognitive terms in their perceptions of peer and family conversations (T2). Frequency analysis suggested that girls' perceptions of conversations referred to more social and psychological aspects of self and relationships, whereas boys focused mainly on physical activities. Most children were more likely to prefer listening to talking during social conversations. The majority of children reported feelings of mixed or ambiguous emotions during experiences of silence. Implications for socioemotional and cognitive development in early adolescents are discussed.	\N	\N
23538131	A total of 64 loci for autosomal dominant non-syndromic hearing impairment have been described, and the causative genes have been identified for 24 of these. The present study reports on the clinical characteristics of an autosomal dominantly inherited hearing impairment that is linked to a region within the DFNA60 locus located on chromosome 2 in q22.1-24.1. A pedigree spanning four generations was established with 13 affected individuals. Linkage analysis demonstrated that the locus extended over a 2.96 Mb region flanked by markers D2S2335 and D2S2275. The audiograms mainly showed a distinctive U-shaped configuration. Deterioration of hearing started at a wide age range, from 12 to 40 years. Cross-sectional analysis showed rapid progression of hearing impairment from mild to severe, between the ages of 40 and 60 years, a phenomenon that is also observed in DFNA9 patients. The results of the individual longitudinal analyses were generally in line with those obtained by the cross-sectional analysis. Speech recognition scores related to the level of hearing impairment (PTA1,2,4 kHz) appeared to be fairly similar to those of presbyacusis patients. It is speculated that hearing impairment starting in mid-life, as shown by DFNA60 patients, could play a role in the development of presbyacusis. Furthermore, speech recognition did not deteriorate appreciably before the sixth decade of life. We conclude that DFNA60 should be considered in hearing impaired patients who undergo a rapid progression in middle age and are negative for DFNA9. Furthermore, cochlear implantation resulted in good rehabilitation in two DFNA60 patients.	\N	\N
23538912	Experiences of adversity in the early years of life alter the developing brain. However, evidence documenting this relationship often focuses on severe stressors and relies on peripheral measures of neurobiological functioning during infancy. In the present study, we employed functional MRI during natural sleep to examine associations between a more moderate environmental stressor (nonphysical interparental conflict) and 6- to 12-month-old infants' neural processing of emotional tone of voice. The primary question was whether interparental conflict experienced by infants is associated with neural responses to emotional tone of voice, particularly very angry speech. Results indicated that maternal report of higher interparental conflict was associated with infants' greater neural responses to very angry relative to neutral speech across several brain regions implicated in emotion and stress reactivity and regulation (including rostral anterior cingulate cortex, caudate, thalamus, and hypothalamus). These findings suggest that even moderate environmental stress may be associated with brain functioning during infancy.	\N	\N
23551061	The N1 and P2 event-related potentials (ERPs) are attenuated when the eliciting sounds coincide with our own actions. Although this ERP attenuation could be caused by central processes, it may also reflect a peripheral mechanism: the coactivation of the stapedius muscle with the task-relevant effector, which reduces signal transmission efficiency in the middle ear, reducing the effective intensity of concurrently presented tones, which, in turn, elicit lower amplitude auditory ERPs. Because stapedius muscle contraction attenuates frequencies below 2 kHz, no attenuation should occur at frequencies above 2 kHz. A self-induced tone paradigm was administered with 0.5, 2.0, and 8.0 kHz pure tones. Self-induced tones elicited attenuated N1 and P2 ERPs, but the magnitude of attenuation was not affected by tone frequency. This result does not support the hypothesis that ERP attenuation to self-induced tones are caused by stapedius muscle contractions.	\N	\N
23553325	Sound pressure level delivered through personal listening devices (PLDs) and reaching the ear drum might be affected by body size and jaw movements. This study aimed to investigate whether jaw movement and/or smaller body mass index (BMI) resulted in decrease of sound pressure level within the ear canals of PLD users via an earbud earphone. Case series. Forty-five normal-hearing subjects (16 males; mean age, 23.3 years) participated in this study. A probe-microphone system was used to measure sound pressure level in the external ear canal with music delivered from a media player via an earbud earphone. Test materials consisted of two 20-second excerpts from a heavy metal music piece. Subjects were instructed to adjust the volume of the media player to conform to three conditions for sound pressure measurement: comfortable, loud, and maximum. Measurements were then repeated while subjects mimicked chewing action under the same listening conditions. Sound pressure levels were significantly lower when measured with jaw movement than without jaw movement (P < .05). Sound pressure levels monitored with/without jaw movement were generally lower in subjects with a BMI<23 than those with a BMI ≥ 23 (P < .05). Jaw movement and low BMI (<23) reduced the overall sound level of PLDs at the ear canal. Sound pressure levels detected in the external ear canal of our subjects using earbud earphones were significantly lower under conditions of jaw movement/BMI <23. Our research invites further studies on a larger group of PLD users to correlate these variables with hearing threshold shifts over time.	\N	\N
23556595	Although bilateral cochlear implantation has the potential to improve sound localization and speech understanding in noise, obstacles exist in presenting maximally useful binaural information to bilateral cochlear-implant (CI) users. One obstacle is that electrode arrays may differ in cochlear position by several millimeters, thereby stimulating different neural populations. Effects of interaural frequency mismatch on binaural processing were studied in normal-hearing (NH) listeners using band-limited pulse trains, thereby avoiding confounding factors that may occur in CI users. In experiment 1, binaural image fusion was measured to capture perceptual number, location, and compactness. Subjects heard a single, compact image on 73% of the trials. In experiment 2, intracranial image location was measured for different interaural time differences (ITDs) and interaural level differences (ILDs). For larger mismatch, locations perceptually shifted towards the ear with the higher carrier frequency. In experiment 3, ITD and ILD just-noticeable differences (JNDs) were measured. JNDs increased with decreasing bandwidth and increasing mismatch, but were always measurable up to 3 mm of mismatch. If binaural-hearing mechanisms are similar between NH and CI subjects, these results may explain reduced sensitivity of ITDs and ILDs in CI users. Large mismatches may lead to distorted spatial maps and reduced binaural image fusion.	\N	\N
23556693	Talking silently to ourselves occupies much of our mental lives, yet the mechanisms underlying this experience remain unclear. The following experiments provide behavioral evidence that the auditory content of inner speech is provided by corollary discharge. Corollary discharge is the motor system's prediction of the sensory consequences of its actions. This prediction can bias perception of other sensations, pushing percepts to match with prediction. The two experiments below show this bias induced by inner speech, demonstrating that inner speech causes external sounds to be heard as similar to the imagined speech, and that this bias operates on subphonemic content.	\N	\N
23565267	Psychophysiological evidence suggests that music and language are intimately coupled such that experience/training in one domain can influence processing required in the other domain. While the influence of music on language processing is now well-documented, evidence of language-to-music effects have yet to be firmly established. Here, using a cross-sectional design, we compared the performance of musicians to that of tone-language (Cantonese) speakers on tasks of auditory pitch acuity, music perception, and general cognitive ability (e.g., fluid intelligence, working memory). While musicians demonstrated superior performance on all auditory measures, comparable perceptual enhancements were observed for Cantonese participants, relative to English-speaking nonmusicians. These results provide evidence that tone-language background is associated with higher auditory perceptual performance for music listening. Musicians and Cantonese speakers also showed superior working memory capacity relative to nonmusician controls, suggesting that in addition to basic perceptual enhancements, tone-language background and music training might also be associated with enhanced general cognitive abilities. Our findings support the notion that tone language speakers and musically trained individuals have higher performance than English-speaking listeners for the perceptual-cognitive processing necessary for basic auditory as well as complex music perception. These results illustrate bidirectional influences between the domains of music and language.	\N	\N
23571299	A variety of noises have been employed for decades in an effort to facilitate habituation, mask, or suppress tinnitus. Many of these sounds have reportedly provided benefit, but success has not been universal. More recently, musical stimuli have been added as a sound therapy component. The potential advantages of using such stimuli, in particular fractal tones, in combination with amplification are discussed in this paper.	\N	\N
23571301	The past decade has seen an escalating enthusiasm to comprehend chronic tinnitus from the perspective of both scientific understanding and clinical management. At the same time, there is a significant interest and commercial investment in providing targeted and individualized approaches to care, which incorporate novel sound-based technologies, with standard audiological and psychological strategies. Commercially produced sound-based devices for the tinnitus market include Co-ordinated Reset Neuromodulation ® , Neuromonics © , Serenade ® , and Widex ® Zen. Additionally, experimental interventions such as those based on frequency-discrimination training are of current interest. Many of these interventions overtly claim to target the underlying neurological causes of tinnitus. Here, we briefly summarize current perspectives on the pathophysiology of tinnitus and evaluate claims made by the device supporters from a critical point of view. We provide an opinion on how future research in the field of individualized sound-based interventions might best provide a reliable evidence-base in this growing area of translational medicine.	\N	\N
23577828	Mismatch negativity (MMN) overlaps with other auditory event-related potential (ERP) components. We examined the ERPs of 50 9- to 11-year-old children for vowels /i/, /y/ and equivalent complex tones. The goal was to separate MMN from obligatory ERP components using principal component analysis and equal probability control condition. In addition to the contrast of the deviant minus standard response, we employed the contrast of the deviant minus control response, to see whether the obligatory processing contributes to MMN in children. When looking for differences in speech deviant minus standard contrast, MMN starts around 112 ms. However, when both contrasts are examined, MMN emerges for speech at 160 ms whereas for nonspeech MMN is observed at 112 ms regardless of contrast. We argue that this discriminative response to speech stimuli at 112 ms is obligatory in nature rather than reflecting change detection processing.	\N	\N
23578016	Music is a cultural universal and a rich part of the human experience. However, little is known about common brain systems that support the processing and integration of extended, naturalistic 'real-world' music stimuli. We examined this question by presenting extended excerpts of symphonic music, and two pseudomusical stimuli in which the temporal and spectral structure of the Natural Music condition were disrupted, to non-musician participants undergoing functional brain imaging and analysing synchronized spatiotemporal activity patterns between listeners. We found that music synchronizes brain responses across listeners in bilateral auditory midbrain and thalamus, primary auditory and auditory association cortex, right-lateralized structures in frontal and parietal cortex, and motor planning regions of the brain. These effects were greater for natural music compared to the pseudo-musical control conditions. Remarkably, inter-subject synchronization in the inferior colliculus and medial geniculate nucleus was also greater for the natural music condition, indicating that synchronization at these early stages of auditory processing is not simply driven by spectro-temporal features of the stimulus. Increased synchronization during music listening was also evident in a right-hemisphere fronto-parietal attention network and bilateral cortical regions involved in motor planning. While these brain structures have previously been implicated in various aspects of musical processing, our results are the first to show that these regions track structural elements of a musical stimulus over extended time periods lasting minutes. Our results show that a hierarchical distributed network is synchronized between individuals during the processing of extended musical sequences, and provide new insight into the temporal integration of complex and biologically salient auditory sequences.	\N	\N
23580330	Schumacher et al. Psychological Science 12:101-108, (2001) demonstrated the elimination of most dual-task costs ("perfect time-sharing") after extensive dual-task practice of a visual and an auditory task in combination. For the present research, we used a transfer methodology to examine this practice effect in more detail, asking what task-processing stages were sped up by this dual-task practice. Such research will be essential to specify mechanisms associated with the practice-related elimination of dual-task costs. In three experiments, we introduced postpractice transfer probes focusing on the perception, central response-selection, and final motor-response stages. The results indicated that the major change achieved by dual-task practice was a speed-up in the central response-selection stages of both tasks. Additionally, perceptual-stage shortening of the auditory task was found to contribute to the improvements in time-sharing. For a better understanding of such time-sharing, we discuss the contributions of the present findings in relation to models of practiced dual-task performance.	\N	\N
23585888	To localize the neural generators of the musically elicited mismatch negativity with high temporal resolution we conducted a beamformer analysis (Synthetic Aperture Magnetometry, SAM) on magnetoencephalography (MEG) data from a previous musical mismatch study. The stimuli consisted of a six-tone melodic sequence comprising broken chords in C- and G-major. The musical sequence was presented within an oddball paradigm in which the last tone was lowered occasionally (20%) by a minor third. The beamforming analysis revealed significant right hemispheric neural activation in the superior temporal (STC), inferior frontal (IFC), superior frontal (SFC) and orbitofrontal (OFC) cortices within a time window of 100-200 ms after the occurrence of a deviant tone. IFC and SFC activation was also observed in the left hemisphere. The pronounced early right inferior frontal activation of the auditory mismatch negativity has not been shown in MEG studies so far. The activation in STC and IFC is consistent with earlier electroencephalography (EEG), optical imaging and functional magnetic resonance imaging (fMRI) studies that reveal the auditory and inferior frontal cortices as main generators of the auditory MMN. The observed right hemispheric IFC is also in line with some previous music studies showing similar activation patterns after harmonic syntactic violations. The results demonstrate that a deviant tone within a musical sequence recruits immediately a distributed neural network in frontal and prefrontal areas suggesting that top-down processes are involved when expectation violation occurs within well-known stimuli.	\N	\N
23586418	The neural dys-synchrony associated with auditory neuropathy spectrum disorder (ANSD) causes a temporal impairment that could degrade spatial hearing, particularly sound localization accuracy (SLA) and spatial release from masking (SRM). Unilateral cochlear implantation has become an accepted treatment for ANSD but treatment options for the contralateral ear remain controversial. We report spatial hearing measures in a child with ANSD before and after receiving a second cochlear implant (CI). An 11-year-7-month old boy with ANSD and expressive and receptive language delay received a second CI eight years after his first implant. The SLA and SRM were measured four months before sequential bilateral CIs (with the contralateral ear plugged and unplugged), and after nine months using both CIs. Testing done before the second CI, with the first CI alone, suggested that residual hearing in the contralateral ear contributed to sound localization accuracy, but not word recognition in quiet or noise. Nine-months after receiving a second CI, SLA improved by 12.76° and SRM increased to 3.8-4.2 dB relative to pre-operative performance. Results were compared to published outcomes for children with bilateral CIs. The addition of a second CI in this child with ANSD improved spatial hearing.	\N	\N
23587808	Whether visual subliminal processing involves semantic processing is still being debated. To examine this, we combined a passive electroencephalogram (EEG) study with an application of transcranial direct current stimulation (tDCS). In the masked-face priming paradigm, we presented a subliminal prime preceding the target stimulus. Participants were asked to determine whether the target face was a famous face, indicated by a button press. The prime and target pair were either the same person's face (congruent) or different person's faces (incongruent), and were always both famous or both non-famous faces. Experiments were performed over 2 days: 1 day for a real tDCS session and another for a sham session as a control condition. In the sham session, a priming effect, reflected in the difference in amplitude of the late positive component (250-500 ms to target onset), was observed only in the famous prime condition. According to a previous study, this effect might indicate a subliminal semantic process [10]. Alternatively, a priming effect toward famous primes disappeared after tDCS stimulation. Our results suggested that a subliminal process might not be limited to processes in the occipital and temporal areas, but may proceed to the semantic level processed in prefrontal cortex.	\N	\N
23616587	Congenital amusia is a lifelong disorder of music perception and production. The present study investigated the cerebral bases of impaired pitch perception and memory in congenital amusia using behavioural measures, magnetoencephalography and voxel-based morphometry. Congenital amusics and matched control subjects performed two melodic tasks (a melodic contour task and an easier transposition task); they had to indicate whether sequences of six tones (presented in pairs) were the same or different. Behavioural data indicated that in comparison with control participants, amusics' short-term memory was impaired for the melodic contour task, but not for the transposition task. The major finding was that pitch processing and short-term memory deficits can be traced down to amusics' early brain responses during encoding of the melodic information. Temporal and frontal generators of the N100m evoked by each note of the melody were abnormally recruited in the amusic brain. Dynamic causal modelling of the N100m further revealed decreased intrinsic connectivity in both auditory cortices, increased lateral connectivity between auditory cortices as well as a decreased right fronto-temporal backward connectivity in amusics relative to control subjects. Abnormal functioning of this fronto-temporal network was also shown during the retention interval and the retrieval of melodic information. In particular, induced gamma oscillations in right frontal areas were decreased in amusics during the retention interval. Using voxel-based morphometry, we confirmed morphological brain anomalies in terms of white and grey matter concentration in the right inferior frontal gyrus and the right superior temporal gyrus in the amusic brain. The convergence between functional and structural brain differences strengthens the hypothesis of abnormalities in the fronto-temporal pathway of the amusic brain. Our data provide first evidence of altered functioning of the auditory cortices during pitch perception and memory in congenital amusia. They further support the hypothesis that in neurodevelopmental disorders impacting high-level functions (here musical abilities), abnormalities in cerebral processing can be observed in early brain responses.	\N	\N
23621479	In some cochlear implant users, success is not achieved in spite of optimal clinical factors (including age at implantation, duration of rehabilitation and post-implant hearing level), which may be attributed to disorders at higher levels of the auditory pathway. We used cortical auditory evoked potentials to investigate the ability to perceive and discriminate auditory stimuli in 10 unsuccessful implant users aged 8-10 years (CI) and 10 healthy age-matched controls with normal hearing (NH). Pure tones (1 and 2 kHz) and double consonant-vowel syllables were applied. The stimuli were presented in an oddball paradigm that required the subjects to react consciously. The latencies and amplitudes of the P1, N1, P2, N2 and P3 waves were analyzed, in addition to reaction times and number of responses. Significant differences in the average response times and number of responses were observed between the CI and NH groups. The latencies also indicate that the CI group took longer to perceive and discriminate between tonal and speech auditory stimuli than the NH group.	\N	\N
23625644	In this study we provide evidence that unconscious priming can be obtained as a result of the processing of the salient region (SR) of illusory figures and without that of illusory contours (ICs). We used a metacontrast masking paradigm where illusory figures were masked by real figures. In Experiment 1 we found a clear priming effect when participants were asked to discriminate between square and diamond masks preceded by congruent or incongruent illusory square or diamond primes. It is likely that metacontrast impairs the processing of ICs but not of the SR; therefore the above result strongly suggests that the priming effect was specifically related to the processing of the SR. In Experiment 2 participants were tested in the same task as in Experiment 1 with additional primes in which the inducers were presented in the same locations but their shapes were changed so as to modify the global configuration. We termed these primes High, Low, and No Salient Region (HSR, LSR, and NSR, respectively). The HSR condition replicated Experiment 1, whereas in the LSR and NSR conditions the priming effect got progressively smaller. The results of Experiment 1 were replicated with the priming effect significantly larger in the HSR than in all other conditions. It was also larger in the HSR than in LSR condition and smallest but still present in the NSR condition. Taken together, these results indicate that the unconscious processing of only the SR yields a priming effect and that a reduction of the saliency of the SR leads to a reduction of the priming effect, while its elimination does not abolish it.	\N	\N
23627625	Fully auditory Brain-computer interfaces based on the dichotic listening task (DL-BCIs) are suited for users unable to do any muscular movement, which includes gazing, exploration or coordination of their eyes looking for inputs in form of feedback, stimulation or visual support. However, one of their disadvantages, in contrast with the visual BCIs, is their lower performance that makes them not adequate in applications that require a high accuracy. To overcome this disadvantage, we employed a Bayesian approach in which the DL-BCI was modeled as a Binary phase shift keying receiver for which the accuracy can be estimated a priori as a function of the signal-to-noise ratio. The results showed the measured accuracy to match the predefined target accuracy, thus validating this model that made possible to estimate in advance the classification accuracy on a trial-by-trial basis. This constitutes a novel methodology in the design of fully auditory DL-BCIs that let us first, define the target accuracy for a specific application and second, classify when the signal-to-noise ratio guarantees that target accuracy.	\N	\N
23633439	This study combines functional and structural magnetic resonance imaging to test the "asymmetric sampling in time" (AST) hypothesis, which makes assertions about the symmetrical and asymmetrical representation of speech in the primary and nonprimary auditory cortex. Twenty-three volunteers participated in this parametric clustered-sparse fMRI study. The availability of slowly changing acoustic cues in spoken sentences was systematically reduced over continuous segments with varying lengths (100, 150, 200, 250 ms) by utilizing local time-reversion. As predicted by the hypothesis, functional lateralization in Heschl's gyrus could not be observed. Lateralization in the planum temporale and posterior superior temporal gyrus shifted towards the right hemisphere with decreasing suprasegmental temporal integrity. Cortical thickness of the planum temporale was automatically measured. Participants with an L > R cortical thickness performed better on the in-scanner auditory pattern-matching task. Taken together, these findings support the AST hypothesis and provide substantial novel insight into the division of labor between left and right nonprimary auditory cortex functions during comprehension of spoken utterances. In addition, the present data yield support for a structural-behavioral relationship in the nonprimary auditory cortex.	\N	\N
23633643	The purpose of this study was to determine the effect of oral reading expressiveness on the comprehension of storybooks by 4- and 5-year-old prekindergarten children. The possible impact of prosody on listening comprehension was explored. Ninety-two prekindergarten children (M age = 57.26 months, SD = 3.89 months) listened to an expressive or inexpressive recording of 1 of 2 similar stories. Story comprehension was tested using assessments of both free recall and cued recall. Children showed statistically significantly better cued recall for the expressive readings of stories compared to the inexpressive readings of stories. This effect generalized across stories and when story length was controlled across both expressive and inexpressive versions. The effect of expressiveness on children's free recall was not significant. Highly expressive readings resulted in better comprehension of storybooks by prekindergarten children. Further, because recordings were used, this effect might be attributed to the facilitation of language processing rather than to enhanced social interaction between the reader and the child.	\N	\N
23645715	Even though language allows us to say exactly what we mean, we often use language to say things indirectly, in a way that depends on the specific communicative context. For example, we can use an apparently straightforward sentence like "It is hard to give a good presentation" to convey deeper meanings, like "Your talk was a mess!" One of the big puzzles in language science is how listeners work out what speakers really mean, which is a skill absolutely central to communication. However, most neuroimaging studies of language comprehension have focused on the arguably much simpler, context-independent process of understanding direct utterances. To examine the neural systems involved in getting at contextually constrained indirect meaning, we used functional magnetic resonance imaging as people listened to indirect replies in spoken dialog. Relative to direct control utterances, indirect replies engaged dorsomedial prefrontal cortex, right temporo-parietal junction and insula, as well as bilateral inferior frontal gyrus and right medial temporal gyrus. This suggests that listeners take the speaker's perspective on both cognitive (theory of mind) and affective (empathy-like) levels. In line with classic pragmatic theories, our results also indicate that currently popular "simulationist" accounts of language comprehension fail to explain how listeners understand the speaker's intended message.	\N	\N
23648960	Speech perception requires the effortless mapping from smooth, seemingly continuous changes in sound features into discrete perceptual units, a conversion exemplified in the phenomenon of categorical perception. Explaining how/when the human brain performs this acoustic-phonetic transformation remains an elusive problem in current models and theories of speech perception. In previous attempts to decipher the neural basis of speech perception, it is often unclear whether the alleged brain correlates reflect an underlying percept or merely changes in neural activity that covary with parameters of the stimulus. Here, we recorded neuroelectric activity generated at both cortical and subcortical levels of the auditory pathway elicited by a speech vowel continuum whose percept varied categorically from /u/ to /a/. This integrative approach allows us to characterize how various auditory structures code, transform, and ultimately render the perception of speech material as well as dissociate brain responses reflecting changes in stimulus acoustics from those that index true internalized percepts. We find that activity from the brainstem mirrors properties of the speech waveform with remarkable fidelity, reflecting progressive changes in speech acoustics but not the discrete phonetic classes reported behaviorally. In comparison, patterns of late cortical evoked activity contain information reflecting distinct perceptual categories and predict the abstract phonetic speech boundaries heard by listeners. Our findings demonstrate a critical transformation in neural speech representations between brainstem and early auditory cortex analogous to an acoustic-phonetic mapping necessary to generate categorical speech percepts. Analytic modeling demonstrates that a simple nonlinearity accounts for the transformation between early (subcortical) brain activity and subsequent cortical/behavioral responses to speech (>150-200 ms) thereby describing a plausible mechanism by which the brain achieves its acoustic-to-phonetic mapping. Results provide evidence that the neurophysiological underpinnings of categorical speech are present cortically by ~175 ms after sound enters the ear.	\N	\N
23651462	To develop and evaluate a 12-item version of the Speech, Spatial and Qualities of Hearing scale for use in clinical research and rehabilitation settings, and provide a formula for converting scores between the full (SSQ49) and abbreviated (SSQ12) versions. Items were selected independently at the three centres (Eriksholm Research Centre, MRC Institute of Hearing Research, University of New England) to be representative of the complete scale. A consensus was achieved after discussion. The data set (n = 1220) used for a factor analysis (Akeroyd et al, submitted) was re-analysed to compare original SSQ scores (SSQ49) with scores on the short version (SSQ12). A scatter-plot of SSQ12 scores against SSQ49 scores showed that SSQ12 score was about 0.6 of a scale point lower than the SSQ49 (0-10 scale) in the re-analysis of the Akeroyd et al data. SSQ12 scores lay on a slightly steeper slope than scores on the SSQ49. The SSQ12 provides similar results to SSQ49 in a large clinical research sample. The slightly lower average SSQ12 score and the slightly steeper slope reflect the composition of this short form relative to the SSQ49.	\N	\N
23652327	To compare speech understanding of the BAHA BP110 and BAHA Intenso sound processors. Prospective experimental study. Tertiary referral center. Twenty experienced user of osseointegrated auditory implants with conductive or mixed hearing loss. In a first session, half of the participants were fitted with an Intenso, the other half with a BP110. After 1 month of use, aided speech understanding in quiet and in noise was measured, and the other test processor was fitted. One month later, speech understanding with the second sound processor was assessed. Speech understanding in quiet and in noise, with noise arriving either from the front, the rear, or the side of the user with the osseointegrated bone conductor. Significant improvements were found for both processors for speech understanding in quiet (+9.6 to +34.8 percent points; p = 0.02 to 0.001) and in noise (+6.2 to +13.8 dB, p < 0.001). No significant differences were found between the 2 devices for speech in quiet. For noise from the rear, subjects were able to understand speech at signal-to-noise ratios which were lower (less favorable) by -5.1 dB (p < 0.001) when compared with the Intenso. Speech understanding is substantially improved by both devices, with no significant differences between the sound processors in quiet. In noise, speech understanding is significantly better with the BP110 when compared to the Intenso for noise from the rear.	\N	\N
23654396	Chen et al. [J. Acoust. Soc. Am. 131, 2987-2998 (2012)] evaluated the effectiveness of an algorithm for enhancing spectral changes over time in improving the intelligibility of speech in background sounds for hearing-impaired subjects. The processing improved intelligibility for speech in steady speech-spectrum noise (SSN) but tended to impair intelligibility in a background of two-talker speech (TTS). Large individual differences were found. The present study assessed whether the effectiveness of the algorithm was improved when the parameters that controlled the degree and type of enhancement were chosen individually for each subject, using a genetic algorithm based on subjective preferences for speech clarity. The parameter values selected by the genetic algorithm varied markedly across subjects. Speech intelligibility was measured for unprocessed stimuli and stimuli processed using the selected parameters, with SSN and TTS maskers and two signal-to-masker ratios (SMRs) for each subject. The intelligibility of speech in the SSN masker at the lower SMR was improved about 14 percentage points by the processing. The overall improvement produced by the processing was significantly larger than the improvement observed in the previous study when the parameter values were fixed across subjects, indicating that use of the genetic algorithm was beneficial.	\N	\N
23659894	Attentional problems are commonly reported as a feature of the behavioural profile in both Williams syndrome (WS) and Down's syndrome (DS). Recent studies have begun to investigate these impairments empirically, acknowledging the need for an approach that considers cross-syndrome comparisons and developmental changes across the different component functions of attention. The present study assessed children with WS and DS using a new preschool attention battery (ECAB: early childhood attention battery), designed to be suitable for mental age 3-6 years including groups with developmental disorders. The ECAB has the advantage of giving an individual profile of attentional abilities for each child, covering different components of attention. In relation to test norms for their mental age, both groups showed a profile of strengths and weaknesses in the attention domain. Both syndrome groups performed relatively well on tests of sustained attention and poorly on aspects of selective attention and attentional control (executive function). The DS group showed a specific strength in auditory sustained attention, whilst the WS group showed a particular deficit in visuo-spatial response control. There was also evidence for considerable differences in the developmental trajectory of these abilities across the two groups. The results provide evidence for syndrome-specific patterns of impairment, and distinct profiles of strengths and weaknesses that may be useful in understanding the nature of everyday attention difficulties in these groups and tailoring interventions to meet these needs.	\N	\N
23664833	Here, we applied a multi-feature mismatch negativity (MMN) paradigm in order to systematically investigate the neuronal representation of vowels and temporally manipulated CV syllables in a homogeneous sample of string players and non-musicians. Based on previous work indicating an increased sensitivity of the musicians' auditory system, we expected to find that musically trained subjects will elicit increased MMN amplitudes in response to temporal variations in CV syllables, namely voice-onset time (VOT) and duration. In addition, since different vowels are principally distinguished by means of frequency information and musicians are superior in extracting tonal (and thus frequency) information from an acoustic stream, we also expected to provide evidence for an increased auditory representation of vowels in the experts. In line with our hypothesis, we could show that musicians are not only advantaged in the pre-attentive encoding of temporal speech cues, but most notably also in processing vowels. Additional "just noticeable difference" measurements suggested that the musicians' perceptual advantage in encoding speech sounds was more likely driven by the generic constitutional properties of a highly trained auditory system, rather than by its specialisation for speech representations per se. These results shed light on the origin of the often reported advantage of musicians in processing a variety of speech sounds.	\N	\N
23683806	The present study aimed to investigate the vocal tract and glottal function during and after phonation into a tube and a stirring straw. A male classically trained singer was assessed. Computerized tomography (CT) was performed when the subject produced [a:] at comfortable speaking pitch, phonated into the resonance tube and when repeating [a:] after the exercise. Similar procedure was performed with a narrow straw after 15 minutes silence. Anatomic distances and area measures were obtained from CT midsagittal and transversal images. Acoustic, perceptual, electroglottographic (EGG), and subglottic pressure measures were also obtained. During and after phonation into the tube or straw, the velum closed the nasal passage better, the larynx position lowered, and hypopharynx area widened. Moreover, the ratio between the inlet of the lower pharynx and the outlet of the epilaryngeal tube became larger during and after tube/straw phonation. Acoustic results revealed a stronger spectral prominence in the singer/speaker's formant cluster region after exercising. Listening test demonstrated better voice quality after straw/tube than before. Contact quotient derived from EGG decreased during both tube and straw and remained lower after exercising. Subglottic pressure increased during straw and remained somewhat higher after it. CT and acoustic results indicated that vocal exercises with increased vocal tract impedance lead to increased vocal efficiency and economy. One of the major changes was the more prominent singer's/speaker's formant cluster. Vocal tract and glottal modifications were more prominent during and after straw exercising compared with tube phonation.	\N	\N
23684420	Bilateral cochlear implant (CI) users encounter difficulties in localizing sound sources in everyday environments, especially in the presence of background noise and reverberation. They tend to show large directional errors and front-back confusions compared to normal hearing (NH) subjects in the same conditions. In this study, the ability of bilateral CI users to use head movements to improve sound source localization was evaluated. Speech sentences of 0.5, 2, and 4.5 seconds were presented in noise to the listeners in conditions with and without head movements. The results show that for middle and long signal durations, the CI users could significantly reduce the number of front-back confusions. The angular accuracy, however, did not improve. Analysis of head trajectories showed that the CI users had great difficulties in moving their head towards the position of the source, whereas the NH listeners targeted the source loudspeaker correctly.	\N	\N
23686398	Morphology of the human brain predicts the speed at which individuals learn to distinguish novel foreign speech sounds after laboratory training. However, little is known about the neuroanatomical basis of individual differences in speech perception when a second language (L2) has been learned in natural environments for extended periods of time. In the present study, two samples of highly proficient bilinguals were selected according to their ability to distinguish between very similar L2 sounds, either isolated (prelexical) or within words (lexical). Structural MRI was acquired and processed to estimate vertex-wise indices of cortical thickness (CT) and surface area (CSA), and the association between cortical morphology and behavioral performance was inspected. Results revealed that performance in the lexical task was negatively associated with the thickness of the left temporal cortex and angular gyrus, as well as with the surface area of the left precuneus. Our findings, consistently with previous fMRI studies, demonstrate that morphology of the reported areas is relevant for word recognition based on phonological information. Further, we discuss the possibility that increased CT and CSA in sound-to-meaning mapping regions, found for poor non-native speech sounds perceivers, would have plastically arisen after extended periods of increased functional activity during L2 exposure.	\N	\N
23688330	A sequence of constant-frequency tones can promote streaming in a subsequent sequence of alternating-frequency tones, but why this effect occurs is not fully understood and its time course has not been investigated. Experiment 1 used a 2.0-s-long constant-frequency inducer (10 repetitions of a low-frequency pure tone) to promote segregation in a subsequent, 1.2-s test sequence of alternating low- and high-frequency tones. Replacing the final inducer tone with silence substantially reduced reported test-sequence segregation. This reduction did not occur when either the 4th or 7th inducer was replaced with silence. This suggests that a change at the induction/test-sequence boundary actively resets build-up, rather than less segregation occurring simply because fewer inducer tones were presented. Furthermore, Experiment 2 found that a constant-frequency inducer produced its maximum segregation-promoting effect after only three tones--this contrasts with the more gradual build-up typically observed for alternating-frequency sequences. Experiment 3 required listeners to judge continuously the grouping of 20-s test sequences. Constant-frequency inducers were considerably more effective at promoting segregation than alternating ones; this difference persisted for ∼10 s. In addition, resetting arising from a single deviant (longer tone) was associated only with constant-frequency inducers. Overall, the results suggest that constant-frequency inducers promote segregation by capturing one subset of test-sequence tones into an ongoing, preestablished stream, and that a deviant tone may reduce segregation by disrupting this capture. These findings offer new insight into the dynamics of stream segregation, and have implications for the neural basis of streaming and the role of attention in stream formation.	\N	\N
23689300	Evaluation of speech perception in noisy environments for normally hearing children was conducted in order to provide normal data for speech perception testing in children with hearing impairments thus improving early intervention alternatives for Mandarin-speaking children with hearing impairments. The speech perception abilities of 174 developmentally normal children ranging aged 2-5 years, in four age groups, were evaluated in environments that were quiet or with high levels of competing noise using the Mandarin pediatric speech intelligibility (MPSI) test. The mean score of MPSI between the four age groups showed notable statistical differences, including a variation in mean score between the four age groups, clearly indicating that the speech perception abilities of young children in noisy environments improved greatly with age, most notably between the ages of 3 and 4 years old. Speech perception ability in noisy environments was shown to be significantly, but weakly, related to age, implying the presence of other, possibly environment factors, in speech perception development. Furthermore, no statistically significant difference between boys and girls was noted in the experimental MPSI scores. The ability of children to increasingly perceive speech in environments containing high competing noise levels was shown to gradually and progressively increase with age. These results indicated that the developing Mandarin speech perception abilities in noisy environments in normal hearing children develops substantially after the age of 3-4 years, suggesting that similar age ranges may be even more critical intervention points for children with hearing impairments. More studies are still needed to confirm that.	\N	\N
23696279	The constituent elements and dynamics of the networks responsible for word production are a central issue to understanding human language. Of particular interest is their dependency on lexical category, particularly the possible segregation of nouns and verbs into separate processing streams. We applied a novel mixed-effects, multilevel analysis to electrocorticographic data collected from 19 patients (1942 electrodes) to examine the activity of broadly disseminated cortical networks during the retrieval of distinct lexical categories. This approach was designed to overcome the issues of sparse sampling and individual variability inherent to invasive electrophysiology. Both noun and verb generation evoked overlapping, yet distinct nonhierarchical processes favoring ventral and dorsal visual streams, respectively. Notable differences in activity patterns were noted in Broca's area and superior lateral temporo-occipital regions (verb > noun) and in parahippocampal and fusiform cortices (noun > verb). Comparisons with functional magnetic resonance imaging (fMRI) results yielded a strong correlation of blood oxygen level-dependent signal and gamma power and an independent estimate of group size needed for fMRI studies of cognition. Our findings imply parallel, lexical category-specific processes and reconcile discrepancies between lesional and functional imaging studies.	\N	\N
23700131	Recent research has reported that spatial modulation effects of audiotactile interactions tend to be limited to the space and body parts around the head. The present study investigated the generality of this finding by manipulating body parts stimulated and spatial relationships between the body parts and sounds. In Experiment 1, tactile stimuli were presented randomly to either left or right cheek, hand (palm or back) placed near the head, and knee while auditory stimuli were presented to either the same or opposite side from loudspeakers close to the head. Participants made speeded spatial discrimination responses regarding the side (left versus right) of the tactile stimulation. For any body part stimulated, the performance was worse when the auditory stimuli were presented from the opposite side rather than from the same side. Experiment 2 demonstrated that the spatial modulation effects for the palm or the back of the hand occurred irrespective of hand position (near or far from the head) and sound position (near or far from the head). The sounds delivered from near the head exerted a greater influence on tactile spatial discrimination performance as compared with the sound delivered from far from the head. Furthermore, the back of the hand was more influenced by the auditory stimuli than the palm when the hands were placed near the sounds. These results suggest that the spatial modulation effects of audiotactile interactions can occur beyond the space and body surface around the head.	\N	\N
23703134	To compare hearing performance relating to the peripheral and central auditory system between solvent-exposed and non-exposed workers. Forty-eight workers exposed to a mixture of solvents and 48 non-exposed control subjects of matched age, gender and educational level were selected to participate in the study. The evaluation procedures included: pure-tone audiometry (500 - 8,000 Hz), to investigate the peripheral auditory system; the Random Gap Detection test, to assess the central auditory system; and the Amsterdam Inventory for Auditory Disability and Handicap, to investigate subjects' self-reported hearing performance in daily-life activities. A Student t test and analyses of covariance (ANCOVA) were computed to determine possible significant differences between solvent-exposed and non-exposed subjects for the hearing level, Random Gap Detection test and Amsterdam Inventory for Auditory Disability and Handicap. Pearson correlations among the three measures were also calculated. Solvent-exposed subjects exhibited significantly poorer hearing thresholds for the right ear than non-exposed subjects. Also, solvent-exposed subjects exhibited poorer results for the Random Gap Detection test and self-reported poorer listening performance than non-exposed subjects. Results of the Amsterdam Inventory for Auditory Disability and Handicap were significantly correlated with the binaural average of subject pure-tone thresholds and Random Gap Detection test performance. Solvent exposure is associated with poorer hearing performance in daily life activities that relate to the function of the peripheral and central auditory system.	\N	\N
23705636	This article explores enhancing sincerity, honesty, or truthfulness in computer-generated synthetic speech by accompanying it with music. Sincerity is important if we are to respond positively to any voice, whether human or artificial. What is sincerity in the artificial disembodied voice? Studies in musical expression and performance may illuminate aspects of the 'musically spoken' or sung voice in rendering deeper levels of expression that may include sincerity. We consider one response to this notion in an especially composed melodrama (music accompanying a (synthetic) spoken voice) designed to convey sincerity.	\N	\N
23709064	Spatial ventriloquism refers to the phenomenon that a visual stimulus such as a flash can attract the perceived location of a spatially discordant but temporally synchronous sound. An analogous example of mutual attraction between audition and vision has been found in the temporal domain, where temporal aspects of a visual event, such as its onset, frequency, or duration, can be biased by a slightly asynchronous sound. In this review, we examine various manifestations of spatial and temporal attraction between the senses (both direct effects and aftereffects), and we discuss important constraints on the occurrence of these effects. Factors that potentially modulate ventriloquism-such as attention, synesthetic correspondence, and other cognitive factors-are described. We trace theories and models of spatial and temporal ventriloquism, from the traditional unity assumption and modality appropriateness hypothesis to more recent Bayesian and neural network approaches. Finally, we summarize recent evidence probing the underlying neural mechanisms of spatial and temporal ventriloquism.	\N	\N
23711533	Auditory cortices can be separated into dissociable processing pathways similar to those observed in the visual domain. Emotional stimuli elicit enhanced neural activation within sensory cortices when compared to neutral stimuli. This effect is particularly notable in the ventral visual stream. Little is known, however, about how emotion interacts with dorsal processing streams, and essentially nothing is known about the impact of emotion on auditory stimulus localization. In the current study, we used fMRI in concert with individualized auditory virtual environments to investigate the effect of emotion during an auditory stimulus localization task. Surprisingly, participants were significantly slower to localize emotional relative to neutral sounds. A separate localizer scan was performed to isolate neural regions sensitive to stimulus location independent of emotion. When applied to the main experimental task, a significant main effect of location, but not emotion, was found in this ROI. A whole-brain analysis of the data revealed that posterior-medial regions of auditory cortex were modulated by sound location; however, additional anterior-lateral areas of auditory cortex demonstrated enhanced neural activity to emotional compared to neutral stimuli. The latter region resembled areas described in dual pathway models of auditory processing as the 'what' processing stream, prompting a follow-up task to generate an identity-sensitive ROI (the 'what' pathway) independent of location and emotion. Within this region, significant main effects of location and emotion were identified, as well as a significant interaction. These results suggest that emotion modulates activity in the 'what,' but not the 'where,' auditory processing pathway.	\N	\N
23716219	The purpose of this study is to investigate the sufficient "similarity" between consecutive auditory events for the auditory system to define the fundamental period for pitch perception. It is possible to contaminate the periodicity of harmonic complex tones by scaling the impulse response in the time domain at every other cycle. Scale-alternating wavelet sequences (SAWS) in which two impulse responses with different scaling factors alternated were generated based on impulse responses obtained from Japanese vowels spoken by a male speaker. Preliminary listening to such signals indicated that the perceived pitch went down an octave relative to the original when the scaling factor exceeded a certain degree. In the first experiment, pitch matching was measured as a function of the scaling factor by the method of adjustment where the comparison stimuli were completely periodic with adjustable base periods. The pitch shift was discontinuous against the base period, chromatic continuum. In the second experiment, pitch matching was investigated with comparison stimuli whose odd harmonics were attenuated. This procedure provides a stimulus continuum where the pitch moved up an octave without changing its pitch chroma. The attenuation of the odd harmonics needed to match the SAWS varied systematically as a function of the degree of scaling. The relation between pitch matching and the peak height along the time interval axis of the stabilized auditory image is discussed.	\N	\N
23716244	This study investigated monaural envelope correlation perception (Richards 1987) for noise bandwidths ranging from 25 to 1,600 Hz. The high-frequency side of the low band was fixed at 3,000 Hz and the low-frequency side of the high band was fixed at 3,500 Hz. When comodulated, the magnitude spectra of the pair of noise bands were either identical or reflected around the midpoint. Six listeners with normal hearing participated. Listeners showed similar performance for identical and reflected-spectrum conditions, with best performance usually occurring for bandwidths between 200 and 800 Hz. Results were considered in terms of envelope comparisons of waveforms at the outputs of multiple peripheral filters or envelope comparisons of waveforms at the outputs of central filters set to the bandwidths of the noise stimuli. Some aspects of the results were incompatible with the account based on multiple peripheral filters. However, the results of a supplementary condition involving the gating of band subregions indicated that this incompatibility could be accounted for by nonoptimal weighting of peripheral filter outputs.	\N	\N
23716245	Envelope fluctuations of complex sounds carry information that is -essential for many types of discrimination and for detection in noise. To study the neural representation of envelope information and mechanisms for processing of this temporal aspect of sounds, it is useful to identify an animal model that can -sensitively detect amplitude modulations (AM). Low modulation frequencies, which dominate speech sounds, are of particular interest. Yet, most animal -models studied previously are relatively insensitive to AM at low modulation -frequencies. Rabbits have high thresholds for low-frequency modulations, -especially for tone carriers. Rhesus macaques are less sensitive than humans to low-frequency -modulations of wideband noise (O'Conner et al. Hear Res 277, 37-43, 2011). Rats and -chinchilla also have higher thresholds than humans for amplitude -modulations of noise (Kelly et al. J Comp Psychol 120, 98-105, 2006; Henderson et al. J Acoust Soc Am 75, -1177-1183, 1984). In contrast, the budgerigar has thresholds for AM detection of wideband noise similar to those of human listeners at low -modulation frequencies (Dooling and Searcy. Percept Psychophys 46, 65-71, 1981). A -one-interval, two-alternative operant conditioning procedure was used to estimate AM -detection thresholds for 4-kHz tone carriers at low modulation -frequencies (4-256 Hz). Budgerigar thresholds are comparable to those of human subjects in a comparable task. Implications of these comparative results for temporal coding of complex sounds are discussed. Comparative results for masked AM detection are also presented.	\N	\N
23716246	Compared to humans, Mongolian gerbils (Meriones unguiculatus) are much more sensitive at detecting mistuning of frequency components of a harmonic complex (Klinge and Klump. J Acoust Soc Am 128:280-290, 2010). One processing mechanism suggested to result in the high sensitivity involves evaluating the phase shift that gradually develops between the mistuned and the remaining components in the same or separate auditory filters. To investigate if this processing mechanism may explain the observed sensitivity, we determined the gerbils' thresholds to detect a constant phase shift in a component of a harmonic complex that is introduced without a frequency shift. The gerbils' detection thresholds for constant phase shifts were considerably lower for a high-frequency component (6,400 Hz) than for a low-frequency component (400 Hz) of a 200-Hz harmonic complex and increased with decreasing stimulus duration. Compared to the phase shifts calculated from the mistuning detection thresholds, the detection thresholds for constant phase shifts were similar to those for gradual phase shifts for the low-frequency harmonic but considerably lower for the high-frequency harmonic. A simulation of the processing of harmonic complexes by the gerbil's peripheral auditory filters when components are phase shifted shows waveform changes comparable to those assessed for mistuning detection Klinge and Klump (J Acoust Soc Am 128:280-290, 2010) and provides evidence that detection of the gradual phase shifts may underlie mistuning detection.	\N	\N
23716247	Detecting rare and surprising events is a useful strategy for sensory -systems. In the human auditory system, deviance detection is indexed by an important component of the auditory event-related potentials, the mismatch negativity (MMN). Responses of single neurons in the inferior colliculus, medial geniculate body, and auditory cortex of mammals (cats, rats, and mice) show responses that share some properties with MMN: they are evoked by rare events, are preattentive (in as much as they occur in anesthetized animals), and, at least at the level of primary auditory cortex, cannot be accounted for by simple fatigue of the incoming sensory information. Here we extend these results to deviations beyond tone frequency. Recording in rat primary auditory cortex and using oddball sequences consisting of two frozen tokens of broadband noise samples, we found differences between the responses to the same token when used as the common and when used as the deviant, showing an exquisite sensitivity to the small differences between two spectro-temporally similar sounds. Similarly, differential adaptation can be demonstrated when using two word-like stimuli that have been derived from human speech but adapted to the rat auditory system. Thus, differential adaptation to common and rare sounds is present also with sounds whose complexity mirrors that of natural environments.	\N	\N
23716255	Many previous studies have shown that a tone that is momentarily -interrupted can be perceived as continuous if the interruption is completely masked by noise. It has been suggested this "continuity illusion" occurs only when peripheral neural responses contain no evidence that the signal was interrupted. In this study, we used a combination of psychophysical measures and computational simulations of peripheral auditory responses to examine whether the continuity illusion can be experienced under conditions where peripheral neural responses contain evidence that the signal did not continue through the masker. Our results provide an example of a salient continuity illusion despite evidence of an interruption in the peripheral representation, indicating that the illusion may depend more on global features of the interrupting sound, such as its long-term specific loudness, than on its fine-grained temporal structure.	\N	\N
23717403	The present study of KCNQ4 mutations was carried out to 1) determine the prevalence by unbiased population-based genetic screening, 2) clarify the mutation spectrum and genotype/phenotype correlations, and 3) summarize clinical characteristics. In addition, a review of the reported mutations was performed for better understanding of this deafness gene. The screening using 287 probands from unbiased Japanese autosomal dominant nonsyndromic hearing loss (ADNSHL) families identified 19 families with 7 different disease causing mutations, indicating that the frequency is 6.62% (19/287). While the majority were private mutations, one particular recurrent mutation, c.211delC, was observed in 13 unrelated families. Haplotype analysis in the vicinity of c.211delC suggests existence of a common ancestor. The majority of the patients showed all frequency, but high-frequency predominant, sensorineural hearing loss. The present study adds a new typical audiogram configuration characterized by mid-frequency predominant hearing loss caused by the p.V230E mutation. A variant at the N-terminal site (c. 211delC) showed typical ski-slope type audiogram configuration. Concerning clinical features, onset age was from 3 to 40 years old, and mostly in the teens, and hearing loss was gradually progressive. Progressive nature is a common feature of patients with KCNQ4 mutations regardless of the mutation type. In conclusion, KCNQ4 mutations are frequent among ADNSHL patients, and therefore screening of the gene and molecular confirmation of these mutations have become important in the diagnosis of these conditions.	\N	\N
23727883	Visual motion aftereffects can occur contingent on arbitrary sounds. Two circles, placed side by side, were alternately presented, and the onsets were accompanied by tone bursts of high and low frequencies, respectively. After a few minutes of exposure to the visual apparent motion with the tones, a circle blinking at a fixed location was perceived as a lateral motion in the same direction as the previously exposed apparent motion (Teramoto et al. in PLoS One 5:e12255, 2010). In the present study, we attempted to reverse this contingency (pitch aftereffects contingent on visual information). Results showed that after prolonged exposure to the audio-visual stimuli, the apparent visual motion systematically affected the perceived pitch of the auditory stimuli. When the leftward apparent visual motion was paired with the high-low-frequency sequence during the adaptation phase, a test tone sequence was more frequently perceived as a high-low-pitch sequence when the leftward apparent visual motion was presented and vice versa. Furthermore, the effect was specific for the exposed visual field and did not transfer to the other side, thus ruling out an explanation in terms of simple response bias. These results suggest that new audiovisual associations can be established within a short time, and visual information processing and auditory processing can mutually influence each other.	\N	\N
23740184	Age-related hearing loss (presbyacusis) has a complex etiology. Results from animal models detailing the effects of specific cochlear injuries on audiometric profiles may be used to understand the mechanisms underlying hearing loss in older humans and predict cochlear pathologies associated with certain audiometric configurations ("audiometric phenotypes"). Patterns of hearing loss associated with cochlear pathology in animal models were used to define schematic boundaries of human audiograms. Pathologies included evidence for metabolic, sensory, and a mixed metabolic + sensory phenotype; an older normal phenotype without threshold elevation was also defined. Audiograms from a large sample of older adults were then searched by a human expert for "exemplars" (best examples) of these phenotypes, without knowledge of the human subject demographic information. Mean thresholds and slopes of higher frequency thresholds of the audiograms assigned to the four phenotypes were consistent with the predefined schematic boundaries and differed significantly from each other. Significant differences in age, gender, and noise exposure history provided external validity for the four phenotypes. Three supervised machine learning classifiers were then used to assess reliability of the exemplar training set to estimate the probability that newly obtained audiograms exhibited one of the four phenotypes. These procedures classified the exemplars with a high degree of accuracy; classifications of the remaining cases were consistent with the exemplars with respect to average thresholds and demographic information. These results suggest that animal models of age-related hearing loss can be used to predict human cochlear pathology by classifying audiograms into phenotypic classifications that reflect probable etiologies for hearing loss in older humans.	\N	\N
23741046	Many manual tasks involve object manipulation and are achieved by an evolving series of actions, or action phases, recruited to achieve task subgoals. The ability to effectively link action phases is an important component of manual dexterity. However, our understanding of how the effective linking of sequential action phases develops with skill learning is limited. Here, we addressed this issue using a task in which participants applied forces to a handle to move a cursor on a computer screen to successively acquire visual targets. Target acquisition required actively holding the cursor within the target zone (hold phase) for a required duration before moving to the next target (transport phase). If the transport phase was initiated prematurely, before the end of the required hold duration, participants had to return to the target to acquire it. The goal was to acquire targets as quickly as possible. Distinct visual and auditory sensory events marked goal completion of each action phase. During initial task performance, the transport phase was reactively triggered by sensory events signaling hold phase completion. However, with practice, participants learned to initiate the transport phase based on a prediction of the time of hold phase completion. Simulations revealed that participants learned to near-optimally compensate for temporal uncertainty, presumably related to estimation of time intervals and execution of motor commands, so as to reduce the average latency between the end of the required hold phase duration and the start of the transport phase, while avoiding an excess of premature exits.	\N	\N
23742366	Estimates of human basilar membrane gain and compression obtained using temporal masking curve (TMC) and additivity of forward masking (AFM) methods with long-duration maskers or long masker-signal silent intervals may be affected by olivocochlear efferent activation, which reduces basilar membrane gain. The present study introduces a fixed-duration masking curve (FDMC) method, which involves a comparison of off- and on-frequency forward masker levels at threshold as a function of masker and signal duration, with the total masker-signal duration fixed at 25 ms to minimize efferent effects. Gain and compression estimates from the FDMC technique were compared with those from TMC (104-ms maskers) and AFM (10- and 200-ms maskers) methods. Compression estimates over an input-masker range of 40-60 dB sound pressure level were similar for the four methods. Maximum compression occurred at a lower input level for the FDMC compared to the TMC method. Estimates of gain were similar for TMC and FDMC methods. The FDMC method may provide a more reliable estimate of BM gain and compression in the absence of efferent activation and could be a useful method for estimating effects of efferent activity when used with a precursor sound (to trigger efferent activation), presented prior to the combined masker-signal stimulus.	\N	\N
23742368	Masking functions and fixed-signal functions were constructed using a narrow range of pedestal intensities for 10-ms, 1000-Hz gated tones. Data from three experiments agreed with previously reported data, clearly demonstrating negative masking and the pedestal effect. The data extend earlier findings by showing (1) the resilience of the pedestal effect when a background noise masker is introduced; (2) a possible indifference of the fixed-signal function to stimulus duration; (3) the ability of a set of psychometric functions to produce both masking and fixed-signal functions; (4) depending on method, the impact of unit choice on the interpretation of both the pedestal effect and negative masking data. Results are discussed in relation to current psychophysical models, and suggest that accounting for the auditory system's sensitivity to differences in low-level sounds remains a challenge.	\N	\N
23745759	This study investigates the influence of stress grouping on verbal short-term memory (STM). English speakers show a preference to combine syllables into trochaic groups, both lexically and in continuous speech. In two serial recall experiments, auditory lists of nonsense syllables were presented with either trochaic (STRONG-weak) or iambic (weak-STRONG) stress patterns, or in monotone. The acoustic correlates that carry stress were also manipulated in order to examine the relationship between input and output processes during recall. In Experiment 1, stressed and unstressed syllables differed in intensity and pitch but were matched for spoken duration. Significantly more syllables were recalled in the trochaic stress pattern condition than in the iambic and monotone conditions, which did not differ. In Experiment 2, spoken duration and pitch were manipulated but intensity was held constant. No effects of stress grouping were observed, suggesting that intensity is a critical acoustic factor for trochaic grouping. Acoustic analyses demonstrated that speech output was not identical to the auditory input, but that participants generated correct stress patterns by manipulating acoustic correlates in the same way in both experiments. These data challenge the idea of a language-independent STM store and support the notion of separable phonological input and output processes.	\N	\N
23751011	Cognitive theories on consciousness propose a strong link between consciousness and working memory (WM). This link is also present at the neural level: Both consciousness and WM have been implicated in a prefrontal parietal network. However, the link remains empirically unexplored. The present study investigates the relation between consciousness and WM by studying the impact of WM load on one aspect of consciousness, the threshold for subjective visibility. At the same time, we investigated how WM affects cognitive control, a function that has been implicated to consciousness. Results showed an increase in the threshold of subjective visibility when WM load increased. Furthermore, the impact of a prime stimulus on the response to the target was also modulated by WM load. We propose that the observed interference is caused by the functional and neural overlap of these functions.	\N	\N
23751171	The extent of visual perceptual processing that occurs in the absence of awareness is as yet unclear. Here we examined event-related-potential (ERP) indices of visual and cognitive processes as awareness was manipulated through object-substitution masking (OSM), an awareness-disrupting effect that has been hypothesized to result from the disruption of reentrant signaling to low-level visual cortical areas. In OSM, a visual stimulus array is briefly presented that includes a parafoveal visual target denoted by a cue, typically consisting of several surrounding dots. When the offset of the target-surrounding cue dots is delayed relative to the rest of the array, a striking reduction in the perception of the target image surrounded by the dots is observed. Using faces and houses as the target stimuli, we found that successful OSM reduced or eliminated all the measured electrophysiological indices of visual processing stages after 130ms post-stimulus. More specifically, when targets were missed within the masked condition (i.e., on trials with effective OSM that disrupted awareness), we observed fully intact early feed-forward processing up through the visual extrastriate P1 ERP component peaking at 100ms, followed by reduced low-level activity over the occipital pole 130-170ms post-stimulus, reduced ERP indices of lateralized shifts of attention toward the parafoveal target, reduced object-generic visual processing, abolished object-category-specific (face-specific) processing, and reduced late visual short-term-memory processing activity. The results provide a comprehensive electrophysiological account of the neurocognitive underpinnings of effective OSM of visual-object images, including evidence for central roles of early reentrant signal disruption and insufficient visual attentional deployment.	\N	\N
23757308	Most people cannot name the musical note that corresponds to a particular pitch without being provided a reference note, but those people with absolute pitch (AP) can do this accurately. Early experience during a developmental period is often thought to convey identity and stability of the note categories in people with AP, but the plasticity of these categories has not been investigated. Here we provide the first evidence that the note categories of adults with AP can change with listening experience. Participants with AP showed shifts in perception in direct accord with prior exposure to music detuned by a fraction of a semitone. This suggests that the apparent stability of AP categories is conferred not by early experience but rather by the cultural norms adopted for tuning music.	\N	\N
23758506	Levitin's findings that nonmusicians could produce from memory the absolute pitches of self-selected pop songs have been widely cited in the music psychology literature. These findings suggest that latent absolute pitch (AP) memory may be a more widespread trait within the population than traditional AP labelling ability. However, it has been left unclear what factors may facilitate absolute pitch retention for familiar pieces of music. The aim of the present paper was to investigate factors that may contribute to latent AP memory using Levitin's sung production paradigm for AP memory and comparing results to the outcomes of a pitch labelling task, a relative pitch memory test, measures of music-induced emotions, and various measures of participants' musical backgrounds. Our results suggest that relative pitch memory and the quality and degree of music-elicited emotions impact on latent AP memory.	\N	\N
23774001	Auditory alarm misperception is one of the critical events that lead aircraft pilots to an erroneous flying decision. The rarity of these alarms associated with their possible unreliability may play a role in this misperception. In order to investigate this hypothesis, we manipulated both audiovisual conflict and sound rarity in a simplified landing task. Behavioral data and event related potentials (ERPs) of thirteen healthy participants were analyzed. We found that the presentation of a rare auditory signal (i.e., an alarm), incongruent with visual information, led to a smaller amplitude of the auditory N100 (i.e., less negative) compared to the condition in which both signals were congruent. Moreover, the incongruity between the visual information and the rare sound did not significantly affect reaction times, suggesting that the rare sound was neglected. We propose that the lower N100 amplitude reflects an early visual-to-auditory gating that depends on the rarity of the sound. In complex aircraft environments, this early effect might be partly responsible for auditory alarm insensitivity. Our results provide a new basis for future aeronautic studies and the development of countermeasures.	\N	\N
23776244	Individuals with autism spectrum disorders (ASDs) often show insensitivity to the human voice, a deficit that is thought to play a key role in communication deficits in this population. The social motivation theory of ASD predicts that impaired function of reward and emotional systems impedes children with ASD from actively engaging with speech. Here we explore this theory by investigating distributed brain systems underlying human voice perception in children with ASD. Using resting-state functional MRI data acquired from 20 children with ASD and 19 age- and intelligence quotient-matched typically developing children, we examined intrinsic functional connectivity of voice-selective bilateral posterior superior temporal sulcus (pSTS). Children with ASD showed a striking pattern of underconnectivity between left-hemisphere pSTS and distributed nodes of the dopaminergic reward pathway, including bilateral ventral tegmental areas and nucleus accumbens, left-hemisphere insula, orbitofrontal cortex, and ventromedial prefrontal cortex. Children with ASD also showed underconnectivity between right-hemisphere pSTS, a region known for processing speech prosody, and the orbitofrontal cortex and amygdala, brain regions critical for emotion-related associative learning. The degree of underconnectivity between voice-selective cortex and reward pathways predicted symptom severity for communication deficits in children with ASD. Our results suggest that weak connectivity of voice-selective cortex and brain structures involved in reward and emotion may impair the ability of children with ASD to experience speech as a pleasurable stimulus, thereby impacting language and social skill development in this population. Our study provides support for the social motivation theory of ASD.	\N	\N
23778471	The audibility thresholds for the sound frequency of 137 upward- and downward-sloping audiograms showing sensorineural hearing loss were selected and analyzed in conjunction with speech recognition thresholds obtained from individuals seen at a public otolaryngology clinic to determine which frequencies in slope audiograms best represent speech recognition thresholds. The linear regression model and mean square error were used to determine the associations between the threshold values. The mean square error identified larger errors when using thresholds of 500, 1000, and 2000 Hz than when using audibility thresholds of 500, 1000, 2000, and 4000 Hz. The linear regression model showed a higher correlation (91%) between the audiogram thresholds for frequencies of 500, 1000, 2000, and 4000 Hz than for the frequencies of 500, 1000, and 2000 Hz (88%). Frequencies of 500, 1000, 2000, and 4000 Hz were the most significant in predicting the speech recognition threshold.	\N	\N
23784072	Several sources of evidence point toward a link between asymmetry of prefrontal brain activity and approach-withdrawal tendencies. Here, we tested the causal nature of this link and examined if the categorization of an ambiguous approach- or withdrawal-related vocal signal can be biased by manipulating left and right frontal neural activity. We used voice morphing of affective non-verbal vocalizations to create individually tailored affectively ambiguous stimuli on an Anger-Fear continuum-two emotions that represent extremes on the approach-withdrawal dimension. We tested perception of these stimuli after 10 min of low-frequency repetitive transcranial magnetic stimulation over left or right dorsolateral prefrontal cortex or over the vertex (control), a technique that has transient inhibitory effects on the targeted brain region. As expected, ambiguous stimuli were more likely perceived as expressing Anger (approach) than Fear (withdrawal) after right prefrontal compared with left prefrontal or control stimulation. These results provide the first evidence that the manipulation of asymmetrical activity in prefrontal cortex can change the explicit categorization of ambiguous emotional signals.	\N	\N
23785181	To evaluate child-adult differences for consonant identification in a noise or a 2-talker masker. Error patterns were compared across age and masker type to test the hypothesis that errors with the noise masker reflect limitations in the peripheral encoding of speech, whereas errors with the 2-talker masker reflect target-masker confusions within the central auditory system. A repeated-measures design compared the performance of children (5-13 years) and adults in continuous speech-shaped noise or a 2-talker masker. Consonants were identified from a closed set of 12 using a picture-pointing response. In speech-shaped noise, children under age 10 years performed more poorly than adults, but performance was adultlike for 11- to 13-year-olds. In the 2-talker masker, significant child-adult differences were observed in even the oldest group of children. Systematic clusters of consonant errors were observed for children in the noise masker and for adults in both maskers, but not for children in the 2-talker masker. These results suggest a more prolonged time course of development for consonant identification in a 2-talker masker than in a noise masker. Differences in error patterns between the maskers support the hypothesis that errors with the 2-talker masker reflect failures of sound segregation.	\N	\N
23785182	In this study, the authors assessed the influence of masking level (29% or 71% sentence perception) and test modality on the processing load during language perception as reflected by the pupil response. In addition, the authors administered a delayed cued stimulus recall test to examine whether processing load affected the encoding of the stimuli in memory. Participants performed speech and text reception threshold tests, during which the pupil response was measured. In the cued recall test, the first half of correctly perceived sentences was presented, and participants were asked to complete the sentences. Reading and listening span tests of working memory capacity were presented as well. Regardless of test modality, the pupil response indicated higher processing load in the 29% condition than in the 71% correct condition. Cued recall was better for the 29% condition. The consistent effect of masking level on the pupil response during listening and reading support the validity of the pupil response as a measure of processing load during language perception. The absent relation between pupil response and cued recall may suggest that cued recall is not directly related to processing load, as reflected by the pupil response.	\N	\N
23786392	Exposure to loud noise can impair cochlear microcirculation and cause noise-induced hearing loss (NIHL). TNF-α signaling has been shown to be activated in NIHL and to control spiral modiolar artery vasoconstriction that regulates cochlear microcirculation. It was the aim of this experimental study to analyse the effects of the TNF-α inhibitor etanercept on cochlear microcirculation and hearing threshold shift in NIHL in vivo. After assessment of normacusis using ABR, loud noise (106 dB SPL, 30 minutes) was applied on both ears in guinea pigs. Etanercept was administered systemically after loud noise exposure while control animals received a saline solution. In vivo fluorescence microscopy of strial capillaries was performed after surgical exposure of the cochlea for microcirculatory analysis. ABR measurements were derived from the contralateral ear. Guinea pigs (n = 6, per group). Compared to controls, cochlear blood flow in strial capillary segments was significantly increased in etanercept-treated animals. Additionally, hearing threshold was preserved in animals receiving the TNF-α inhibitor in contrast to a significant threshold raising in controls. TNF-α inhibition using etanercept improves cochlear microcirculation and protects hearing levels after loud noise exposure and appears as a promising treatment strategy for human NIHL.	\N	\N
23786395	This study investigates the relation between diagnosis of dead regions based on the off-frequency psychophysical tuning curve (PTC) tip and the frequency and level of the probe tone. A previously developed functional model of auditory processing was used to simulate the complete loss of inner hair cells (IHC), dysfunction of outer hair cells (OHC), complete loss of IHCs in combination with OHC dysfunction, and IHC insensitivity. The model predictions were verified through comparison with experimental data. This study compares PTC data of five normal-hearing listeners and six hearing-impaired listeners with model-simulated PTC data. It was shown that OHC activity and IHC insensitivity may significantly alter the shift of PTC tips with increasing probe level. Model results suggest that OHC activity and IHC insensitivity can change the outcome of dead region diagnosis using PTCs. Supplementary to PTC dead region diagnostic information, model results may provide additional information regarding the edge frequency of a dead region and OHC function.	\N	\N
23789623	Pickering & Garrod's (P&G's) integrated model of production and comprehension includes no explicit role for nonlinguistic cognitive processes. Yet, how domain-general cognitive functions contribute to language processing has become clearer with well-specified theories and supporting data. We therefore believe that their account can benefit by incorporating functions like working memory and cognitive control into a unified model of language processing.	\N	\N
23789938	Pickering & Garrod (P&G) consider the possibility that inner speech might be a product of forward production models. Here I consider the idea of inner speech as a forward model in light of empirical work from the past few decades, concluding that, while forward models could contribute to it, inner speech nonetheless requires activity from the implementers.	\N	\N
23790092	The purpose of this study was to evaluate the effect of lengthening of voice onset time and burst duration of selected speech stimuli on perception by individuals with auditory dys-synchrony. This is the second of a series of articles reporting the effect of signal enhancing strategies on speech perception by such individuals. Two experiments were conducted: (1) assessment of the 'just-noticeable difference' for voice onset time and burst duration of speech sounds; and (2) assessment of speech identification scores when speech sounds were modified by lengthening the voice onset time and the burst duration in units of one just-noticeable difference, both in isolation and in combination with each other plus transition duration modification. Lengthening of voice onset time as well as burst duration improved perception of voicing. However, the effect of voice onset time modification was greater than that of burst duration modification. Although combined lengthening of voice onset time, burst duration and transition duration resulted in improved speech perception, the improvement was less than that due to lengthening of transition duration alone. These results suggest that innovative speech processing strategies that enhance temporal cues may benefit individuals with auditory dys-synchrony.	\N	\N
23790958	To determine the prevalence of otitis media with effusion (OME) in children with Down syndrome (DS), and the associated to hearing loss at the age of 8 years. A national population based clinical study of all children with DS born in Norway in 2002. OME was found in 20 out of 52 (38%) children. Those with OME had a significant lower hearing level with a mean pure tone average (PTA) of 33.4 dB HL compared to children with no OME whose mean PTA was 21.7 dB HL (p < 0.0001). Verified hearing loss above 25 dB HL in the better hearing ear was found in 12 out of the 20 with OME, compared to 5 out 31 without OME. The findings of this present study uncover the increased risk of OME in eight year old children with DS as current otitis media was found in one of three. This reduced hearing ability in children with DS due to OME at age of 8 strongly emphasizes the need for optimal treatment and follow up to optimize hearing rehabilitation. The findings are further supported by the population based study design, the focus on the narrow age band and the high response rate.	\N	\N
23801322	When a deviant (oddball) stimulus is presented within a series of otherwise identical (standard) stimuli, the duration of the oddball tends to be overestimated. Two experiments investigated factors affecting systematic distortions in the perceived duration of oddball stimuli. Both experiments used an auditory oddball paradigm where oddball tones varied in both their pitch distance from the pitch of a standard tone and their likelihood of occurrence. Experiment 1 revealed that (1) far-pitch oddballs were perceived to be longer than near-pitch oddballs, (2) effects of pitch distance were greater in low-likelihood conditions, and (3) oddballs in later serial positions were perceived to be longer than oddballs in earlier serial positions. The above effects held regardless of whether oddballs were higher or lower in pitch than the standard. Experiment 2 revealed a pattern of response times in an oddball detection task that generally paralleled the pattern of data observed in Experiment 1; across conditions, there was a negative correlation between detection times and perceived duration. Taken together, the results suggest that the observed effects of oddball pitch, likelihood, and position on perceived duration are at least partly driven by how quickly individuals are able to initiate timing the oddball following its onset. Implications for different theoretical accounts of the oddball effect are discussed.	\N	\N
23817922	For this research, we used a dual-task approach to investigate the involvement of working memory in following written instructions. In two experiments, participants read instructions to perform a series of actions on objects and then recalled the instructions either by spoken repetition or performance of the action sequence. Participants engaged in concurrent articulatory suppression, backward-counting, and spatial-tapping tasks during the presentation of the instructions, in order to disrupt the phonological-loop, central-executive, and visuospatial-sketchpad components of working memory, respectively. Recall accuracy was substantially disrupted by all three concurrent tasks, indicating that encoding and retaining verbal instructions depends on multiple components of working memory. The accuracy of recalling the instructions was greater when the actions were performed than when the instructions were repeated, and this advantage was unaffected by the concurrent tasks, suggesting that the benefit of enactment over oral repetition does not cost additional working memory resources.	\N	\N
23831479	Mismatch negativity (MMN) is a promising window on how the functional integrity of auditory sensory memory and change discrimination is modulated by age and relevant clinical conditions. However, the effects of aging on MMN have remained somewhat elusive, particularly at short interstimulus intervals (ISIs). We performed a meta-analysis of peer-reviewed MMN studies that had targeted both young and elderly adults to estimate the mean effect size. Nine studies, consisting of 29 individual investigations, were included and the final total study population consisted of 182 young and 165 elderly subjects. The effects of different deviant types and duration of ISIs on the effect size were assessed. The overall mean effect size was 0.63 (95% CI at 0.43-0.82). The effect sizes for long ISI (>2s, effect size 0.68, 95% CI at 0.31-1.06) and short ISI (<2s, effect size 0.61, 95% CI at 0.39-0.84) were both considered moderate. A further analysis showed a prominent aging-related decrease in MMN responses to duration and frequency changes at short ISIs. It was also interesting to note that the effect size was about 25% larger for duration deviant condition compared to the frequency deviant condition. In conclusion, a reduced MMN response to duration and frequency deviants is a robust feature among the aged adults, which suggests that there has been a decline in the functional integrity of central auditory processing in this population.	\N	\N
23842602	The aim of this study was to investigate the influence of impulse noise on age-related hearing loss. The study consisted of two groups. Each group contained 109 men. Group I comprised veterans with normal hearing at the end of 1979 sino-vietnamese war. All these veterans were randomly selected from Guangzhou Military Command. Group II were men with no military experience randomly chosen from the health examination center of Guangzhou General Hospital of Guangzhou Military Command. Pure-tone thresholds of these two groups were measured and compared. The pure-tone thresholds of Group I were poorer than those of Group II at the frequencies of 4, 6 and 8 kHz. Thus, impulse noise accelerates age-related hearing loss.	\N	\N
23855495	Recent evidence suggests that humans can become fearful after exposure to olfactory fear signals, yet these studies have reported the effects of fear chemosignals without examining emotion-relevant input from traditional communication modalities (i.e., vision, audition). The question that we pursued here was therefore: How significant is an olfactory fear signal in the broader context of audiovisual input that either confirms or contradicts olfactory information? To test this, we manipulated olfactory (fear, no fear) and audiovisual (fear, no fear) information and demonstrated that olfactory fear signals were as potent as audiovisual fear signals in eliciting a fearful facial expression. Irrespective of confirmatory or contradictory audiovisual information, olfactory fear signals produced by senders induced fear in receivers outside of conscious access. These findings run counter to traditional views that emotions are communicated exclusively via visual and linguistic channels.	\N	\N
23864263	Similarities have been observed in the localization of the final position of moving visual and moving auditory stimuli: Perceived endpoints that are judged to be farther in the direction of motion in both modalities likely reflect extrapolation of the trajectory, mediated by predictive mechanisms at higher cognitive levels. However, actual comparisons of the magnitudes of displacement between visual tasks and auditory tasks using the same experimental setup are rare. As such, the purpose of the present free-field study was to investigate the influences of the spatial location of motion offset, stimulus velocity, and motion direction on the localization of the final positions of moving auditory stimuli (Experiment 1 and 2) and moving visual stimuli (Experiment 3). To assess whether auditory performance is affected by dynamically changing binaural cues that are used for the localization of moving auditory stimuli (interaural time differences for low-frequency sounds and interaural intensity differences for high-frequency sounds), two distinct noise bands were employed in Experiments 1 and 2. In all three experiments, less precise encoding of spatial coordinates in paralateral space resulted in larger forward displacements, but this effect was drowned out by the underestimation of target eccentricity in the extreme periphery. Furthermore, our results revealed clear differences between visual and auditory tasks. Displacements in the visual task were dependent on velocity and the spatial location of the final position, but an additional influence of motion direction was observed in the auditory tasks. Together, these findings indicate that the modality-specific processing of motion parameters affects the extrapolation of the trajectory.	\N	\N
23866207	Although much research has been done to study the working memory structure in children in their first school years, the relation of cognitive constructs involved in this process remains uncertain. In particular, it is unclear whether working memory is a domain general construct that coordinates separate codes of verbal and visuospatial storage or whether it is a domain-specific construct with distinct resources of verbal and visuospatial information. This paper investigates the structure of working memory, by using the Working Memory Test Battery for Children (WMTB-C) and by doing confirmatory factor analyses (CFAs) on a sample of Portuguese children (n = 103) between 8 and 9 years of age. The results of the confirmatory factor analyses that provide the best fit of the data correspond to the model that includes Central Executive and Visuospatial Sketchpad in the same factor, co-varying with a Phonological Loop factor. Moreover, the traditional working memory tripartite structure--based on the Baddeley and Hitch Model--revealed good fit to the data.	\N	\N
23871868	Accounts of the functional role of the frontal cortex in pre-attentive auditory change detection include attention switching, response inhibition, contrast enhancement, and activation of a predictive model. These accounts assume different sequential activation patterns between the temporal and frontal cortices: Change detection in the auditory areas of the superior temporal cortex (STC) followed by inferior frontal cortex (IFC) activation for attention switching and response inhibition; STC preceded by IFC activation for contrast enhancement; and an IFC-STC-IFC activation sequence for the predictive model. We used the event-related optical signal (EROS), which provides a temporal resolution of milliseconds and a spatial resolution of 5 to 10mm, combined with lagged correlation path modeling to examine the response of the right frontal and temporal cortices to auditory duration deviants of varying magnitude. Event-related potentials (ERPs) were also recorded, as was the slow optical (hemodynamic) brain response. The data analyses revealed temporal-frontal, frontal-temporal-frontal, and temporal-frontal activation patterns when the deviants represented relatively large, medium, and small changes from the standard stimulus, respectively. These results indicate that the degree of deviance modulates spatio-temporal dynamics within the STC-IFC auditory change detection network.	\N	\N
23874705	Besides the influence of dopaminergic neurotransmission on negative symptoms in schizophrenia, there is evidence that alterations of serotonin (5-HT) system functioning also play a crucial role in the pathophysiology of these disabling symptoms. From post mortem and genetic studies on patients with negative symptoms a 5-HT dysfunction is documented. In addition atypical neuroleptics and some antidepressants improve negative symptoms via serotonergic action. So far no research has been done to directly clarify the association between the serotonergic functioning and the extent of negative symptoms. Therefore, we examined the status of brain 5-HT level in negative symptoms in schizophrenia by means of the loudness dependence of auditory evoked potentials (LDAEP). The LDAEP provides a well established and non-invasive in vivo marker of the central 5-HT activity. We investigated 13 patients with schizophrenia with predominant negative symptoms treated with atypical neuroleptics and 13 healthy age and gender matched controls with a 32-channel EEG. The LDAEP of the N1/P2 component was evaluated by dipole source analysis and single electrode estimation at Cz. Psychopathological parameters, nicotine use and medication were assessed to control for additional influencing factors. Schizophrenic patients showed significantly higher LDAEP in both hemispheres than controls. Furthermore, the LDAEP in the right hemisphere in patients was related to higher scores in scales assessing negative symptoms. A relationship with positive symptoms was not found. These data might suggest a diminished central serotonergic neurotransmission in patients with predominant negative symptoms.	\N	\N
23876942	The goal of the present study was to determine if students can be trained to reliably perceive dysphonia using the Dysphonic Severity Percentage (DSP) scale, a perceptual measure shown to have high interrater reliability when used by speech-language pathologists experienced with voice disorders. Because the DSP scale was found to be useful as a research tool in the measurement of dysphonia, using it to train students to recognize dysphonia can enhance their education as future clinicians and researchers. This method involved having five inexperienced speech-language pathology students listen to voice samples in two conditions (spontaneous speech and paragraph reading) of 10 clients with moderate to severe dysphonia (phonotrauma); the students simultaneously tallied the nondysphonic syllables on written content of the samples to obtain a DSP for both conditions. Because the clients' dysphonias were moderate to severe, and there were many dysphonic syllables, it was more efficient and advantageous for the students' perception and training to tally the nondysphonic syllables, leaving the dysphonic syllables to calculate the DSP. By tallying the nondysphonic syllables, the students were still recognizing which syllables were dysphonic by not choosing them, thus increasing their perception of both normal and disordered syllables. Statistical analysis using the intraclass correlation coefficient revealed high interrater reliability and high correlations among the trained students for both spontaneous speech and paragraph reading, thus indicating similar training experiences and perceptions. This method appeared to be a more quantitative measure of perceptual ratings than current scales, which use general gradations of dysphonic severity. Moreover, the DSPs were similar between the newly trained students and experienced raters for spontaneous speech, indicating that the students could be trained in the direction experienced by voice clinicians. There was, however, a significant difference between the two groups for paragraph reading, which will be discussed. It was concluded that the DSP method was an effective technique to train students to recognize dysphonia.	\N	\N
23882007	In this article, the authors examine (a) the effect of semantic context on accentedness, comprehensibility, and intelligibility of Spanish-accented American English (AE) as judged by monolingual AE listeners and (b) the interaction of semantic context and accentedness on comprehensibility and intelligibility. Twenty adult native (L1) Spanish speakers proficient in AE and 4 L1 AE speakers (controls) read 48 statements consisting of true-false, semantically meaningful, and semantically anomalous sentences. Eighty monolingual AE listeners assessed accentedness, comprehensibility, and intelligibility of the statements. A significant main effect was found for semantic category on all 3 dependent variables. Accents were perceived to be stronger, and both comprehensibility and intelligibility were worse, in semantically anomalous contexts. Speaker data were grouped into strong, mid-level, and mild accents. The interaction between semantic category and accent was significant for both comprehensibility and intelligibility. The effect of semantic context was strongest for strong accents. Intelligibility was excellent for speakers with mid-level accents in true-false and semantically meaningful contexts, and it was excellent for mild accents in all contexts. Listeners access semantic information, in addition to phonetic and phonotactic features, in the perception of nonnative speech. Both accent level and semantic context are important in research on foreign-accented speech.	\N	\N
23883307	The irrelevant sound effect (ISE) is the finding that serial recall performance is impaired under complex auditory backgrounds such as speech as compared to white noise or silence. Several findings have demonstrated that ISE occurs with nonspeech backgrounds and that the changing-state complexity of the background stimuli is critical to ISE. In a pair of experiments, we investigate whether speech-like qualities of the irrelevant background have an effect beyond their changing-state complexity. We do so by using two kinds of transformations of speech with identical changing-state complexity: one kind that preserved speech-like information (sinewave speech and fully reversed sinewave speech) and others in which this information was distorted (two selectively reversed sinewave speech conditions). Our results indicate that even when changing-state complexity is held constant, sinewave speech conditions in which speech-like interformant relationships are disrupted, produce less ISE than those in which these relationships are preserved. This indicates that speech-like properties of the background are important beyond their changing-state complexity for ISE.	\N	\N
23885549	In patients with epileptic lesions in the hippocampus as well as in the temporal lobe and hippocampus simultaneously, studies were made on the perception of sound signals imitating sound source movement. It was established that hippocampal lesion results in disturbance of estimation of sound spatial characteristics which manifests in a change accuracy of localization and shortening of subjective sound image movement trajectory. Maximum disturbances of localization function are observed during lesions of hippocampus and temporal lobe. Possible neurophysiological mechanism underling observed disturbances are considered.	\N	\N
23886425	Communication while traveling in an automobile often is very difficult for hearing aid users. This is because the automobile/road noise level is usually high, and listeners/drivers often do not have access to visual cues. Since the talker of interest usually is not located in front of the listener/driver, conventional directional processing that places the directivity beam toward the listener's front may not be helpful and, in fact, could have a negative impact on speech recognition (when compared to omnidirectional processing). Recently, technologies have become available in commercial hearing aids that are designed to improve speech recognition and/or listening effort in noisy conditions where talkers are located behind or beside the listener. These technologies include (1) a directional microphone system that uses a backward-facing directivity pattern (Back-DIR processing), (2) a technology that transmits audio signals from the ear with the better signal-to-noise ratio (SNR) to the ear with the poorer SNR (Side-Transmission processing), and (3) a signal processing scheme that suppresses the noise at the ear with the poorer SNR (Side-Suppression processing). The purpose of the current study was to determine the effect of (1) conventional directional microphones and (2) newer signal processing schemes (Back-DIR, Side-Transmission, and Side-Suppression) on listener's speech recognition performance and preference for communication in a traveling automobile. A single-blinded, repeated-measures design was used. Twenty-five adults with bilateral symmetrical sensorineural hearing loss aged 44 through 84 yr participated in the study. The automobile/road noise and sentences of the Connected Speech Test (CST) were recorded through hearing aids in a standard van moving at a speed of 70 mph on a paved highway. The hearing aids were programmed to omnidirectional microphone, conventional adaptive directional microphone, and the three newer schemes. CST sentences were presented from the side and back of the hearing aids, which were placed on the ears of a manikin. The recorded stimuli were presented to listeners via earphones in a sound-treated booth to assess speech recognition performance and preference with each programmed condition. Compared to omnidirectional microphones, conventional adaptive directional processing had a detrimental effect on speech recognition when speech was presented from the back or side of the listener. Back-DIR and Side-Transmission processing improved speech recognition performance (relative to both omnidirectional and adaptive directional processing) when speech was from the back and side, respectively. The performance with Side-Suppression processing was better than with adaptive directional processing when speech was from the side. The participants' preferences for a given processing scheme were generally consistent with speech recognition results. The finding that performance with adaptive directional processing was poorer than with omnidirectional microphones demonstrates the importance of selecting the correct microphone technology for different listening situations. The results also suggest the feasibility of using hearing aid technologies to provide a better listening experience for hearing aid users in automobiles.	\N	\N
23888869	Binding is key in multisensory perception. This study investigated the audio-visual (A-V) temporal binding window in 4-, 5-, and 6-year-old children (total N = 120). Children watched a person uttering a syllable whose auditory and visual components were either temporally synchronized or desynchronized by 366, 500, or 666 ms. They were asked whether the voice and face went together (Experiment 1) or whether the desynchronized videos differed from the synchronized one (Experiment 2). Four-year-olds detected the 666-ms asynchrony, 5-year-olds detected the 666- and 500-ms asynchrony, and 6-year-olds detected all asynchronies. These results show that the A-V temporal binding window narrows slowly during early childhood and that it is still wider at 6 years of age than in older children and adults.	\N	\N
23891107	Biologically salient sounds, including speech, are rarely heard in isolation. Our brains must therefore organize the input arising from multiple sources into separate "streams" and, in the case of speech, map the acoustic components of the target signal onto meaning. These auditory and linguistic processes have traditionally been considered to occur sequentially and are typically studied independently [1, 2]. However, evidence that streaming is modified or reset by attention [3], and that lexical knowledge can affect reports of speech sound identity [4, 5], suggests that higher-level factors may influence perceptual organization. In two experiments, listeners heard sequences of repeated words or acoustically matched nonwords. After several presentations, they reported that the initial /s/ sound in each syllable formed a separate stream; the percept then fluctuated between the streamed and fused states in a bistable manner. In addition to measuring these verbal transformations, we assessed streaming objectively by requiring listeners to detect occasional targets-syllables containing a gap after the initial /s/. Performance was better when streaming caused the syllables preceding the target to transform from words into nonwords, rather than from nonwords into words. Our results show that auditory stream formation is influenced not only by the acoustic properties of speech sounds, but also by higher-level processes involved in recognizing familiar words.	\N	\N
23893201	Mimicking the human ear on the basis of auditory models has become a viable approach in many applications by now. However, only a few attempts have been made to extend the scope of physiological ear models to be employed in cochlear implants (CI). Contemporary CI systems rely on much simpler filter banks and simulate the natural signal processing of a healthy cochlea to only a very limited extent. When looking at rehabilitation outcomes, current systems seem to have reached their peak potential, which signals the need for better algorithms and/or technologies. In this paper, we present a novel sound processing strategy, SAM (Stimulation based on Auditory Modeling), that is based on neurophysiological models of the human ear and can be employed in auditory prostheses. It incorporates active cochlear filtering (basilar membrane and outer hair cells) along with the mechanoelectrical transduction of the inner hair cells, so that several psychoacoustic phenomena are accounted for inherently. Although possible, current implementation does not make use of parallel stimulation of the electrodes, which matches state-of-the-art CI hardware. This paper elaborates on SAM's signal processing and provides a computational evaluation of the strategy. Results show that aspects of normal cochlear processing that are missing in common strategies can be replicated by SAM. This is supposed to improve overall CI user performance, which we have at least partly proven in a pilot study with implantees.	\N	\N
23893677	Several studies suggest that auditory perception in general and the perception of speech in noise in particular continue to develop until late childhood or early adolescence. It remains unclear, however, whether this prolonged development results from the maturation of the cognitive factors associated with the performance of auditory tasks or from the slow development of auditory sensory processing. We investigated the perception of monosyllabic words embedded in white noise in Hebrew-speaking school-age children and adults. Although identification thresholds did not become adult-like until 11 years of age, we found no evidence linking this prolonged development to non-sensory factors associated with performance consistency. Therefore, we suggest that similar to the development of amplitude and frequency modulation detection thresholds, this protracted development is related to the maturation of auditory sensory processing.	\N	\N
23893940	Videos can be used as didactic tools for self-learning under several circumstances, including those cases in which students are responsible for the development of this resource as an audiovisual notebook. We compared students' and teachers' perceptions regarding the main features that an audiovisual notebook should include. Four questionnaires with items about information, images, text and music, and filmmaking were used to investigate students' (n = 115) and teachers' perceptions (n = 28) regarding the development of a video focused on a histological technique. The results show that both students and teachers significantly prioritize informative components, images and filmmaking more than text and music. The scores were significantly higher for teachers than for students for all four components analyzed. The highest scores were given to items related to practical and medically oriented elements, and the lowest values were given to theoretical and complementary elements. For most items, there were no differences between genders. A strong positive correlation was found between the scores given to each item by teachers and students. These results show that both students' and teachers' perceptions tend to coincide for most items, and suggest that audiovisual notebooks developed by students would emphasize the same items as those perceived by teachers to be the most relevant. Further, these findings suggest that the use of video as an audiovisual learning notebook would not only preserve the curricular objectives but would also offer the advantages of self-learning processes.	\N	\N
23905279	Recent studies in the field of intonational phonology have shown that information-seeking questions can be distinguished from confirmation-seeking questions by prosodic means in a variety of languages (Armstrong, 2010, for Puerto Rican Spanish; Grice & Savino, 1997, for Bari Italian; Kügler, 2003, for Leipzig German; Mata & Santos, 2010, for European Portuguese; Vanrell, Mascaró, Prieto, & Torres-Tamarit, 2010, for Catalan). However, all these studies have relied on production experiments and little is known about the perceptual relevance of these intonational cues. This paper explores whether Majorcan Catalan listeners distinguish information- and confirmation-seeking questions by means of two distinct nuclear falling pitch accents. Three behavioral tasks were conducted with 20 Majorcan Catalan subjects, namely a semantic congruity test, a rating test, and a classical categorical perception identification/discrimination test. The results show that a difference in pitch scaling on the leading H tone of the H+L* nuclear pitch accent is the main cue used by Majorcan Catalan listeners to distinguish confirmation questions from information-seeking questions. Thus, while a iH+L* pitch accent signals an information-seeking question (i.e., the speaker has no expectation about the nature of the answer), the H+L* pitch accent indicates that the speaker is asking about mutually shared information. We argue that these results have implications in representing the distinctions of tonal height in Catalan. The results also support the claim that phonological contrasts in intonation, together with other linguistic strategies, can signal the speakers' beliefs about the certainty of the proposition expressed.	\N	\N
23906967	Training people on temporal discrimination can substantially improve performance in the trained modality but also in untrained modalities. A pretest-training-posttest design was used to investigate whether consolidation plays a crucial role for training effects within the trained modality and its transfer to another modality. In the pretest, both auditory and visual discrimination performance was assessed. In the training phase, participants performed only the auditory task. After a consolidation interval of either 5 min or 24h, participants were again tested in both the auditory and visual tasks. Irrespective of the consolidation interval, performance improved from the pretest to the posttest in both modalities. Most importantly, the training effect for the trained auditory modality was independent of the consolidation interval whereas the transfer effect to the visual modality was larger after 24h than after 5 min. This finding shows that transfer effects benefit from extended consolidation.	\N	\N
23921930	To confirm the clinical efficacy and safety of a direct acoustic cochlear implant. Prospective multicenter study. The study was performed at 3 university hospitals in Europe (Germany, The Netherlands, and Switzerland). Fifteen patients with severe-to-profound mixed hearing loss because of otosclerosis or previous failed stapes surgery. Implantation with a Codacs direct acoustic cochlear implant investigational device (ID) combined with a stapedotomy with a conventional stapes prosthesis Preoperative and postoperative (3 months after activation of the investigational direct acoustic cochlear implant) audiometric evaluation measuring conventional pure tone and speech audiometry, tympanometry, aided thresholds in sound field and hearing difficulty by the Abbreviated Profile of Hearing Aid Benefit questionnaire. The preoperative and postoperative air and bone conduction thresholds did not change significantly by the implantation with the investigational Direct Acoustic Cochlear Implant. The mean sound field thresholds (0.25-8 kHz) improved significantly by 48 dB. The word recognition scores (WRS) at 50, 65, and 80 dB SPL improved significantly by 30.4%, 75%, and 78.2%, respectively, after implantation with the investigational direct acoustic cochlear implant compared with the preoperative unaided condition. The difficulty in hearing, measured by the Abbreviated Profile of Hearing Aid Benefit, decreased by 27% after implantation with the investigational direct acoustic cochlear implant. Patients with moderate-to-severe mixed hearing loss because of otosclerosis can benefit substantially using the Codacs investigational device.	\N	\N
23927112	The present study evaluated the influence of suppressor frequency (fs) and level (Ls) on stimulus-frequency otoacoustic emissions (SFOAEs) recorded using the amplitude-modulated (AM) suppressor technique described by Neely et al. [J. Acoust. Soc. Am. 118, 2124-2127 (2005a)]. Data were collected in normal-hearing subjects, with data collection occurring in two phases. In phase 1, SFOAEs were recorded with probe frequency (fp) = 1, 2, and 4 kHz and probe levels (Lp) ranging from 0 to 60 dB sound pressure level (SPL). At each fp, Ls ranged from Ls = Lp to Ls = Lp + 30 dB. Additionally, nine relationships between fs and fp were evaluated, ranging from fs/fp = 0.80 to fs/fp = 1.16. Results indicated that for low suppressor levels, suppressors higher in frequency than fp (fs > fp) resulted in higher AM-SFOAE levels than suppressors lower in frequency than fp (fs < fp). At higher suppressor levels, suppressors both higher and lower in frequency than fp produced similar AM-SFOAE levels, and, in many cases, low-frequency suppressors produced the largest response. Recommendations for stimulus parameters that maximize AM-SFOAE level were derived from these data. In phase 2, AM-SFOAEs were recorded using these parameters for fp = 0.7-8 kHz and Lp = 20-60 dB SPL. Robust AM-SFOAE responses were recorded in this group of subjects using the parameters developed in phase 1.	\N	\N
23927121	Real-world sound sources are usually perceived as externalized and thus properly localized in both direction and distance. This is largely due to (1) the acoustic filtering by the head, torso, and pinna, resulting in modifications of the signal spectrum and thereby a frequency-dependent shaping of interaural cues and (2) interaural cues provided by the reverberation inside an enclosed space. This study first investigated the effect of room reverberation on the spectro-temporal behavior of interaural level differences (ILDs) by analyzing dummy-head recordings of speech played at different distances in a standard listening room. Next, the effect of ILD fluctuations on the degree of externalization was investigated in a psychoacoustic experiment performed in the same listening room. Individual binaural impulse responses were used to simulate a distant sound source delivered via headphones. The ILDs were altered using a gammatone filterbank for analysis and resynthesis, where the envelopes of the left and right-ear signals were modified such that the naturally occurring fluctuations of the ILDs were restricted. This manipulation reduced the perceived degree of externalization. This was consistent with the analysis of short-term ILDs at different distances showing that a decreased distance to the sound source also reduced the ILD fluctuations.	\N	\N
23927128	The perturbation of acoustic features in a speaker's auditory feedback elicits rapid compensatory responses that demonstrate the importance of auditory feedback for control of speech output. The current study investigated whether responses to a perturbation of speech auditory feedback vary depending on the importance of the perturbed feature to perception of the vowel being produced. Auditory feedback of speakers' first formant frequency (F1) was shifted upward by 130 mels in randomly selected trials during the speakers' production of consonant-vowel-consonant words containing either the vowel /Λ/ or the vowel /ɝ/. Although these vowels exhibit comparable F1 frequencies, the contribution of F1 to perception of /Λ/ is greater than its contribution to perception of /ɝ/. Compensation to the F1 perturbation was observed during production of both vowels, but compensatory responses during /Λ/ occurred at significantly shorter latencies and exhibited significantly larger magnitudes than compensatory responses during /ɝ/. The finding that perturbation of vowel F1 during /Λ/ and /ɝ/ yielded compensatory differences that mirrored the contributions of F1 to perception of these vowels indicates that some portion of feedback control is weighted toward monitoring and preservation of acoustic cues for speech perception.	\N	\N
23933139	A series of five experiments investigated the extent of subliminal processing of negation. Participants were presented with a subliminal instruction to either pick or not pick an accompanying noun, followed by a choice of two nouns. By employing subjective measures to determine individual thresholds of subliminal priming, the results of these studies indicated that participants were able to identify the correct noun of the pair--even when the correct noun was specified by negation. Furthermore, using a grey-scale contrast method of masking, Experiment 5 confirmed that these priming effects were evidenced in the absence of partial awareness, and without the effect being attributed to the retrieval of stimulus-response links established during conscious rehearsal.	\N	\N
23937006	To analyse the impact of tinnitus loudness, tinnitus frequency, hearing loss, tinnitus subjective loudness on the life of tinnitus patient. To inspect the 154 tinnitus patients with pure tone audiometry, tinnitus matching, tinnitus classification questionnaire and THI scale. This study applies THI scale to evaluate the impact of tinnitus on the life of tinnitus patient. Using statistical methods to analyse the relationship between tinnitus loudness, tinnitus frequency, hearing loss, tinnitus subjective loudness and the impact of tinnitus on the life of tinnitus patient. (1) Tinnitus frequency is closed with the frequency of hearing loss. (2) There is no significant correlation between tinnitus loudness and the impact of tinnitus on the life of tinnitus patient. (3) There is no distinction between hearing loss and the THI scores. (4) The patient gets more scores in subgroup of THI with the increase of tinnitus subjective loudness classification. The impact of tinnitus loudness, hearing loss on the life of tinnitus patient is not very clearly, while the impact of tinnitus subjective loudness classification on the life of tinnitus patient is significant. In clinical, we can not evaluate the effect of the tinnitus treatment relying on tinnitus loudness and hearing loss simply.The finding provides us individual treatment to tinnitus patients.	\N	\N
23937689	Several accounts of speech perception propose that the areas involved in producing language are also involved in perceiving it. In line with this view, neuroimaging studies show activation of premotor cortex (PMC) during phoneme judgment tasks; however, there is debate about whether speech perception necessarily involves motor processes, across all task contexts, or whether the contribution of PMC is restricted to tasks requiring explicit phoneme awareness. Some aspects of speech processing, such as mapping sounds onto meaning, may proceed without the involvement of motor speech areas if PMC specifically contributes to the manipulation and categorical perception of phonemes. We applied TMS to three sites-PMC, posterior superior temporal gyrus, and occipital pole-and for the first time within the TMS literature, directly contrasted two speech perception tasks that required explicit phoneme decisions and mapping of speech sounds onto semantic categories, respectively. TMS to PMC disrupted explicit phonological judgments but not access to meaning for the same speech stimuli. TMS to two further sites confirmed that this pattern was site specific and did not reflect a generic difference in the susceptibility of our experimental tasks to TMS: stimulation of pSTG, a site involved in auditory processing, disrupted performance in both language tasks, whereas stimulation of occipital pole had no effect on performance in either task. These findings demonstrate that, although PMC is important for explicit phonological judgments, crucially, PMC is not necessary for mapping speech onto meanings.	\N	\N
23943499	To investigate the effect of semantic congruity on audiovisual target responses, participants detected a semantic concept that was embedded in a series of rapidly presented stimuli. The target concept appeared as a picture, an environmental sound, or both; and in bimodal trials, the audiovisual events were either consistent or inconsistent in their representation of a semantic concept. The results showed faster detection latencies to bimodal than to unimodal targets and a higher rate of missed targets when visual distractors were presented together with auditory targets, in comparison to auditory targets presented alone. The findings of Experiment 2 showed a cross-modal asymmetry, such that visual distractors were found to interfere with the accuracy of auditory target detection, but auditory distractors had no effect on either the speed or the accuracy of visual target detection. The biased-competition theory of attention (Desimone & Duncan Annual Review of Neuroscience 18: 1995; Duncan, Humphreys, & Ward Current Opinion in Neurobiology 7: 255-261 1997) was used to explain the findings because, when the saliency of the visual stimuli was reduced by the addition of a noise filter in Experiment 4, visual interference on auditory target detection was diminished. Additionally, the results showed faster and more accurate target detection when semantic concepts were represented in a visual rather than an auditory format.	\N	\N
23966690	Aging listeners experience greater difficulty understanding speech in adverse listening conditions and exhibit degraded temporal resolution, even when audiometric thresholds are normal. When threshold evidence for peripheral involvement is lacking, central and cognitive factors are often cited as underlying performance declines. However, previous work has uncovered widespread loss of cochlear afferent synapses and progressive cochlear nerve degeneration in noise-exposed ears with recovered thresholds and no hair cell loss (Kujawa and Liberman 2009). Here, we characterize age-related cochlear synaptic and neural degeneration in CBA/CaJ mice never exposed to high-level noise. Cochlear hair cell and neuronal function was assessed via distortion product otoacoustic emissions and auditory brainstem responses, respectively. Immunostained cochlear whole mounts and plastic-embedded sections were studied by confocal and conventional light microscopy to quantify hair cells, cochlear neurons, and synaptic structures, i.e., presynaptic ribbons and postsynaptic glutamate receptors. Cochlear synaptic loss progresses from youth (4 weeks) to old age (144 weeks) and is seen throughout the cochlea long before age-related changes in thresholds or hair cell counts. Cochlear nerve loss parallels the synaptic loss, after a delay of several months. Key functional clues to the synaptopathy are available in the neural response; these can be accessed noninvasively, enhancing the possibilities for translation to human clinical characterization.	\N	\N
23966965	Williams syndrome (WS), a genetic, neurodevelopmental disorder, is of keen interest to music cognition researchers because of its characteristic auditory sensitivities and emotional responsiveness to music. However, actual musical perception and production abilities are more variable. We examined musicality in WS through the lens of amusia and explored how their musical perception abilities related to their auditory sensitivities, musical production skills, and emotional responsiveness to music. In our sample of 73 adolescents and adults with WS, 11% met criteria for amusia, which is higher than the 4% prevalence rate reported in the typically developing (TD) population. Amusia was not related to auditory sensitivities but was related to musical training. Performance on the amusia measure strongly predicted musical skill but not emotional responsiveness to music, which was better predicted by general auditory sensitivities. This study represents the first time amusia has been examined in a population with a known neurodevelopmental genetic disorder with a range of cognitive abilities. Results have implications for the relationships across different levels of auditory processing, musical skill development, and emotional responsiveness to music, as well as the understanding of gene-brain-behavior relationships in individuals with WS and TD individuals with and without amusia.	\N	\N
23967947	The purpose of this study was to analyze vowel articulation across various speaking tasks in a group of 20 early Parkinson's disease (PD) individuals prior to pharmacotherapy. Vowels were extracted from sustained phonation, sentence repetition, reading passage, and monologue. Acoustic analysis was based upon measures of the first (F1) and second (F2) formant of the vowels /a/, /i/, and /u/, vowel space area (VSA), F2i/F2u and vowel articulation index (VAI). Parkinsonian speakers manifested abnormalities in vowel articulation across F2u, VSA, F2i/F2u, and VAI in all speaking tasks except sustained phonation, compared to 15 age-matched healthy control participants. Findings suggest that sustained phonation is an inappropriate task to investigate vowel articulation in early PD. In contrast, monologue was the most sensitive in differentiating between controls and PD patients, with classification accuracy up to 80%. Measurements of vowel articulation were able to capture even minor abnormalities in speech of PD patients with no perceptible dysarthria. In conclusion, impaired vowel articulation may be considered as a possible early marker of PD. A certain type of speaking task can exert significant influence on vowel articulation. Specifically, complex tasks such as monologue are more likely to elicit articulatory deficits in parkinsonian speech, compared to other speaking tasks.	\N	\N
23977030	Mechanisms of propofol-induced loss of consciousness remain poorly understood. Recent fMRI studies have shown decreases in functional connectivity during unconsciousness induced by this anesthetic agent. Functional connectivity does not provide information of directional changes in the dynamics observed during unconsciousness. The aim of the present study was to investigate, in healthy humans during an auditory task, the changes in effective connectivity resulting from propofol induced loss of consciousness. We used Dynamic Causal Modeling for fMRI (fMRI-DCM) to assess how causal connectivity is influenced by the anesthetic agent in the auditory system. Our results suggest that the dynamic observed in the auditory system during unconsciousness induced by propofol, can result in a mixture of two effects: a local inhibitory connectivity increase and a decrease in the effective connectivity in sensory cortices.	\N	\N
23978930	Faces presented upside-down are harder to recognize than presented right-side up, an effect known as the face inversion effect. With inversion the perceptual processing of the spatial relationship among facial parts is disrupted. Previous literature indicates a face inversion effect in chimpanzees toward familiar and conspecific faces. Although these results are not inconsistent with findings from humans they have some controversy in their methodology. Here, we employed a delayed matching-to-sample task to test captive chimpanzees on discriminating chimpanzee and human faces. Their performances were deteriorated by inversion. More importantly, the discrimination deterioration was systematically different between the two age groups of chimpanzee participants, i.e. young chimpanzees showed a stronger inversion effect for chimpanzee than for human faces, while old chimpanzees showed a stronger inversion effect for human than for chimpanzee faces. We conclude that the face inversion effect in chimpanzees is modulated by the level of expertise of face processing.	\N	\N
23980148	Learning, the foundation of adaptive and intelligent behavior, is based on plastic changes in neural assemblies, reflected by the modulation of electric brain responses. In infancy, auditory learning implicates the formation and strengthening of neural long-term memory traces, improving discrimination skills, in particular those forming the prerequisites for speech perception and understanding. Although previous behavioral observations show that newborns react differentially to unfamiliar sounds vs. familiar sound material that they were exposed to as fetuses, the neural basis of fetal learning has not thus far been investigated. Here we demonstrate direct neural correlates of human fetal learning of speech-like auditory stimuli. We presented variants of words to fetuses; unlike infants with no exposure to these stimuli, the exposed fetuses showed enhanced brain activity (mismatch responses) in response to pitch changes for the trained variants after birth. Furthermore, a significant correlation existed between the amount of prenatal exposure and brain activity, with greater activity being associated with a higher amount of prenatal speech exposure. Moreover, the learning effect was generalized to other types of similar speech sounds not included in the training material. Consequently, our results indicate neural commitment specifically tuned to the speech features heard before birth and their memory representations.	\N	\N
23992232	The detection of auditory stimuli that deviate from a simple or complex auditory regularity is reflected by the mismatch negativity component of the human auditory evoked potential. Moreover, simple deviants of an oddball paradigm modulate the preceding middle-latency response of the auditory evoked potential. For the frequency oddball paradigms it has been shown that the Nb wave, at approximately 40 ms from stimulus onset, is enhanced in response to deviant compared with standard stimuli. In this study we tested whether the detection of auditory deviants in a (frequency-location) feature-conjunction paradigm is reflected by modulations of the Na, Pa or Nb wave of healthy human participants. In addition, a frequency oddball paradigm was applied to directly contrast the results of a simple and a complex invariance. Feature-conjunction deviants did not elicit any modulations of the tested middle-latency waves. Deviants of the frequency oddball paradigm, by contrast, elicited an enhancement of the Nb wave, confirming the outcome of precedent studies. In both conditions a significant mismatch negativity component was elicited, which showed larger amplitudes and shorter latencies in the oddball condition than in the feature-conjunction condition. These findings corroborate the idea that simple auditory regularities are encoded upstream of those of more complex auditory features and are in line with the idea of a hierarchically working auditory novelty system.	\N	\N
24003981	This study explores if increasing number of repetitions might improve the precision of the acceptable noise level (ANL) test. We measured twelve ANL repetitions, i.e. four complete ANL tests (4 × 3 repetitions), at one session using diotic presentation and a non-semantic ANL version. Thirty-two normal-hearing adults. Small order and fatigue effects were seen. We used the coefficient of repeatability (CR) to assess the repeatability; CRs ranged between 3.9 and 7.6 dB for the four ANL tests. Using the twelve ANL repetitions we removed the variability of the ANL across subjects by normalizing the data to the individual mean ANL for the twelve repetitions. The mean normalized ANL across the subjects rapidly approached the ANL normalized to the individual mean for the 12 repetitions (0 dB), and after three repetitions the SD seemed to be stable at about 3 dB. The findings suggest that both order and fatigue affect the ANL. The findings also suggest that it may be more accurate to speak of an acceptable noise range than ANL. These findings have large implications for how we understand acceptable noise and it would explain a large part of the variability seen among normal-hearing and perhaps hearing-impaired subjects.	\N	\N
24005271	The objective of the present study was to evaluate the hearing function in the airport technical personnel and estimate the effectiveness of multicomponent anti-noise hearing protectors used by the specialists engaged in the aircraft maintenance. The tonal threshold audiometry was carried out before and after a shiftwork. The extra-aural effect of noise was assessed from the characteristics of cardiac rhythm variability. The study included two groups of subjects: in one of them (n=8) they used ordinary flight headsets (control) in the other the protection was ensured with the help of multi-insert hearing protectors (n=16). The initial hearing thresholds were found to be increased up to 70 and 60 dB at the frequencies of 4 and 8 kHz respectively. The regression analysis revealed the relationship between these parameters and the duration of aerodrome work experience. Temporary threshold shifts were observed only in the control group. An increase in the tone of the sympathetic nervous system was observed in the control subjects but was absent in the study group. It is concluded that the multi-component hearing protectors employed in the present study are highly efficacious anti-noise devices. The mechanisms of noise-induced hearing loss are discussed.	\N	\N
24007920	Many previous studies have shown that the human language processor is capable of rapidly integrating information from different sources during reading or listening. Yet, little is known about how this ability develops from child to adulthood. To gain insight into how children (in comparison to adults) handle different kinds of linguistic information during on-line language comprehension, the current study investigates a well-known morphological phenomenon that is subject to both structural and semantic constraints, the plurals-in-compounds effect, i.e. the dislike of plural (specifically regular plural) modifiers inside compounds (e.g. rats eater). We examined 96 seven-to-twelve-year-old children and a control group of 32 adults measuring their eye-gaze changes in response to compound-internal plural and singular forms. Our results indicate that children rely more upon structural properties of language (in the present case, morphological cues) early in development and that the ability to efficiently integrate information from multiple sources takes time for children to reach adult-like levels.	\N	\N
24012681	It was recently shown that brain activity can be represented as a stimulation-specific vector field. Since the vector field of brain activity is specifically transformed by sensory input, we suggested that a tensor field that transforms brain activity reflects sensory input. We calculated the tensor fields that transform brain activity between visual baseline and auditory word processing in PET data and between environmental sounds and auditory word processing in fMRI data. In the first comparison, significant clusters formed a distributed network over the brain cortex. In the second comparison, clusters were more localised in the temporo-frontal network of speech processing. Our study therefore demonstrated that tensor fields reflect the sensory input that specifically transforms brain activity.	\N	\N
24016155	For studying multistable auditory perception, we propose a paradigm that evokes integrated or segregated perception of a sound sequence, and permits decomposition of the segregated grouping into foreground and background sounds. The paradigm combines 3-tone pitch patterns with alternating timbres, resulting in a repeating 6-tone structure that can be perceived as rising based on temporal proximity, or as falling based on timbre similarity. Listeners continuously report their percept while EEG is recorded. Results show an ERP modulation starting at ∼70 ms after sound onset that can be explained by whether a sound belongs to perceived foreground or background, with no additional effect of integrated versus segregated grouping. Auditory grouping as indexed by the mismatch negativity did not correspond with reported sound grouping. The paradigm offers a new possibility for investigating effects of conscious perceptual organization on sound processing.	\N	\N
24018572	The purpose of this study was to determine the effects of hearing instruments set to Desired Sensation Level version 5 (DSL v5) hearing instrument prescription algorithm targets and equipped with directional microphones and digital noise reduction (DNR) on children's sentence recognition in noise performance and loudness perception in a classroom environment. Ten children (ages 8-17 years) with stable, congenital sensorineural hearing losses participated in the study. Participants were fitted bilaterally with behind-the-ear hearing instruments set to DSL v5 prescriptive targets. Sentence recognition in noise was evaluated using the Bamford-Kowal-Bench Speech in Noise Test (Niquette et al., 2003). Loudness perception was evaluated using a modified version of the Contour Test of Loudness Perception (Cox, Alexander, Taylor, & Gray, 1997). Children's sentence recognition in noise performance was significantly better when using directional microphones alone or in combination with DNR than when using omnidirectional microphones alone or in combination with DNR. Children's loudness ratings for sounds above 72 dB SPL were lowest when fitted with the DSL v5 Noise prescription combined with directional microphones. DNR use showed no effect on loudness ratings. Use of the DSL v5 Noise prescription with a directional microphone improved sentence recognition in noise performance and reduced loudness perception ratings for loud sounds relative to a typical clinical reference fitting with the DSL v5 Quiet prescription with no digital signal processing features enabled. Potential clinical strategies are discussed.	\N	\N
24021849	Dehaene et al. (2003) showed an absence of conscious, but not masked, conflict effects when patients with schizophrenia performed a number-categorisation priming task. We aimed to replicate these influential results using a different word-categorisation priming task. Counter to Dehaene et al.'s findings, 21 patients and 20 healthy controls showed similar congruence effects for both masked and visible primes. Within patients, a reduced congruence effect for visible primes associated with longer duration of illness and more severe behavioural disorganisation. Patients, unlike controls, were no slower to respond to targets that followed visible compared to masked primes. Conscious conflict effects on priming tasks are not universally reduced in schizophrenia but may associate with chronicity and behavioural disorganisation. That patients were no slower when the preceding primes were clearly visible accords with evidence elsewhere that information processing in schizophrenia is driven more by immediate conscious experience and constrained less by prior events.	\N	\N
24024543	Emotion in audio-voice signals, as synthesized by text-to-speech (TTS) technologies, was investigated to formulate a theory of expression for user interface design. Emotional parameters were specified with markup tags, and the resulting audio was further modulated with post-processing techniques. Software was then developed to link a selected TTS synthesizer with an automatic speech recognition (ASR) engine, producing a chatbot that could speak and listen. Using these two artificial voice subsystems, investigators explored both artistic and psychological implications of artificial speech emotion. Goals of the investigation were interdisciplinary, with interest in musical composition, augmentative and alternative communication (AAC), commercial voice announcement applications, human-computer interaction (HCI), and artificial intelligence (AI). The work-in-progress points towards an emerging interdisciplinary ontology for artificial voices. As one study output, HCI tools are proposed for future collaboration.	\N	\N
24028995	Recent theory of physiology of language suggests a dual stream dorsal/ventral organization of speech perception. Using intra-cerebral Event-related potentials (ERPs) during pre-surgical assessment of twelve drug-resistant epileptic patients, we aimed to single out electrophysiological patterns during both lexical-semantic and phonological monitoring tasks involving ventral and dorsal regions respectively. Phonological information processing predominantly occurred in the left supra-marginal gyrus (dorsal stream) and lexico-semantic information occurred in anterior/middle temporal and fusiform gyri (ventral stream). Similar latencies were identified in response to phonological and lexico-semantic tasks, suggesting parallel processing. Typical ERP components were strongly left lateralized since no evoked responses were recorded in homologous right structures. Finally, ERP patterns suggested the inferior frontal gyrus as the likely final common pathway of both dorsal and ventral streams. These results brought out detailed evidence of the spatial-temporal information processing in the dual pathways involved in speech perception.	\N	\N
24032320	The purpose was the develop a questionnaire to identify the specific listening difficulties of second language (L2) learners. Based on previous research, a questionnaire containing 31 items was developed and administered to 1,056 college freshmen. The whole sample was split randomly into two subsamples, each containing 528 cases. Exploratory factor analysis was performed to analyse the first subsample, and six factors were extracted, explaining a total of 57.1% of variance. To test the factor model, confirmatory factor analysis was conducted with the second subsample. Various fit indices were examined. The best fitting model for the data was a 23-item, six-factor model representing text, input channel and surroundings, relevance, listener, speaker, and task. Apart from the listener factor, all components are external ones and deemed to be uncontrollable by listeners. L2 learners must take an active role in listening practice to overcome L2 listening difficulties.	\N	\N
24034879	This paper presents an analytic procedure to assist safety practitioners in evaluating the audibility of an existing auditory warning system in their workplaces. Two alarm location models are described: (a) a model with an unknown signal sound level, and (b) a model with a known signal sound level. A heuristic algorithm to determine a minimum number of alarm devices and their locations so that the warning signals can be clearly heard by workers is also proposed. The algorithm considers the ambient noise level, noise levels generated by individual machines, locations where workers are likely to be present, and noise levels at worker locations. From the numerical examples and the computation experiment, both the optimization and heuristic approaches yield solutions that satisfy the 15-dBA constraints. The heuristic approach is efficient in solving large alarm location problems due its capability to find near-optimal solutions within reasonable computation time.	\N	\N
24035819	Given recent interest in syllabic rates (∼2-5 Hz) for speech processing, we review the perception of "fluctuation" range (∼1-10 Hz) modulations during listening to speech and technical auditory stimuli (AM and FM tones and noises, and ripple sounds). We find evidence that the temporal modulation transfer function (TMTF) of human auditory perception is not simply low-pass in nature, but rather exhibits a peak in sensitivity in the syllabic range (∼2-5 Hz). We also address human and animal neurophysiological evidence, and argue that this bandpass tuning arises at the thalamocortical level and is more associated with non-primary regions than primary regions of cortex. The bandpass rather than low-pass TMTF has implications for modeling auditory central physiology and speech processing: this implicates temporal contrast rather than simple temporal integration, with contrast enhancement for dynamic stimuli in the fluctuation range. This article is part of a Special Issue entitled "Communication Sounds and the Brain: New Directions and Perspectives".	\N	\N
24042339	Behavioral improvement within the first hour of training is commonly explained as procedural learning (i.e., strategy changes resulting from task familiarization). However, it may additionally reflect a rapid adjustment of the perceptual and/or attentional system in a goal-directed task. In support of this latter hypothesis, we show feature-specific gains in performance for groups of participants briefly trained to use either a spectral or spatial difference between 2 vowels presented simultaneously during a vowel identification task. In both groups, the neuromagnetic activity measured during the vowel identification task following training revealed source activity in auditory cortices, prefrontal, inferior parietal, and motor areas. More importantly, the contrast between the 2 groups revealed a striking double dissociation in which listeners trained on spectral or spatial cues showed higher source activity in ventral ("what") and dorsal ("where") brain areas, respectively. These feature-specific effects indicate that brief training can implicitly bias top-down processing to a trained acoustic cue and induce a rapid recalibration of the ventral and dorsal auditory streams during speech segregation and identification.	\N	\N
24047945	Tests of auditory perception, such as those used in the assessment of central auditory processing disorders ([C]APDs), represent a domain in audiological assessment where measurement of this theoretical construct is often confounded by nonauditory abilities due to methodological shortcomings. These confounds include the effects of cognitive variables such as memory and attention and suboptimal testing paradigms, including the use of verbal reproduction as a form of response selection. We argue that these factors need to be controlled more carefully and/or modified so that their impact on tests of auditory and visual perception is only minimal. To advocate for a stronger theoretical framework than currently exists and to suggest better methodological strategies to improve assessment of auditory processing disorders (APDs). Emphasis is placed on adaptive forced-choice psychophysical methods and the use of matched tasks in multiple sensory modalities to achieve these goals. Together, this approach has potential to improve the construct validity of the diagnosis, enhance and develop theory, and evolve into a preferred method of testing. Examination of methods commonly used in studies of APDs. Where possible, currently used methodology is compared to contemporary psychophysical methods that emphasize computer-controlled forced-choice paradigms. In many cases, the procedures used in studies of APD introduce confounding factors that could be minimized if computer-controlled forced-choice psychophysical methods were utilized. Ambiguities of interpretation, indeterminate diagnoses, and unwanted confounds can be avoided by minimizing memory and attentional demands on the input end and precluding the use of response-selection strategies that use complex motor processes on the output end. Advocated are the use of computer-controlled forced-choice psychophysical paradigms in combination with matched tasks in multiple sensory modalities to enhance the prospect of obtaining a valid diagnosis.	\N	\N
24048514	We studied autistics by quantitative EEG spectral and coherence analysis during three experimental conditions: basal, watching a cartoon with audio (V-A), and with muted audio band (VwA). Significant reductions were found for the absolute power spectral density (PSD) in the central region for delta and theta, and in the posterior region for sigma and beta bands, lateralized to the right hemisphere. When comparing VwA versus the V-A in the midline regions, we found significant decrements of absolute PSD for delta, theta and alpha, and increments for the beta and gamma bands. In autistics, VwA versus V-A tended to show lower coherence values in the right hemisphere. An impairment of visual and auditory sensory integration in autistics might explain our results.	\N	\N
24059595	The frequency-following response (FFR) is the compound phase-locked brainstem response to periodic components of sound stimuli, and is closely related to pitch perception. Its weak amplitude often prevents its measurement with a high signal-to-noise ratio (SNR). Recording of FFR using multichannel EEG is possible but expensive and it involves the manual screening of raw data. We describe a new method to extract FFR features by prescreening the raw data using automatic monitoring of sound pressure in the ear canal. Removal of stimulus artifacts, noise reduction, and data selection were systematically studied. The reliability of our new method was tested by comparing FFRs tracking accuracy and pitch perception in fifteen individuals with normal hearing. The extracted FFRs tracking accuracy was significantly correlated with behavioral measures of pitch perception, indicating that FFR could be used to represent individual differences in pitch perception ability among a population with similar hearing characteristics. The designed system could extract FFR signals more accurately with high SNR after signal prescreen and noise reduction.	\N	\N
24060845	The present study investigated whether and how beat gesture (small baton-like hand movements used to emphasize information in speech) influences semantic processing as well as its interaction with pitch accent during speech comprehension. Event-related potentials were recorded as participants watched videos of a person gesturing and speaking simultaneously. The critical words in the spoken sentences were accompanied by a beat gesture, a control hand movement, or no hand movement, and were expressed either with or without pitch accent. We found that both beat gesture and control hand movement induced smaller negativities in the N400 time window than when no hand movement was presented. The reduced N400s indicate that both beat gesture and control movement facilitated the semantic integration of the critical word into the sentence context. In addition, the words accompanied by beat gesture elicited smaller negativities in the N400 time window than those accompanied by control hand movement over right posterior electrodes, suggesting that beat gesture has a unique role for enhancing semantic processing during speech comprehension. Finally, no interaction was observed between beat gesture and pitch accent, indicating that they affect semantic processing independently.	\N	\N
24060967	Some dialogues are perceived as running more smoothly than others. To some extent that impression could be related to how well speakers adapt their prosody to each other. Adaptation in prosody can be signaled by the use of pitch accents that indicate how utterances are structurally related to those of the interlocutor (prosodic function) or by copying the interlocutor's prosodic features (prosodic form). The same acoustic features, such as pitch, are involved in both ways of adaptation. Further, function and form may require a different prosody for successful adaptation in certain discourse contexts. In this study we investigate to what extent interlocutors are perceived as good adapters, depending on whether the prosody of both speakers is functionally coherent or similar in form. This is done in two perception tests using prosodically manipulated dialogues. Results show that coherent functional prosody can be a cue for speaker adaptation and that this cue is more powerful than similarity in prosodic form.	\N	\N
24066179	We tested non-musicians and musicians in an auditory psychophysical experiment to assess the effects of timbre manipulation on pitch-interval discrimination. Both groups were asked to indicate the larger of two presented intervals, comprised of four sequentially presented pitches; the second or fourth stimulus within a trial was either a sinusoidal (or "pure"), flute, piano, or synthetic voice tone, while the remaining three stimuli were all pure tones. The interval-discrimination tasks were administered parametrically to assess performance across varying pitch distances between intervals ("interval-differences"). Irrespective of timbre, musicians displayed a steady improvement across interval-differences, while non-musicians only demonstrated enhanced interval discrimination at an interval-difference of 100 cents (one semitone in Western music). Surprisingly, the best discrimination performance across both groups was observed with pure-tone intervals, followed by intervals containing a piano tone. More specifically, we observed that: 1) timbre changes within a trial affect interval discrimination; and 2) the broad spectral characteristics of an instrumental timbre may influence perceived pitch or interval magnitude and make interval discrimination more difficult.	\N	\N
24073580	To establish music reference values for normal-hearing (NH) person in China, in order to give convenience in clinical application. The NH participant group included 39 subjects, of which 21 females and 18 males. Musical Sounds in Cochlear Implants test battery was used to assess the music perception ability for normal-hearing participants. The median pitch difference NH participants could discriminate for string was 2.5 semitones and 0.5 for flute. The average scores of rhythm discrimination, melody discrimination, chord discrimination, instrument identification and instrument number detection test were 86.1% (SD = 11.2), 76.5% (SD = 11.1), 75.6% (SD = 11.4), 89.9% (SD = 13.0) and 74.1% (SD = 20.7), respectively. The MuSIC test could be a test for music perception ability for China users and in further study the material that more suited for our culture should be added into it.	\N	\N
24073684	Work on the perception of urban soundscapes has generated a number of perceptual models which are proposed as tools to test and evaluate soundscape interventions. However, despite the excessive sound levels and noise within hospital environments, perceptual models have not been developed for these spaces. To address this, a two-stage approach was developed by the authors to create such a model. First, semantics were obtained from listening evaluations which captured the feelings of individuals from hearing hospital sounds. Then, 30 participants rated a range of sound clips representative of a ward soundscape based on these semantics. Principal component analysis extracted a two-dimensional space representing an emotional-cognitive response. The framework enables soundscape interventions to be tested which may improve the perception of these hospital environments.	\N	\N
24080979	Cochlear implantation (CI) is currently the main device option for children with auditory neuropathy spectrum disorder (ANSD) who receive minimal benefit from conventional amplification. This study examines potential prognostic factors associated with post-CI speech performance in this population. Retrospective chart review. Academic center. ANSD patients without inner ear abnormalities implanted with unilateral or bilateral CI between 1998 and 2010. CI and speech perception testing. Post-CI speech perception testing at 50 dBHL. "Good" performers were defined as patients with greater than 70% speech perception and "poor" performers less than 70%. Medical comorbidity, educational information, and social history were gathered. Twenty-seven patients met inclusion criteria. Mean age at diagnosis, first CI, and second CI in good performers were 2.5 ± 3.4, 3.4 ± 3.6, and 3.8 ± 1.6 years, respectively, compared with 9.7 ± 7.8, 14.8 ± 12.9, and 8.9 ± 3.5 in poor performers. Mean speech perception after first and second implantation for good performers trended at 85% and 90%, respectively, compared with 36% and 73% in poor performers. Better pre-CI PTA correlated with better post-CI speech perception. Patients with bilateral CI demonstrated better speech perception outcomes compared with unilateral CI use. Poor performers had later age of implantation, lower socioeconomic status, and lack of family support compared with good performers. ANSD patients who do not benefit from conventional amplification do well when implanted at a young age with proper access to education and habilitation training. Medical, social, and economic information may be helpful in predicting positive outcomes.	\N	\N
24083896	In this cross-language study, six Italian and six French voice experts evaluated perceptually the speech of 27 Italian and 40 French patients with dysphonia to determine if there were differences based on native language. French and Italian voice specialists agreed substantially in their evaluations of the overall grade of dysphonia and moderately concerning roughness and breathiness. No statistically significant effects were found related to the language of the speakers with the exception of breathiness, a finding that was interpreted as being due to different voice pathologies in the patient groups. It was concluded that the perception of the overall grade of dysphonia and breathiness is not language-dependent, whereas the significant difference in the perception of roughness may be related to a perception/adaption process.	\N	\N
24089502	Linguistic content can be conveyed both in speech and in writing. But how similar is the neural processing when the same real-life information is presented in spoken and written form? Using functional magnetic resonance imaging, we recorded neural responses from human subjects who either listened to a 7 min spoken narrative or read a time-locked presentation of its transcript. Next, within each brain area, we directly compared the response time courses elicited by the written and spoken narrative. Early visual areas responded selectively to the written version, and early auditory areas to the spoken version of the narrative. In addition, many higher-order parietal and frontal areas demonstrated strong selectivity, responding far more reliably to either the spoken or written form of the narrative. By contrast, the response time courses along the superior temporal gyrus and inferior frontal gyrus were remarkably similar for spoken and written narratives, indicating strong modality-invariance of linguistic processing in these circuits. These results suggest that our ability to extract the same information from spoken and written forms arises from a mixture of selective neural processes in early (perceptual) and high-order (control) areas, and modality-invariant responses in linguistic and extra-linguistic areas.	\N	\N
24091182	The auditory nervous system is highly nonlinear. Some nonlinear responses arise through active processes in the cochlea, while others may arise in neural populations of the cochlear nucleus, inferior colliculus and higher auditory areas. In humans, auditory brainstem recordings reveal nonlinear population responses to combinations of pure tones, and to musical intervals composed of complex tones. Yet the biophysical origin of central auditory nonlinearities, their signal processing properties, and their relationship to auditory perception remain largely unknown. Both stimulus components and nonlinear resonances are well represented in auditory brainstem nuclei due to neural phase-locking. Recently mode-locking, a generalization of phase-locking that implies an intrinsically nonlinear processing of sound, has been observed in mammalian auditory brainstem nuclei. Here we show that a canonical model of mode-locked neural oscillation predicts the complex nonlinear population responses to musical intervals that have been observed in the human brainstem. The model makes predictions about auditory signal processing and perception that are different from traditional delay-based models, and may provide insight into the nature of auditory population responses. We anticipate that the application of dynamical systems analysis will provide the starting point for generic models of auditory population dynamics, and lead to a deeper understanding of nonlinear auditory signal processing possibly arising in excitatory-inhibitory networks of the central auditory nervous system. This approach has the potential to link neural dynamics with the perception of pitch, music, and speech, and lead to dynamical models of auditory system development.	\N	\N
24094802	Although reduced stress is thought to be one of the most deviant speech dimensions in hypokinetic dysarthria associated with Parkinson's disease (PD), the mechanisms of stress production in PD have not been thoroughly explored by objective methods. The aim of the present study was to quantify the effect of PD on prosodic characteristics and to describe contrastive stress patterns in parkinsonian speech. The ability of 20 male speakers with early PD and 16 age- and gender-matched healthy controls (HCs) to signal contrastive stress was investigated. Each participant was instructed to unnaturally emphasize five key words while reading a short block of text. Acoustic analyses were based on the measurement of pitch, intensity, and duration. In addition, an innovative measurement termed the stress pattern index (SPI) was designed to mirror the effect of all distinct acoustic cues exploited during stress production. Although PD patients demonstrated a reduced ability to convey contrastive stress, they could still notably increase pitch, intensity, and duration to emphasize a word within a sentence. No differences were revealed between PD and HC stress productions using the measurements of pitch, intensity, duration, and intensity range. However, restricted SPI and pitch range were evident in the PD group. A reduced ability to express stress seems to be the distinctive pattern of hypokinetic dysarthria, even in the early stages of PD. Because PD patients were able to consciously improve their speech performance using multiple acoustic cues, the introduction of speech therapy may be rewarding.	\N	\N
24098565	In the present study, we investigated brain morphological signatures of dyslexia by using a voxel-based asymmetry analysis. Dyslexia is a developmental disorder that affects the acquisition of reading and spelling abilities and is associated with a phonological deficit. Speech perception disabilities have been associated with this deficit, particularly when listening conditions are challenging, such as in noisy environments. These deficits are associated with known neurophysiological correlates, such as a reduction in the functional activation or a modification of functional asymmetry in the cortical regions involved in speech processing, such as the bilateral superior temporal areas. These functional deficits have been associated with macroscopic morphological abnormalities, which potentially include a reduction in gray and white matter volumes, combined with modifications of the leftward asymmetry along the perisylvian areas. The purpose of this study was to investigate gray/white matter distribution asymmetries in dyslexic adults using automated image processing derived from the voxel-based morphometry technique. Correlations with speech-in-noise perception abilities were also investigated. The results confirmed the presence of gray matter distribution abnormalities in the superior temporal gyrus (STG) and the superior temporal Sulcus (STS) in individuals with dyslexia. Specifically, the gray matter of adults with dyslexia was symmetrically distributed over one particular region of the STS, the temporal voice area, whereas normal readers showed a clear rightward gray matter asymmetry in this area. We also identified a region in the left posterior STG in which the white matter distribution asymmetry was correlated to speech-in-noise comprehension abilities in dyslexic adults. These results provide further information concerning the morphological alterations observed in dyslexia, revealing the presence of both gray and white matter distribution anomalies and the potential involvement of these defects in speech-in-noise deficits.	\N	\N
24098665	Numerous studies have documented the phenomenon of phonetic imitation: the process by which the production patterns of an individual become more similar on some phonetic or acoustic dimension to those of her interlocutor. Though social factors have been suggested as a motivator for imitation, few studies has established a tight connection between language-external factors and a speaker's likelihood to imitate. The present study investigated the phenomenon of phonetic imitation using a within-subject design embedded in an individual-differences framework. Participants were administered a phonetic imitation task, which included two speech production tasks separated by a perceptual learning task, and a battery of measures assessing traits associated with Autism-Spectrum Condition, working memory, and personality. To examine the effects of subjective attitude on phonetic imitation, participants were randomly assigned to four experimental conditions, where the perceived sexual orientation of the narrator (homosexual vs. heterosexual) and the outcome (positive vs. negative) of the story depicted in the exposure materials differed. The extent of phonetic imitation by an individual is significantly modulated by the story outcome, as well as by the participant's subjective attitude toward the model talker, the participant's personality trait of openness and the autistic-like trait associated with attention switching.	\N	\N
24099584	The objective of this prospective study was to investigate the relationship between acceptable noise level (ANL), which was measured using Taiwanese and the international speech test signal (ISTS), and real-world hearing-aid success for listeners who were representative of the population commonly seen in clinics. Unaided ANLs were measured pre-hearing-aid fitting. Hearing-aid success was assessed three months post-fitting using the international outcome inventory for hearing aids (IOI-HA) and a hearing-aid use questionnaire. Eighty adults with hearing impairment completed the study. Both Taiwanese and ISTS ANLs were significantly associated with hearing-aid success, with higher ANLs suggesting poorer outcomes. However, the ANL's prediction accuracy for the probability of hearing-aid success was either much lower than that suggested by some literature, or was not much different from that of simply predicting all listeners as successful users. The current study suggested the possibility of using ANL to predict hearing-aid success. However, the usefulness of ANL as a clinical tool is unlikely to be as great as indicated by the literature.	\N	\N
24101343	In a series of three experiments, we used an ambiguous plaid motion stimulus to explore the behavioral and electrophysiological effects of prior stimulus exposures and perceptual states on current awareness. The results showed that prior exposure to a stimulus biased toward one percept led to subsequent suppression of that percept. In contrast, in the absence of stimulus bias, prior perceptual experience can have a facilitative influence. The suppressive effects caused by the prior stimulus were found to transfer to an ambiguous plaid test stimulus rotated 180º relative to the adaptation stimulus, but were abolished if (1) the ambiguous test stimulus was only rotated 90º relative to the adaptation stimulus or (2) the adaptation stimulus was heavily biased toward the component grating percept. Event-related potential recordings were consistent with the involvement of visual cortical areas and suggested that the influence of recent stimulus exposure may involve recruitment of additional brain processes beyond those responsible for initial stimulus encoding. In contrast, the effects of prior and current perceptual experience appeared to depend on similar brain processes. Although the data presented here focus on vision, the work is discussed within the context of data from a parallel series of experiments in audition.	\N	\N
24110307	The cocktail party problem is a multi-faceted challenge which encompasses various aspects of auditory perception. Its processes underlie the brain's ability to detect, identify and classify sound objects; to robustly represent and maintain speech intelligibility amidst severe distortions; and to guide actions and behaviors in line with complex goals and shifting acoustic soundscapes. Here, we present a perspective that considers the powerful Bayesian inference as a unifying framework to integrate the role of sensory cues as well as stimulus-driven priors and top-down schemas including attention.	\N	\N
24110658	Temporal fine structure (TFS) carries important information for the speech perception of hearing-impaired listeners and for the design of novel prosthetic hearing devices. This study assessed the performance of present intelligibility indices for predicting the intelligibility of speech containing different amount of TFS information. Speech intelligibility data was collected from vocoded and wideband Mandarin sentences containing little/partial and intact TFS information, respectively, and was then subjected to the correlation analysis with existing intelligibility indices. It was found that, though performing well in predicting the intelligibility of vocoded or wideband speech separately, present intelligibility indices were not highly correlated with the intelligibility scores when a general function was used to map all intelligibility measures to intelligibility scores. Analysis further showed that the intelligibility prediction power could be significantly improved when multiple condition-dependent functions were used for mapping intelligibility measures to intelligibility scores.	\N	\N
24116428	Bilateral cochlear implants (CIs) have provided some success in improving spatial hearing abilities to patients, but with large variability in performance. One reason for the variability is that there may be a mismatch in the place-of-stimulation arising from electrode arrays being inserted at different depths in each cochlea. Goupell et al. [(2013b). J. Acoust. Soc. Am. 133(4), 2272-2287] showed that increasing interaural mismatch led to non-fused auditory images and poor lateralization of interaural time differences in normal hearing subjects listening to a vocoder. However, a greater bandwidth of activation helped mitigate these effects. In the present study, the same experiments were conducted in post-lingually deafened bilateral CI users with deliberate and controlled interaural mismatch of single electrode pairs. Results show that lateralization was still possible with up to 3 mm of interaural mismatch, even when off-center, or multiple, auditory images were perceived. However, mismatched inputs are not ideal since it leads to a distorted auditory spatial map. Comparison of CI and normal hearing listeners showed that the CI data were best modeled by a vocoder using Gaussian-pulsed tones with 1.5 mm bandwidth. These results suggest that interaural matching of electrodes is important for binaural cues to be maximally effective.	\N	\N
24116537	Using molecular psychophysics, temporal loudness weights were measured for 2-s, 1-kHz tones with flat, increasing and decreasing time-intensity profiles. While primacy and recency effects were observed for flat profile stimuli, the so-called "level dominance" effect was observed for both increasing and decreasing profile stimuli, fully determining their temporal weights. The weighs obtained for these profiles were basically zero for all but the most intense parts of these sounds. This supports the view that the "level dominance" effect is prominent with intensity-varying sounds and that it persists over time since temporal weights are not affected by the direction of intensity change.	\N	\N
24124356	To assess the benefits of cochlear implantation in the elderly. A retrospective analysis of 31 postlingually deafened elderly (≥60 years of age) with unilateral cochlear implants was conducted. Audiological testing included preoperative and postoperative pure-tone audiometry and a monosyllabic word recognition test presented from recorded material in free field. Speech perception tests included Ling's six sound test (sound detection, discrimination, and identification), syllable discrimination, and monosyllabic and multisyllabic word recognition (open set) without lip-reading. Everyday life benefits from cochlear implantation were also evaluated. The mean age at the time of cochlear implantation was 72.4 years old. The mean postimplantation follow-up time was 2.34 years. All patients significantly improved their audiological and speech understanding performances. The preoperative mean pure-tone average threshold for 500 Hz, 1,000 Hz, 2,000 Hz, and 4,000 Hz was 110.17 dB HL. Before cochlear implantation, all patients scored 0% on the monosyllabic word recognition test in free field at 70 dB SPL intensity level. The postoperative pure-tone average was 37.14 dB HL (the best mean threshold was 17.50 dB HL, the worst was 58.75 dB HL). After the surgery, mean monosyllabic word recognition reached 47.25%. Speech perception tests showed statistically significant improvement in speech recognition. The results of this study showed that cochlear implantation is indeed a successful treatment for improving speech recognition and offers a great help in everyday life to deafened elderly patients. Therefore, they can be good candidates for cochlear implantation and their age alone should not be a relevant or excluding factor when choosing candidates for cochlear implantation.	\N	\N
24129008	PURPOSE Previous work has shown that monolingual French and English speakers use distinct articulatory settings, the underlying articulatory posture of a language. In the present article, the authors report on an experiment in which they investigated articulatory settings in bilingual speakers. The authors first tested the hypothesis that in order to sound native-like, bilinguals must use distinct, language-specific articulatory settings in monolingual mode. The authors then tested the hypothesis that in bilingual mode, a bilingual individual's articulatory setting is identical to the monolingual-mode setting of 1 of his or her languages. METHOD Eight French-English bilinguals each read 90 English and 90 French sentences, and the authors measured their interspeech posture (ISP) using optical tracking of the lips and jaw and ultrasound imaging of the tongue. RESULTS Results show that bilingual speakers who are perceived as native in both languages exhibit distinct, language-specific ISPs, and those who are not perceived as native in one or more languages do not. In bilingual mode, bilinguals use an ISP that is equivalent to the monolingual-mode ISP of their currently most used language. The most balanced bilingual used a French lip ISP but an English tongue-tip ISP. CONCLUSION Results support the claim that bilinguals who sound native in each of their languages have distinct articulatory settings for each language.	\N	\N
24130256	Biological motion research is an increasingly active field, with a great potential to contribute to a wide range of applications, such as behavioral monitoring/motion detection in surveillance situations, intention inference in social interactions, and diagnostic tools in autism research. In recent years, a large amount of motion capture data has become freely available online, potentially providing rich stimulus sets for biological motion research. However, there currently does not exist an easy-to-use tool to extract, present and manipulate motion capture data in the MATLAB environment, which many researchers use to program their experiments. We have developed the Biomotion Toolbox, which allows researchers to import motion capture data in a variety of formats, to display actions using Psychtoolbox 3, and to manipulate action displays in specific ways (e.g., inversion, three-dimensional rotation, spatial scrambling, phase-scrambling, and limited lifetime). The toolbox was designed to allow researchers with a minimal level of MATLAB programming skills to code experiments using biological motion stimuli.	\N	\N
24130865	Temporal processing underlies both music and language skills. There is increasing evidence that rhythm abilities track with reading performance and that language disorders such as dyslexia are associated with poor rhythm abilities. However, little is known about how basic time-keeping skills can be shaped by musical training, particularly during critical literacy development years. This study was carried out in collaboration with Harmony Project, a non-profit organization providing free music education to children in the gang reduction zones of Los Angeles. Our findings reveal that elementary school children with just one year of classroom music instruction perform more accurately in a basic finger-tapping task than their untrained peers, providing important evidence that fundamental time-keeping skills may be strengthened by short-term music training. This sets the stage for further examination of how music programs may be used to support the development of basic skills underlying learning and literacy, particularly in at-risk populations which may benefit the most.	\N	\N
24131604	The Dichotic Verbal Memory Test (DVMT) is useful in detecting verbal memory deficits and differences in memory function between the brain hemispheres. The purpose of this study was to prepare the Persian version of DVMT, to obtain its results in 18- to 25-yr-old Iranian individuals, and to examine the ear, gender, and serial position effect. The Persian version of DVMT consisted of 18 10-word lists. After preparing the 18 lists, content validity was assessed by a panel of eight experts and the equivalency of the lists was evaluated. Then the words were recorded on CD in a dichotic mode such that 10 words were presented to one ear, with the same words reversed simultaneously presented to the other ear. Thereafter, it was performed on a sample of young, normal, Iranian individuals. Thirty normal individuals (no history of neurological, ontological, or psychological diseases) with ages ranging from 18 to 25 yr were examined for evaluating the equivalency of the lists, and 110 subjects within the same age range participated in the final stage of the study to obtain the normative data on the developed test. There was no significant difference between the mean scores of the 18 developed lists (p > 0.05). The mean content validity index (CVI) score was .96. A significant difference was found between the mean score of the two ears (p < 0.05) and between female and male participants (p < 0.05). The Persian version of DVMT has good content validity and can be used for verbal memory assessment in Iranian young adults.	\N	\N
24131606	Current bone anchored hearing solutions (BAHSs) have incorporated automatic adaptive multichannel directional microphones (DMs). Previous fixed single-channel hypercardioid DMs in BAHSs have provided benefit in a diffuse listening environment, but little data are available on the performance of adaptive multichannel DMs in BAHSs for persons with unilateral sensorineural hearing loss (USNHL). The primary goal was to determine if statistically significant differences existed in the mean Reception Threshold for Sentences (RTS in dB) in diffuse uncorrelated restaurant noise between unaided, an omnidirectional microphone (OM), split DM (SDM), and full DM (FDM) in the Oticon Medical Ponto Pro. A second goal was to assess subjective benefit using the Abbreviated Profile of Hearing Aid Benefit (APHAB) comparing the Ponto Pro to the participant's current BAHS, and the Ponto Pro and participant's own BAHS to unaided. The third goal was to compare RTS data of the Ponto Pro to data from an identical study examining Cochlear Americas' Divino. A randomized repeated measures, single blind design was used to measure an RTS for each participant for unaided, OM, SDM, and FDM. Fifteen BAHS users with USNHL were recruited from Washington University in St. Louis and the surrounding area. The Ponto Pro was fit by measuring in-situ bone conduction thresholds and was worn for 4 wk. An RTS was obtained utilizing Hearing in Noise Test (HINT) sentences in uncorrelated restaurant noise from an eight loudspeaker array, and subjective benefit was determined utilizing the APHAB. Analysis of variance (ANOVA) was used to analyze the results of the Ponto Pro HINT and APHAB data, and comparisons between the Ponto Pro and previous Divino data. No statistically significant differences existed in mean RTS between unaided, the Ponto Pro's OM, SDM, or FDM (p = 0.10). The Ponto Pro provided statistically significant benefit for the Background Noise (BN) (p < 0.01) and Reverberation (RV) (p < 0.05) subscales compared to the participant's own BAHS. The Ponto Pro (Ease of Communication [EC] [p < 0.01], BN [p < 0.001], and RV [p < 0.01] subscales) and participant's own BAHS (BN [p < 0.01] and RV [p < 0.01] subscales) overall provided statistically significant benefit compared to unaided. Clinically significant benefit of 5% was present for the Ponto Pro compared to the participant's own BAHS and 10% for the Ponto Pro and the participant's own BAHS compared to unaided. The Ponto Pro's OM (p = 0.05), SDM (p = 0.05), and FDM (p < 0.01) were statistically significantly better than the Divino's OM. No significant differences existed between the Ponto Pro's OM, SDM, and FDM compared to the Divino's DM. No statistically significant differences existed between unaided, OM, SDM, or FDM. Participants preferred the Ponto Pro compared to the participant's own BAHS and the Ponto Pro and participant's own BAHS compared to unaided. The RTS of the Ponto Pro's adaptive multichannel DM was similar to the Divino's fixed hypercardioid DM, but the Ponto Pro's OM was statistically significantly better than the Divino's OM.	\N	\N
24136318	Hearing loss resulting from bilateral vestibular schwannomas (VSs) has a significant effect on the quality of life of patients with neurofibromatosis Type 2 (NF2). A national consensus protocol was produced in England as a guide for cochlear implantation (CI) and auditory brainstem implantation (ABI) in these patients. Consensus statement. English NF2 Service. Clinicians from all 4 lead NF2 units in England. A protocol for the assessment, insertion and rehabilitation of CI and ABI in NF2 patients. Patients should undergo more detailed hearing assessment once their maximum aided speech discrimination score falls below 50% in the better hearing ear. Bamford-Kowal-Bench sentence testing scores below 50% should trigger assessment for auditory implantation, as recommended by the National Institute for Clinical Excellence guidelines on CI. Where this occurs in patients with bilateral stable VS or a unilateral stable VS where the contralateral cochlear nerve was lost at previous surgery, CI should be considered. Where VS surgery is planned, CI should be considered where cochlear nerve preservation is thought possible, otherwise an ABI should be considered. Intraoperative testing using electrically evoked auditory brainstem responses or cochlear nerve action potentials may be used to determine whether a CI or ABI is inserted. The NF2 centers in England agreed on this protocol. Multisite, prospective assessments of standardized protocols for auditory implantation in NF2 provide an essential model for evaluating candidacy and outcomes in this challenging patient population.	\N	\N
24139706	Language experience can alter perceptual abilities and the neural specialization for phonological contrasts. Here we investigated whether dialectal differences in the lexical use of pitch information lead to differences in functional lateralization for pitch processing. We measured cortical hemodynamic responses to pitch pattern changes in native speakers of Standard (Tokyo) Japanese, which has a lexical pitch accent system, and native speakers of 'accentless' dialects, which do not have any lexical tonal phenomena. While the Standard Japanese speakers showed left-dominant responses in temporal regions to pitch pattern changes within words, the accentless dialects speakers did not show such left-dominance. Pitch pattern changes within harmonic-complex tones also elicited different brain activation patterns between the two groups. These results indicate that the neural processing of pitch information differs depending on the listener's native dialect, and that listeners' linguistic experiences may further affect the processing of pitch changes even for non-linguistic sounds.	\N	\N
24141311	Across all sensory modalities, the effect of context-dependent neural adaptation can be observed at every level, from receptors to perception. Nonetheless, it has long been assumed that the processing of interaural time differences, which is the primary cue for sound localization, is nonadaptive, as its outputs are mapped directly onto a hard-wired representation of space. Here we present evidence derived from in vitro and in vivo experiments in gerbils indicating that the coincidence-detector neurons in the medial superior olive modulate their sensitivity to interaural time differences through a rapid, GABA(B) receptor-mediated feedback mechanism. We show that this mechanism provides a gain control in the form of output normalization, which influences the neuronal population code of auditory space. Furthermore, psychophysical tests showed that the paradigm used to evoke neuronal GABA(B) receptor-mediated adaptation causes the perceptual shift in sound localization in humans that was expected on the basis of our physiological results in gerbils.	\N	\N
24141681	The signal processing strategy is a parameter that may influence the auditory performance of cochlear implant and is important to optimize this parameter to provide better speech perception, especially in difficult listening situations. To evaluate the individual's auditory performance using two different signal processing strategy. Prospective study with 11 prelingually deafened children with open-set speech recognition. A within-subjects design was used to compare performance with standard HiRes and HiRes 120 in three different moments. During test sessions, subject's performance was evaluated by warble-tone sound-field thresholds, speech perception evaluation, in quiet and in noise. In the silence, children S1, S4, S5, S7 showed better performance with the HiRes 120 strategy and children S2, S9, S11 showed better performance with the HiRes strategy. In the noise was also observed that some children performed better using the HiRes 120 strategy and other with HiRes. Not all children presented the same pattern of response to the different strategies used in this study, which reinforces the need to look at optimizing cochlear implant clinical programming.	\N	\N
24148845	Autism spectrum disorders (ASDs) are associated with auditory hyper- or hyposensitivity; atypicalities in central auditory processes, such as speech-processing and selective auditory attention; and neural connectivity deficits. We sought to investigate whether the low-level integrative processes underlying sound localization and spatial discrimination are affected in ASDs. We performed 3 behavioural experiments to probe different connecting neural pathways: 1) horizontal and vertical localization of auditory stimuli in a noisy background, 2) vertical localization of repetitive frequency sweeps and 3) discrimination of horizontally separated sound stimuli with a short onset difference (precedence effect). Ten adult participants with ASDs and 10 healthy control listeners participated in experiments 1 and 3; sample sizes for experiment 2 were 18 adults with ASDs and 19 controls. Horizontal localization was unaffected, but vertical localization performance was significantly worse in participants with ASDs. The temporal window for the precedence effect was shorter in participants with ASDs than in controls. The study was performed with adult participants and hence does not provide insight into the developmental aspects of auditory processing in individuals with ASDs. Changes in low-level auditory processing could underlie degraded performance in vertical localization, which would be in agreement with recently reported changes in the neuroanatomy of the auditory brainstem in individuals with ASDs. The results are further discussed in the context of theories about abnormal brain connectivity in individuals with ASDs.	\N	\N
24150886	Facilitatory effects have been noted between tools and the objects that they act upon (their "action recipients") across several paradigms. However, it has not been convincingly established that the motor system is directly involved in the joint visual processing of these object pairings. Here, we used the attentional blink (AB) paradigm to demonstrate privileged access to perceptual awareness for tool-action recipient object pairs and to investigate how motor affordances modulate their joint processing. We demonstrated a reduction in the size of the AB that was greater for congruent tool-action recipient pairings (e.g., hammer-nail) than for incongruent pairings (e.g., scissors-nail). Moreover, the AB was reduced only when action recipients followed their associated tool in the temporal sequence, but not when this order was reversed. Importantly, we also found that the effect was sensitive to manipulations of the motor congruence between the tool and the action recipient. First, we observed a greater reduction in the AB when the tool and action recipient were correctly aligned for action than when the tool was rotated to face away from the action recipient. Second, presenting a different tool as a distractor between the tool and action recipient target objects removed any benefit seen for congruent pairings. This was likely due to interference from the motor properties of the distractor tool that disrupted the motor synergy between the congruent tool and action recipient targets. Overall, these findings demonstrate that the contextual motoric relationship between tools and their action recipients facilitates their visual encoding and access to perceptual awareness.	\N	\N
24157488	The aim of this study was to evaluate electrode array position in relation to cochlear anatomy and its influence on hearing performance in cochlear implantees. Twenty-two patients (25 ears) with Med-El cochlear implants were included in this retrospective study. A negative correlation was observed between electrode-modiolus distance (EMD) at the cochlear base and monosyllabic word discrimination 6 months after implantation. We found no correlation between EMD and hearing outcome at 12 months. The insertion depth/cochlear perimeter ratio appeared to negatively influence the EMD at the base. Indeed, deep insertions in small cochleae appeared to yield smaller EMD and better hearing performance. This observation supports the idea of preplanning the surgery by adapting the electrode array to the length of the available scala tympani.	\N	\N
24157596	Rhythmic disturbances are a hallmark of motor speech disorders, in which the motor control deficits interfere with the outward flow of speech and by extension speech understanding. As the functions of rhythm are language-specific, breakdowns in rhythm should have language-specific consequences for communication. The goals of this paper are to (i) provide a review of the cognitive-linguistic role of rhythm in speech perception in a general sense and crosslinguistically; (ii) present new results of lexical segmentation challenges posed by different types of dysarthria in American English, and (iii) offer a framework for crosslinguistic considerations for speech rhythm disturbances in the diagnosis and treatment of communication disorders associated with motor speech disorders. This review presents theoretical and empirical reasons for considering speech rhythm as a critical component of communication deficits in motor speech disorders, and addresses the need for crosslinguistic research to explore language-universal versus language-specific aspects of motor speech disorders.	\N	\N
24157638	This study sought to determine if a monolingual English listener could rate nasality in English and in Spanish with the same proficiency as a bilingual English-Spanish listener, and to compare nasalance scores with nasality ratings. Speakers for this study were 26 bilingual English-Spanish-speaking children. Speech samples and nasalance scores were obtained simultaneously as each speaker recited one English sentence and one Spanish sentence. A monolingual listener and a bilingual listener rated nasality. For the English sentences, the intrajudge correlation coefficient was r = 0.89 for the monolingual listener and r = 0.89 for the bilingual listener. For the Spanish sentences, the intrajudge correlation coefficient was r = 0.91 for the monolingual listener and r = 0.92 for the bilingual listener. Interjudge agreement was r = 0.86 for rating English sentences and r = 0.78 for rating Spanish sentences. All correlation coefficients were significant (p < 0.001). The correlation coefficients between nasality ratings and nasalance scores were essentially the same for both listeners and both languages. A monolingual and a bilingual judge had high agreement on ratings of nasality for English and Spanish speech. The relationship between nasalance and nasality was not different across languages.	\N	\N
24157861	Quite often, magnetoencephalography (MEG) measurements are contaminated by a series of artifacts that degrade the quality of the various source localization methods applied to them. In particular, eye blinking, minor head movement and related activities are a constant source of measurement contamination. In order to solve this problem, trial selection and rejection is applied, a task that is usually performed manually. The present work shows an automatic trial selection and rejection algorithm based on clustering techniques. These techniques employ a measurement of the dissimilarity of the items belonging to a set. This measure, based on the projection of the eigenvector corresponding to the largest eigenvalue of the covariance matrix, is provided and its rationale is explained. Subsequently, covariance matrices belonging to the selected cluster are averaged and used in the well-known Linearly Constrained Minimum Variance (LCMV) Beamformer. The results show a marked improvement of the specificity of the localization algorithm compared to the application of the LCMV without clustering. The method shows a marked reduction in computational cost compared with other data cleaning procedure widely used: Independent Component Analysis (ICA). Thus, we propose clustering techniques to be used in brain localization activity algorithms.	\N	\N
24161466	A current view proposes that the right inferior frontal cortex (IFC) is particularly responsible for attentive decoding and cognitive evaluation of emotional cues in human vocalizations. Although some studies seem to support this view, an exhaustive review of all recent imaging studies points to an important functional role of both the right and the left IFC in processing vocal emotions. Second, besides a supposed predominant role of the IFC for an attentive processing and evaluation of emotional voices in IFC, these recent studies also point to a possible role of the IFC in preattentive and implicit processing of vocal emotions. The studies specifically provide evidence that both the right and the left IFC show a similar anterior-to-posterior gradient of functional activity in response to emotional vocalizations. This bilateral IFC gradient depends both on the nature or medium of emotional vocalizations (emotional prosody versus nonverbal expressions) and on the level of attentive processing (explicit versus implicit processing), closely resembling the distribution of terminal regions of distinct auditory pathways, which provide either global or dynamic acoustic information. Here we suggest a functional distribution in which several IFC subregions process different acoustic information conveyed by emotional vocalizations. Although the rostro-ventral IFC might categorize emotional vocalizations, the caudo-dorsal IFC might be specifically sensitive to their temporal features.	\N	\N
24163248	Aphasic deficits are usually only interpreted in terms of domain-specific language processes. However, effective human communication and tests that probe this complex cognitive skill are also dependent on domain-general processes. In the clinical context, it is a pragmatic observation that impaired attention and executive functions interfere with the rehabilitation of aphasia. One system that is important in cognitive control is the salience network, which includes dorsal anterior cingulate cortex and adjacent cortex in the superior frontal gyrus (midline frontal cortex). This functional imaging study assessed domain-general activity in the midline frontal cortex, which was remote from the infarct, in relation to performance on a standard test of spoken language in 16 chronic aphasic patients both before and after a rehabilitation programme. During scanning, participants heard simple sentences, with each listening trial followed immediately by a trial in which they repeated back the previous sentence. Listening to sentences in the context of a listen-repeat task was expected to activate regions involved in both language-specific processes (speech perception and comprehension, verbal working memory and pre-articulatory rehearsal) and a number of task-specific processes (including attention to utterances and attempts to overcome pre-response conflict and decision uncertainty during impaired speech perception). To visualize the same system in healthy participants, sentences were presented to them as three-channel noise-vocoded speech, thereby impairing speech perception and assessing whether this evokes domain general cognitive systems. As expected, contrasting the more difficult task of perceiving and preparing to repeat noise-vocoded speech with the same task on clear speech demonstrated increased activity in the midline frontal cortex in the healthy participants. The same region was activated in the aphasic patients as they listened to standard (undistorted) sentences. Using a region of interest defined from the data on the healthy participants, data from the midline frontal cortex was obtained from the patients. Across the group and across different scanning sessions, activity correlated significantly with the patients' communicative abilities. This correlation was not influenced by the sizes of the lesion or the patients' chronological ages. This is the first study that has directly correlated activity in a domain general system, specifically the salience network, with residual language performance in post-stroke aphasia. It provides direct evidence in support of the clinical intuition that domain-general cognitive control is an essential factor contributing to the potential for recovery from aphasic stroke.	\N	\N
24183205	To evaluate both monaural and binaural processing skills in a group of children with autism spectrum disorder (ASD) and to determine the degree to which personal frequency modulation (radio transmission) (FM) listening systems could ameliorate their listening difficulties. Auditory temporal processing (amplitude modulation detection), spatial listening (integration of binaural difference cues), and functional hearing (speech perception in background noise) were evaluated in 20 children with ASD. Ten of these subsequently underwent a 6-week device trial in which they wore the FM system for up to 7 hours per day. Auditory temporal processing and spatial listening ability were poorer in subjects with ASD than in matched controls (temporal: P = .014 [95% CI -6.4 to -0.8 dB], spatial: P = .003 [1.0 to 4.4 dB]), and performance on both of these basic processing measures was correlated with speech perception ability (temporal: r = -0.44, P = .022; spatial: r = -0.50, P = .015). The provision of FM listening systems resulted in improved discrimination of speech in noise (P < .001 [11.6% to 21.7%]). Furthermore, both participant and teacher questionnaire data revealed device-related benefits across a range of evaluation categories including Effect of Background Noise (P = .036 [-60.7% to -2.8%]) and Ease of Communication (P = .019 [-40.1% to -5.0%]). Eight of the 10 participants who undertook the 6-week device trial remained consistent FM users at study completion. Sustained use of FM listening devices can enhance speech perception in noise, aid social interaction, and improve educational outcomes in children with ASD.	\N	\N
24216384	To investigate automatic event-related potentials (ERPs) to an auditory change in migraine patients. Auditory ERPs were recorded in 22 female patients suffering from menstrually-related migraine and in 20 age-matched control subjects, in three sessions: in the middle of the menstrual cycle, before and during menses. In each session, 200 trains of tone-bursts each including two duration deviants were presented in a passive listening condition. In all sessions, duration deviance elicited a mismatch negativity (MMN) showing no difference between the two groups. However, migraine patients showed an increased N1 orienting component to all incoming stimuli and a prolonged N2b to deviance. They also presented a different modulation of P3a amplitude along the menstrual cycle, which tended to normalise during migraine attacks. None of the studied ERP components showed a default of habituation. This passive paradigm highlighted increased automatic attention orienting to auditory changes but normal auditory sensory processing in migraineurs. Our observations suggest normal auditory processing up to attention triggering but enhanced activation of attention-related frontal networks in migraineurs.	\N	\N
24219698	In Williams Syndrome (WS), a known genetic deletion results in atypical brain function with strengths in face and language processing. We examined how genetic influences on brain activity change with development. In three studies, event-related potentials (ERPs) from large samples of children, adolescents, and adults with the full genetic deletion for WS were compared to typically developing controls, and two adults with partial deletions for WS. Studies 1 and 2 identified ERP markers of brain plasticity in WS across development. Study 3 suggested that, in adults with partial deletions for WS, specific genes may be differentially implicated in face and language processing.	\N	\N
24231421	A technology of backup alarms based on the use of a broadband signal has recently gained popularity in many countries. In this study, the performance of this broadband technology is compared to that of a conventional tonal alarm and a multi-tone alarm from a worker-safety standpoint. Field measurements of sound pressure level patterns behind heavy vehicles were performed in real work environments and psychoacoustic measurements (sound detection thresholds, equal loudness, perceived urgency and sound localization) were carried out in the laboratory with human subjects. Compared with the conventional tonal alarm, the broadband alarm generates a much more uniform sound field behind vehicles, is easier to localize in space and is judged slighter louder at representative alarm levels. Slight advantages were found with the tonal alarm for sound detection and for perceived urgency at low levels, but these benefits observed in laboratory conditions would not overcome the detrimental effects associated with the large and abrupt variations in sound pressure levels (up to 15-20 dB within short distances) observed in the field behind vehicles for this alarm, which are significantly higher than those obtained with the broadband alarm. Performance with the multi-tone alarm generally fell between that of the tonal and broadband alarms on most measures.	\N	\N
24231629	This study aimed to (1) determine the sensitivity of the electrically evoked auditory change complex (eACC) to changes in stimulating electrode position; and (2) investigate the association between results of eACC measures and behavioral electrode discrimination and their association with speech-perception performance in pediatric cochlear implant (CI) users who have auditory neuropathy spectrum disorder (ANSD). Fifteen children with ANSD ranging in age between 5.4 and 18.6 years participated in this study. All subjects used Cochlear Nucleus devices. For each subject, open-set speech-perception ability was assessed using the Phonetically Balanced Kindergarten word lists presented at 60 dB SPL, using monitored live voice in a sound booth. Behavioral and objective measures of electrode discrimination were assessed in a nonclinical test environment. The stimuli used to elicit these measures were 800 msec biphasic pulse trains delivered by a direct interface to the CI. Data were collected from two basic stimulation conditions. In the standard condition, the entire pulse train was delivered to a mid-array electrode (electrode 11 or 12) at the maximum comfortable level (C level). In the change condition, the stimulus was split into two 400 msec pulse train segments presented sequentially on two different electrodes. The stimulation level of the second 400 msec pulse train was loudness balanced to the C level of the mid-array electrode used in the standard condition. The separation between the pair of stimulating electrodes was systematically varied. For behavioral electrode-discrimination measures, each subject was required to determine whether he or she heard one or two sounds for stimuli presented in different stimulation conditions. For the eACC measures, two replicates of 100 artifact-free sweeps were recorded for each stimulation condition. The eACC in response to changes in stimulating electrode position was recorded from all subjects with ANSD using direct electrical stimulation. Electrode-discrimination thresholds determined with the eACC and behavioral measures were consistent. Children with ANSD using CIs who showed poorer speech performance also required larger separations between the stimulating electrode pair to reliably elicit the eACC than subjects with better speech-perception performance. There was a robust correlation between electrode-discrimination capacities and speech-perception performances in subjects tested in this study. The effect of electrode separation on eACC amplitudes was not monotonic. These results demonstrate the feasibility of using eACC to evaluate electrode-discrimination capacities in children with ANSD. These results suggest that the eACC elicited by changes in stimulating electrode position holds great promise as an objective tool for evaluating spectral-pattern detection in such subjects, which may be predictive of their potential speech-perception performance.	\N	\N
24232062	Children with auditory neuropathy (AN) have variable hearing on pure tone testing, and the presence of speech and language delays often play a major role in the decision to offer cochlear implantation (CI) in this population. Despite this fact, the speech and language outcomes in this group after CI are not well described. This study compares speech and language outcomes after CI in a subset of the pediatric AN population that does not have a confounding cognitive disorder with those of their peers with cochlear hearing loss (CoHL). Retrospective chart review. Tertiary referral center. Seventeen pediatric patients with AN who received a CI and a group of children with CoHL who received a CI were the subjects of this study. The 2 groups demonstrated similar ages at implant. Children with cognitive delays were excluded from each group. Cochlear implantation. All subjects were evaluated preoperatively and postoperatively with standardized age appropriate speech and language measures, including the Expressive Vocabulary Test (EVT), Peabody Picture Vocabulary Test (PPVT), and Preschool Language Scale (PLS). There was no significant difference between the groups on age of activation of the CI. Children with a diagnosis of AN had a significantly lower unaided pure tone average preoperatively as compared with children with cochlear hearing loss; however, there was no significant difference between the groups on either their preimplantation or postimplantation speech and language scores. Children with a diagnosis of AN without associated cognitive or developmental disorders have speech and language outcomes comparable to other children who received a CI.	\N	\N
24236696	Evidence in animals and humans indicates that there are sensitive periods during development, times when experience or stimulation has a greater influence on behavior and brain structure. Sensitive periods are the result of an interaction between maturational processes and experience-dependent plasticity mechanisms. Previous work from our laboratory has shown that adult musicians who begin training before the age of 7 show enhancements in behavior and white matter structure compared with those who begin later. Plastic changes in white matter and gray matter are hypothesized to co-occur; therefore, the current study investigated possible differences in gray matter structure between early-trained (ET; <7) and late-trained (LT; >7) musicians, matched for years of experience. Gray matter structure was assessed using voxel-wise analysis techniques (optimized voxel-based morphometry, traditional voxel-based morphometry, and deformation-based morphometry) and surface-based measures (cortical thickness, surface area and mean curvature). Deformation-based morphometry analyses identified group differences between ET and LT musicians in right ventral premotor cortex (vPMC), which correlated with performance on an auditory motor synchronization task and with age of onset of musical training. In addition, cortical surface area in vPMC was greater for ET musicians. These results are consistent with evidence that premotor cortex shows greatest maturational change between the ages of 6-9 years and that this region is important for integrating auditory and motor information. We propose that the auditory and motor interactions required by musical practice drive plasticity in vPMC and that this plasticity is greatest when maturation is near its peak.	\N	\N
24236753	Does temporal regularity facilitate prediction in audition? To test this, we recorded human event-related potentials to frequent standard tones and infrequent pitch deviant tones, pre-attentively delivered within isochronous and anisochronous (20% onset jitter) rapid sequences. Deviant tones were repeated, either with high or low probability. Standard tone repetition sets a first-order prediction, which is violated by deviant tone onset, leading to a first-order prediction error response (Mismatch Negativity). The response to highly probable deviant repetitions is, however, attenuated relative to less probable repetitions, reflecting the formation of higher-order sensory predictions. Results show that temporal regularity is required for higher-order predictions, but does not modulate first-order prediction error responses. Inverse solution analyses (Variable Resolution Electrical Tomography; VARETA) localized the error response attenuation to posterior regions of the left superior temporal gyrus. In a control experiment with a slower stimulus rate, we found no evidence for higher-order predictions, and again no effect of temporal information on first-order prediction error. We conclude that: (i) temporal regularity facilitates the establishing of higher-order sensory predictions, i.e. 'knowing what next', in fast auditory sequences; (ii) first-order prediction error relies predominantly on stimulus feature mismatch, reflecting the adaptive fit of fast deviance detection processes.	\N	\N
24244617	Due to their different propagation times, visual and auditory signals from external events arrive at the human sensory receptors with a disparate delay. This delay consistently varies with distance, but, despite such variability, most events are perceived as synchronic. There is, however, contradictory data and claims regarding the existence of compensatory mechanisms for distance in simultaneity judgments. In this paper we have used familiar audiovisual events--a visual walker and footstep sounds--and manipulated the number of depth cues. In a simultaneity judgment task we presented a large range of stimulus onset asynchronies corresponding to distances of up to 35 meters. We found an effect of distance over the simultaneity estimates, with greater distances requiring larger stimulus onset asynchronies, and vision always leading. This effect was stronger when both visual and auditory cues were present but was interestingly not found when depth cues were impoverished. These findings reveal that there should be an internal mechanism to compensate for audiovisual delays, which critically depends on the depth information available.	\N	\N
24257810	Remifentanil (Ultiva(®)) is a potent ultra-short acting mu-opioid receptor agonist used for perioperative pain treatment and anaesthesia. So far, it is not known how sensitive the cognitive processing of auditory perception elicited by the mismatch negativity (MMN) paradigm is to opioids. The present exploratory study investigated how the opioid remifentanil modulates different stages of auditory processing as reflected in the MMN(m) and P3a(m). We recorded electroencephalography (EEG) and magnetoencephalography (MEG) during auditory stimulation under remifentanil or placebo infusion in 20 healthy participants. For the MMN, a gender effect was found for tones deviating in frequency (± 10%) from the standard tone. Remifentanil increased the amplitude of the frequency MMN at F3 in females but not in males. No effect of treatment was found for the MMN(m) or the novel P3a(m). These results suggest that while the bottom-up stimulus change detection system for auditory stimuli appears to be relatively insensitive to opioids, the automatic attention switch caused by the change detection seems to be modulated by the opioid system in females. The multiple deviant paradigm including novel sounds is a promising tool for investigating pharmacological manipulation of different stages of auditory processing. Furthermore, combining the two techniques will yield more specific information about the drug effects on MMN(m).	\N	\N
24259564	One of the more enduring mysteries of neuroscience is how the visual system constructs robust maps of the world that remain stable in the face of frequent eye movements. Here we show that encoding the position of objects in external space is a relatively slow process, building up over hundreds of milliseconds. We display targets to which human subjects saccade after a variable preview duration. As they saccade, the target is displaced leftwards or rightwards, and subjects report the displacement direction. When subjects saccade to targets without delay, sensitivity is poor; but if the target is viewed for 300-500 ms before saccading, sensitivity is similar to that during fixation with a strong visual mask to dampen transients. These results suggest that the poor displacement thresholds usually observed in the "saccadic suppression of displacement" paradigm are a result of the fact that the target has had insufficient time to be encoded in memory, and not a result of the action of special mechanisms conferring saccadic stability. Under more natural conditions, trans-saccadic displacement detection is as good as in fixation, when the displacement transients are masked.	\N	\N
24259673	Viewers can recognize the gist of a scene (i.e., its holistic semantic representation, such as its category) in less time than a single fixation, and backward masking has traditionally been employed as a means to determine that time course. The masks used in those paradigms are often characterized by either specific amplitude spectra only, or amplitude and phase spectra-defined structural properties. However, it remains unclear whether there would be a differential contribution of amplitude only or amplitude + phase defined image statistics to the effective backward masking of rapid scene categorization. The current study addresses this issue. Experiments 1-3 explored amplitude spectra defined contributions to category masking and revealed that the slope of the amplitude spectrum was more important for modulating scene category masking strength than amplitude orientation. Further, the masking effects followed an "amplitude spectrum slope similarity principle" whereby the more similar the amplitude spectrum slope of the mask was to the target's amplitude spectrum slope, the stronger the masking. Experiment 5 showed that, when holding mask amplitude spectrum slope approximately constant, both categorically specific unrecognizable amplitude only and amplitude + phase statistical regularities disrupted rapid scene categorization. Specifically, the masking effects observed in Experiment 5 followed a target-mask categorical dissimilarity principle whereby the more dissimilar the mask category is to the target image category, the stronger the masking. Overall, the results support the notion that amplitude only or amplitude + phase-defined image statistics differentially contribute to the effective backward masking of rapid scene gist recognition.	\N	\N
24265213	This study assesses the effects of adding low- or high-frequency information to the band-limited telephone-processed speech on bimodal listeners' telephone speech perception in quiet environments. In the proposed experiments, bimodal users were presented under quiet listening conditions with wideband speech (WB), bandpass-filtered telephone speech (300-3,400 Hz, BP), high-pass filtered speech (f > 300 Hz, HP, i.e., distorted frequency components above 3,400 Hz in telephone speech were restored), and low-pass filtered speech (f < 3,400 Hz, LP, i.e., distorted frequency components below 300 Hz in telephone speech were restored). Results indicated that in quiet environments, for all four types of stimuli, listening with both hearing aid (HA) and cochlear implant (CI) was significantly better than listening with CI alone. For both bimodal and CI-alone modes, there were no statistically significant differences between the LP and BP scores and between the WB and HP scores. However, the HP scores were significantly better than the BP scores. In quiet conditions, both CI alone and bimodal listening achieved the largest benefits when telephone speech was augmented with high rather than low-frequency information. These findings provide support for the design of algorithms that would extend higher frequency information, at least in quiet environments.	\N	\N
24268879	Timing performance becomes less precise for longer intervals, which makes it difficult to achieve simultaneity in synchronisation with a rhythm. The metrical structure of music, characterised by hierarchical levels of binary or ternary subdivisions of time, may function to increase precision by providing additional timing information when the subdivisions are explicit. This hypothesis was tested by comparing synchronisation performance across different numbers of metrical levels conveyed by loudness of sounds, such that the slowest level was loudest and the fastest was softest. Fifteen participants moved their hand with one of 9 inter-beat intervals (IBIs) ranging from 524 to 3,125 ms in 4 metrical level (ML) conditions ranging from 1 (one movement for each sound) to 4 (one movement for every 8th sound). The lowest relative variability (SD/IBI<1.5%) was obtained for the 3 longest IBIs (1600-3,125 ms) and MLs 3-4, significantly less than the smallest value (4-5% at 524-1024 ms) for any ML 1 condition in which all sounds are identical. Asynchronies were also more negative with higher ML. In conclusion, metrical subdivision provides information that facilitates temporal performance, which suggests an underlying neural multi-level mechanism capable of integrating information across levels.	\N	\N
24270967	An important parameter for characterization of the acoustic quality of closed rooms is reverberation. There is a rising interest in evaluating the ability of cochlear implant (CI) users to understand speech in real-world environments. Whereas the influence of noise on speech perception has been widely investigated, much less is known about the detrimental effect of reverberation. The present study aimed to investigate the influence of reverberation time on the speech perception of CI users and subjects with normal hearing. A reverberated version of the sentences of the Oldenburg sentence test (OLSA) which is a widely used German test to measure speech reception thresholds (SRT) in cochlear implant users was generated using professional audio processing software. The reverberation times used were 0.7, 1.0, 1.5 and 2.0 s. For these four reverberation times and for a non-reverberated control condition, the SRT was measured in eight adult CI users and in eight subjects with normal hearing. To characterize the detrimental effect of reverberation the SRT differences between the reverberated and non-reverberated conditions were calculated. These SRT differences revealed a significant effect of reverberation in CI users with, e.g. a mean SRT increase of 2.9 dB in CI users and 0.9 dB in subjects with normal hearing for a reverberation time of 0.7 s. A strong correlation was found between the SRT increase and the SRT in the non-reverberated condition, highlighting the problems of poor performers in reverberant environments. The results of the current investigation indicated that reverberation results in decreased speech understanding of CI users.	\N	\N
24274362	Infant vocalizations and "looming sounds" are classes of environmental stimuli that are critically important to survival but can have dramatically different emotional valences. Here, we simultaneously presented listeners with a stationary infant vocalization and a 3D virtual looming tone for which listeners made auditory time-to-arrival judgments. Negatively valenced infant cries produced more cautious (anticipatory) estimates of auditory arrival time of the tone over a no-vocalization control. Positively valenced laughs had the opposite effect, and across all conditions, men showed smaller anticipatory biases than women. In Experiment 2, vocalization-matched vocoded noise stimuli did not influence concurrent auditory time-to-arrival estimates compared with a control condition. In Experiment 3, listeners estimated the egocentric distance of a looming tone that stopped before arriving. For distant stopping points, women estimated the stopping point as closer when the tone was presented with an infant cry than when it was presented with a laugh. For near stopping points, women showed no differential effect of vocalization type. Men did not show differential effects of vocalization type at either distance. Our results support the idea that both the sex of the listener and the emotional valence of infant vocalizations can influence auditory motion perception and can modulate motor responses to other behaviorally relevant environmental sounds. We also find support for previous work that shows sex differences in emotion processing are diminished under conditions of higher stress.	\N	\N
24293020	Multisensory enhancement, as a facilitation phenomenon, is responsible for superior behavioral performance when an individual is responding to cross-modal versus modality-specific stimuli. However, the event-related potential (ERP) counterparts of behavioral multisensory enhancement are not well known. We recorded ERPs and behavioral data from 14 healthy volunteers with three types of target stimuli (modality-specific, bimodal, and trimodal) to examine the spatio-temporal electrophysiological characteristics of multisensory enhancement by comparing behavioral data with ERPs. We found a strong correlation between P3 latency and behavioral performance in terms of reaction time (RT) (R = 0.98, P <0.001), suggesting that P3 latency constitutes a temporal measure of behavioral multisensory enhancement. In addition, a fast RT and short P3 latency were found when comparing the modality-specific visual target with the modality-specific auditory and somatosensory targets. Our results indicate that behavioral multisensory enhancement can be identified by the latency and source distribution of the P3 component. These findings may advance our understanding of the neuronal mechanisms of multisensory enhancement.	\N	\N
24306440	Vection is the illusion of self-motion in the absence of real physical movement. The aim of the present study was to analyze how multisensory inputs (visual and auditory) contribute to the perception of vection. Participants were seated in a stationary position in front of a large, curved projection display and were exposed to a virtual scene that constantly rotated around the yaw-axis, simulating a 360° rotation. The virtual scene contained either only visual, only auditory, or a combination of visual and auditory cues. Additionally, simulated rotation speed (90°/s vs. 60°/s) and the number of sound sources (1 vs. 3) were varied for all three stimulus conditions. All participants were exposed to every condition in a randomized order. Data specific to vection latency, vection strength, the severity of motion sickness (MS), and postural steadiness were collected. Results revealed reduced vection onset latencies and increased vection strength when auditory cues were added to the visual stimuli, whereas MS and postural steadiness were not affected by the presence of auditory cues. Half of the participants reported experiencing auditorily induced vection, although the sensation was rather weak and less robust than visually induced vection. Results demonstrate that the combination of visual and auditory cues can enhance the sensation of vection.	\N	\N
24313638	This study examined the time-course of reading single words in children and adults using masked repetition priming and the recording of event-related potentials. The N250 and N400 repetition priming effects were used to characterize form- and meaning-level processing, respectively. Children had larger amplitude N250 effects than adults for both shorter and longer duration primes. Children did not differ from adults on the N400 effect. The difference on the N250 suggests that automaticity for form processing is still maturing in children relative to adults, while the lack of differentiation on the N400 effect suggests that meaning processing is relatively mature by late childhood. The overall similarity in the children's repetition priming effects to adults' effects is in line with theories of reading acquisition, according to which children rapidly transition to an orthographic strategy for fast access to semantic information from print.	\N	\N
24315729	Goal-directed behavior is well-known to show declines in elderly individuals, possibly because of alterations in dopaminergic neural transmission. The dopaminergic system is modulated by a number of other different factors. One of these factors, which has attracted a considerable amount of interest in neurobiology, but has only rarely been examined with respect to its possible modulatory role for cognitive functions in elderly individuals, is latent Toxoplasma gondii (T. gondii) infection. Latent T. gondii infection may be of relevance to goal-directed behavior as it alters dopaminergic neural transmission. We examine goal-directed behavior in T. gondii IgG positive and negative elderly subjects in auditory distraction paradigm. We apply event-related potentials to examine which cognitive subprocesses are affected by latent T. gondii infection on a neurophysiological level. We show that latent T. gondii infection compromises the management of auditory distraction in elderly by specifically delaying processes of attentional allocation and disengagement. The results show that latent T. gondii infection is neglected but an important neurobiological modulator of cognitive functions in elderly individuals.	\N	\N
24320112	There are increasing reports that individual variation in behavioral and neurophysiological measures of infant speech processing predicts later language outcomes, and specifically concurrent or subsequent vocabulary size. If such findings are held up under scrutiny, they could both illuminate theoretical models of language development and contribute to the prediction of communicative disorders. A qualitative, systematic review of this emergent literature illustrated the variety of approaches that have been used and highlighted some conceptual problems regarding the measurements. A quantitative analysis of the same data established that the bivariate relation was significant, with correlations of similar strength to those found for well-established nonlinguistic predictors of language. Further exploration of infant speech perception predictors, particularly from a methodological perspective, is recommended.	\N	\N
24321583	The voice is a primary work tool for call center operators, but the main risk factors for voice disorders in this category have not yet been clarified. This study aimed to analyze the vocal behavior in call center operators and search for correlations between the daily voice dose and the self-perceived voice-related handicap. Prospective. Ninety-two call center operators (aged 24-50 years) underwent ambulatory phonation monitoring during a working day and were administered the Voice Handicap Index (VHI) questionnaire and a questionnaire concerning smoking habits, symptoms, and extrawork activities requiring intensive voice use. Mean percentage phonation time (PT) during work was 14.74% and ranged from 4% to 31%. There was a significant difference between the percentage PT in working time and in extrawork time; however, subjects with high percentage PT in working time maintained a high value also in extrawork time. The mean PT was 87.5 ± 35.8 minutes and was not correlated with age, gender, number of work hours, symptoms, extraprofessional voice use, and VHI scores. The mean amplitude was significantly higher in subjects with longer PT and higher pitch (P < 0.001). VHI score (median = 9) was slightly higher than in the general population but not related to the number of work hours, indicating that work time was not a critical factor in causing the perception of voice problems. Our study provides data about the voice behavior of a large cohort of call center operators and demonstrates that the number of work hours and the percentage PT are not statistically related to the perception of voice disturbances in this working category.	\N	\N
24323099	In the study of the spatial characteristics of the visual channels, the power spectrum model of visual masking is one of the most widely used. When the task is to detect a signal masked by visual noise, this classical model assumes that the signal and the noise are previously processed by a bank of linear channels and that the power of the signal at threshold is proportional to the power of the noise passing through the visual channel that mediates detection. The model also assumes that this visual channel will have the highest ratio of signal power to noise power at its output. According to this, there are masking conditions where the highest signal-to-noise ratio (SNR) occurs in a channel centered in a spatial frequency different from the spatial frequency of the signal (off-frequency looking). Under these conditions the channel mediating detection could vary with the type of noise used in the masking experiment and this could affect the estimation of the shape and the bandwidth of the visual channels. It is generally believed that notched noise, white noise and double bandpass noise prevent off-frequency looking, and high-pass, low-pass and bandpass noises can promote it independently of the channel's shape. In this study, by means of a procedure that finds the channel that maximizes the SNR at its output, we performed numerical simulations using the power spectrum model to study the characteristics of masking caused by six types of one-dimensional noise (white, high-pass, low-pass, bandpass, notched, and double bandpass) for two types of channel's shape (symmetric and asymmetric). Our simulations confirm that (1) high-pass, low-pass, and bandpass noises do not prevent the off-frequency looking, (2) white noise satisfactorily prevents the off-frequency looking independently of the shape and bandwidth of the visual channel, and interestingly we proved for the first time that (3) notched and double bandpass noises prevent off-frequency looking only when the noise cutoffs around the spatial frequency of the signal match the shape of the visual channel (symmetric or asymmetric) involved in the detection. In order to test the explanatory power of the model with empirical data, we performed six visual masking experiments. We show that this model, with only two free parameters, fits the empirical masking data with high precision. Finally, we provide equations of the power spectrum model for six masking noises used in the simulations and in the experiments.	\N	\N
24336606	Sensory-specific cortices appear to be sensitive to information from another modality. Here we investigate whether the human brain automatically extracts the phonological information in visual words in early visual processing. We continuously presented native Chinese speakers peripherally with Chinese homophone characters in an oddball paradigm, while they performed a visual detection task presented in the centre of the visual field. We found the lexical tone phonology embedded in the characters is processed automatically by the brain of native speakers, as revealed by whole-head electrical recordings of the mismatch negativity (MMN). Source solution further revealed the MMN involved the neural activations from the visual cortex to the auditory cortex (130-460 ms). The spatial-temporal dynamics indicate a visual-auditory interaction in the early, automatic processing of phonological information in visual words.	\N	\N
24349800	Perceptual learning can be specific to a trained stimulus or optimally generalized to novel stimuli with the breadth of generalization being imperative for how we structure perceptual training programs. Adapting an established auditory interval discrimination paradigm to utilise complex signals, we trained human adults on a standard interval for either 2, 4, or 10 days. We then tested the standard, alternate frequency, interval, and stereo input conditions to evaluate the rapidity of specific learning and breadth of generalization over the time course. In comparison with previous research using simple stimuli, the speed of perceptual learning and breadth of generalization were more rapid and greater in magnitude, including novel generalization to an alternate temporal interval within stimulus type. We also investigated the long term maintenance of learning and found that specific and generalized learning was maintained over 3 and 6 months. We discuss these findings regarding stimulus complexity in perceptual learning and how they can inform the development of effective training protocols.	\N	\N
24361298	Prestin, the motor protein of cochlear outer hair cells, was identified 14 years ago. Prestin-based outer hair cell motility is responsible for the exquisite sensitivity and frequency selectivity seen in the mammalian cochlea. Prestin is the 5th member of an eleven-member membrane transporter superfamily of SLC26A proteins. Unlike its paralogs, which are capable of transporting anions across the cell membrane, prestin primarily functions as a motor protein with unique capability of performing direct and reciprocal electromechanical conversion on microsecond time scale. Significant progress in the understanding of its structure and the molecular mechanism has been made in recent years using electrophysiological, biochemical, comparative genomics, structural bioinformatics, molecular dynamics simulation, site-directed mutagenesis and domain-swapping techniques. This article reviews recent advances of the structural and functional properties of prestin with focus on the areas that are critical but still controversial in understanding the molecular mechanism of how prestin works: The structural domains for voltage sensing and interaction with anions and for conformational change. Future research directions and potential application of prestin are also discussed. This article is part of a Special Issue entitled <Annual Reviews 2014>.	\N	\N
24365660	SIRT1 is a highly conserved NAD(+)-dependent protein deacetylase known to have protective effects against a variety of age-related diseases. However, there is a lack of information concerning SIRT1 expression in the cochlea and auditory cortex of C57BL/6 mice, a mouse model of age-related hearing loss. Using RT-PCR and immunohistochemistry, we show that SIRT1 is abundantly expressed in the inner hair cells, strial marginal cells, strial intermediate cells, type I and type IV fibrocytes of the spiral ligament and spiral ganglion neurons. In addition, moderate SIRT1 is also detected in the outer hair cells and neurons of the auditory cortex. Associated with elevated hearing thresholds and hair cells loss during aging, there is also a significant reduction of SIRT1 expression in the cochlea and auditory cortex. The expression pattern of SIRT1 in the peripheral and central auditory system suggests that SIRT1 may play an important role in auditory function and therefore may serve as a protective molecule against age-related hearing loss.	\N	\N
24383225	In current terminology, auditory neuropathy spectrum disorder (ANSD) is a disease involving the disruption of the temporal coding of acoustic signals in auditory nerve fibres, resulting in the impairment of auditory perceptions that rely on temporal cues. There is debate about almost every aspect of the disorder, including aetiology, lesion sites, and the terminology used to describe it. ANSD is a heterogeneous disease despite similar audiological findings. The absence of an auditory brainstem response (ABR) and the presence of otoacoustic emissions (OAE) suggest an ANSD profile. However, to determine the exact anatomical site of the disorder, more in-depth audiological and electrophysiological tests must be combined with imaging, genetics and neurological examinations. Greater diagnostic specificity is therefore needed to provide these patients with more adequate treatment.	\N	\N
24384079	Previous research has suggested that electrically coupled frequency modulation (FM) systems substantially improved speech-recognition performance in noise in individuals with cochlear implants (CIs). However, there is limited evidence to support the use of electromagnetically coupled (neck loop) FM receivers with contemporary CI sound processors containing telecoils. The primary goal of this study was to compare speech-recognition performance in noise and subjective ratings of adolescents and adults using one of three contemporary CI sound processors coupled to electromagnetically and electrically coupled FM receivers from Oticon. A repeated-measures design was used to compare speech-recognition performance in noise and subjective ratings without and with the FM systems across three test sessions (Experiment 1) and to compare performance at different FM-gain settings (Experiment 2). Descriptive statistics were used in Experiment 3 to describe output differences measured through a CI sound processor. Experiment 1 included nine adolescents or adults with unilateral or bilateral Advanced Bionics Harmony (n = 3), Cochlear Nucleus 5 (n = 3), and MED-EL OPUS 2 (n = 3) CI sound processors. In Experiment 2, seven of the original nine participants were tested. In Experiment 3, electroacoustic output was measured from a Nucleus 5 sound processor when coupled to the electromagnetically coupled Oticon Arc neck loop and electrically coupled Oticon R2. In Experiment 1, participants completed a field trial with each FM receiver and three test sessions that included speech-recognition performance in noise and a subjective rating scale. In Experiment 2, participants were tested in three receiver-gain conditions. Results in both experiments were analyzed using repeated-measures analysis of variance. Experiment 3 involved electroacoustic-test measures to determine the monitor-earphone output of the CI alone and CI coupled to the two FM receivers. The results in Experiment 1 suggested that both FM receivers provided significantly better speech-recognition performance in noise than the CI alone; however, the electromagnetically coupled receiver provided significantly better speech-recognition performance in noise and better ratings in some situations than the electrically coupled receiver when set to the same gain. In Experiment 2, the primary analysis suggested significantly better speech-recognition performance in noise for the neck-loop versus electrically coupled receiver, but a second analysis, using the best performance across gain settings for each device, revealed no significant differences between the two FM receivers. Experiment 3 revealed monitor-earphone output differences in the Nucleus 5 sound processor for the two FM receivers when set to the +8 setting used in Experiment 1 but equal output when the electrically coupled device was set to a +16 gain setting and the electromagnetically coupled device was set to the +8 gain setting. Individuals with contemporary sound processors may show more favorable speech-recognition performance in noise electromagnetically coupled FM systems (i.e., Oticon Arc), which is most likely related to the input processing and signal processing pathway within the CI sound processor for direct input versus telecoil input. Further research is warranted to replicate these findings with a larger sample size and to develop and validate a more objective approach to fitting FM systems to CI sound processors.	\N	\N
24384084	To validate diagnostic pure-tone audiometry in schools without a sound-treated environment using an audiometer that incorporates insert earphones covered by circumaural earcups and real-time environmental noise monitoring. A within-subject repeated measures design was employed to compare air (250 to 8000 Hz) and bone (250 to 4000 Hz) conduction pure-tone thresholds measured in natural school environments with thresholds measured in a sound-treated booth. 149 children (54% female) with an average age of 6.9 yr (SD = 0.6; range = 5-8). Average difference between the booth and natural environment thresholds was 0.0 dB (SD = 3.6) for air conduction and 0.1 dB (SD = 3.1) for bone conduction. Average absolute difference between the booth and natural environment was 2.1 dB (SD = 2.9) for air conduction and 1.6 dB (SD = 2.7) for bone conduction. Almost all air- (96%) and bone-conduction (97%) threshold comparisons between the natural and booth test environments were within 0 to 5 dB. No statistically significant differences between thresholds recorded in the natural and booth environments for air- and bone-conduction audiometry were found (p > 0.01). Diagnostic air- and bone-conduction audiometry in schools, without a sound-treated room, is possible with sufficient earphone attenuation and real-time monitoring of environmental noise. Audiological diagnosis on-site for school screening may address concerns of false-positive referrals and poor follow-up compliance and allow for direct referral to audiological and/or medical intervention.	\N	\N
24386403	The objective was to determine if one of the neural temporal features, neural adaptation, can account for the across-subject variability in behavioral measures of temporal processing and speech perception performance in cochlear implant (CI) recipients. Neural adaptation is the phenomenon in which neural responses are the strongest at the beginning of the stimulus and decline following stimulus repetition (e.g., stimulus trains). It is unclear how this temporal property of neural responses relates to psychophysical measures of temporal processing (e.g., gap detection) or speech perception. The adaptation of the electrical compound action potential (ECAP) was obtained using 1000 pulses per second (pps) biphasic pulse trains presented directly to the electrode. The adaptation of the late auditory evoked potential (LAEP) was obtained using a sequence of 1-kHz tone bursts presented acoustically, through the cochlear implant. Behavioral temporal processing was measured using the Random Gap Detection Test at the most comfortable listening level. Consonant nucleus consonant (CNC) word and AzBio sentences were also tested. The results showed that both ECAP and LAEP display adaptive patterns, with a substantial across-subject variability in the amount of adaptation. No correlations between the amount of neural adaptation and gap detection thresholds (GDTs) or speech perception scores were found. The correlations between the degree of neural adaptation and demographic factors showed that CI users having more LAEP adaptation were likely to be those implanted at a younger age than CI users with less LAEP adaptation. The results suggested that neural adaptation, at least this feature alone, cannot account for the across-subject variability in temporal processing ability in the CI users. However, the finding that the LAEP adaptive pattern was less prominent in the CI group compared to the normal hearing group may suggest the important role of normal adaptation pattern at the cortical level in speech perception.	\N	\N
24389260	The left temporal pole (LTP) has been posited to be a heteromodal hub for retrieving proper names for semantically unique entities. Previous investigations have demonstrated that LTP is important for retrieving names for famous faces and unique landmarks. However, whether such a relationship would hold for unique entities apprehended through stimulus modalities other than vision has not been well established, and such evidence is critical to adjudicate claims about the "heteromodal" nature of the LTP. Here, we tested the hypothesis that the LTP would be important for naming famous voices. Individuals with LTP lesions were asked to recognize and name famous persons speaking in audio clips. Relative to neurologically normal and brain damaged comparison participants, patients with LTP lesions were able to recognize famous persons from their voices normally, but were selectively impaired in naming famous persons from their voices. The current results extend previous research and provide further support for the notion that the LTP is a convergence region serving as a heteromodal hub for retrieving the names of semantically unique entities.	\N	\N
24391928	The brain is able to realign asynchronous signals that approximately coincide in both space and time. Given that many experience-based links between visual and auditory stimuli are established in the absence of spatiotemporal proximity, we investigated whether or not temporal realignment arises in these conditions. Participants received a 3-min exposure to visual and auditory stimuli that were separated by 706 ms and appeared either from the same (Experiment 1) or from different spatial positions (Experiment 2). A simultaneity judgment task (SJ) was administered right afterwards. Temporal realignment between vision and audition was observed, in both Experiment 1 and 2, when comparing the participants' SJs after this exposure phase with those obtained after a baseline exposure to audiovisual synchrony. However, this effect was present only when the visual stimuli preceded the auditory stimuli during the exposure to asynchrony. A similar pattern of results (temporal realignment after exposure to visual-leading asynchrony but not after exposure to auditory-leading asynchrony) was obtained using temporal order judgments (TOJs) instead of SJs (Experiment 3). Taken together, these results suggest that temporal recalibration still occurs for visual and auditory stimuli that fall clearly outside the so-called temporal window for multisensory integration and appear from different spatial positions. This temporal realignment may be modulated by long-term experience with the kind of asynchrony (vision-leading) that we most frequently encounter in the outside world (e.g., while perceiving distant events).	\N	\N
24398259	There is currently no consensus regarding what measures are most valid to demonstrate perceptual processing without awareness. Likewise, whether conscious perception and unconscious processing rely on independent mechanisms or lie on a continuum remains a matter of debate. Here, we addressed these issues by comparing the time courses of subjective reports, objective discrimination performance and response priming during meta-contrast masking, under similar attentional demands. We found these to be strikingly similar, suggesting that conscious perception and unconscious processing cannot be dissociated by their time course. Our results also demonstrate that unconscious processing, indexed by response priming, occurs, and that objective discrimination performance indexes the same conscious processes as subjective visibility reports. Finally, our results underscore the role of attention by showing that how much attention the stimulus receives relative to the mask, rather than whether processing is measured by conscious discrimination or by priming, determines the time course of meta-contrast masking.	\N	\N
24402676	While deafness-induced plasticity has been investigated in the visual and auditory domains, not much is known about language processing in audiovisual multimodal environments for patients with restored hearing via cochlear implant (CI) devices. Here, we examined the effect of agreeing or conflicting visual inputs on auditory processing in deaf patients equipped with degraded artificial hearing. Ten post-lingually deafened CI users with good performance, along with matched control subjects, underwent H 2 (15) O-positron emission tomography scans while carrying out a behavioral task requiring the extraction of speech information from unimodal auditory stimuli, bimodal audiovisual congruent stimuli, and incongruent stimuli. Regardless of congruency, the control subjects demonstrated activation of the auditory and visual sensory cortices, as well as the superior temporal sulcus, the classical multisensory integration area, indicating a bottom-up multisensory processing strategy. Compared to CI users, the control subjects exhibited activation of the right ventral premotor-supramarginal pathway. In contrast, CI users activated primarily the visual cortices more in the congruent audiovisual condition than in the null condition. In addition, compared to controls, CI users displayed an activation focus in the right amygdala for congruent audiovisual stimuli. The most notable difference between the two groups was an activation focus in the left inferior frontal gyrus in CI users confronted with incongruent audiovisual stimuli, suggesting top-down cognitive modulation for audiovisual conflict. Correlation analysis revealed that good speech performance was positively correlated with right amygdala activity for the congruent condition, but negatively correlated with bilateral visual cortices regardless of congruency. Taken together these results suggest that for multimodal inputs, cochlear implant users are more vision-reliant when processing congruent stimuli and are disturbed more by visual distractors when confronted with incongruent audiovisual stimuli. To cope with this multimodal conflict, CI users activate the left inferior frontal gyrus to adopt a top-down cognitive modulation pathway, whereas normal hearing individuals primarily adopt a bottom-up strategy.	\N	\N
24405904	Although HIV is associated with decreased emotional and cognitive functioning, the mechanisms through which affective changes can alter cognitive processes in HIV-infected individuals are unknown. We aimed to clarify this question through testing the extent to which emotionally negative stimuli prime attention to a subsequent infrequently occurring auditory tone in HIV+ compared to HIV- females. Attention to emotional compared to non-emotional pictures was measured via the LPP ERP. Subsequent attention was indexed through the N1 and late processing negativity ERP. We also assessed mood and cognitive functioning in both groups. In HIV- females, emotionally negative pictures, compared to neutral pictures, resulted in an enhanced LPP to the pictures and an enhanced N1 to subsequent tones. The HIV+ group did not show a difference in the LPP measure between picture categories, and accordingly, did not show a priming effect to the subsequent infrequent tones. The ERP findings, combined with neuropsychological deficits, suggest that HIV+ females show impairments in attention to emotionally-laden stimuli and that this impairment might be related to a loss of affective priming. This study is the first to provide physiological evidence that the LPP, a measure of attention to emotionally-charged visual stimuli, is reduced in HIV-infected individuals. These results set the stage for future work aimed at localizing brain activation to emotional stimuli in HIV+ individuals.	\N	\N
24414279	Speech production, both overt and covert, down-regulates the activation of auditory cortex. This is thought to be due to forward prediction of the sensory consequences of speech, contributing to a feedback control mechanism for speech production. Critically, however, these regulatory effects should be specific to speech content to enable accurate speech monitoring. To determine the extent to which such forward prediction is content-specific, we recorded the brain's neuromagnetic responses to heard multisyllabic pseudowords during covert rehearsal in working memory, contrasted with a control task. The cortical auditory processing of target syllables was significantly suppressed during rehearsal compared with control, but only when they matched the rehearsed items. This critical specificity to speech content enables accurate speech monitoring by forward prediction, as proposed by current models of speech production. The one-to-one phonological motor-to-auditory mappings also appear to serve the maintenance of information in phonological working memory. Further findings of right-hemispheric suppression in the case of whole-item matches and left-hemispheric enhancement for last-syllable mismatches suggest that speech production is monitored by 2 auditory-motor circuits operating on different timescales: Finer grain in the left versus coarser grain in the right hemisphere. Taken together, our findings provide hemisphere-specific evidence of the interface between inner and heard speech.	\N	\N
24423729	Across the animal kingdom, sensations resulting from an animal's own actions are processed differently from sensations resulting from external sources, with self-generated sensations being suppressed. A forward model has been proposed to explain this process across sensorimotor domains. During vocalization, reduced processing of one's own speech is believed to result from a comparison of speech sounds to corollary discharges of intended speech production generated from efference copies of commands to speak. Until now, anatomical and functional evidence validating this model in humans has been indirect. Using EEG with anatomical MRI to facilitate source localization, we demonstrate that inferior frontal gyrus activity during the 300ms before speaking was associated with suppressed processing of speech sounds in auditory cortex around 100ms after speech onset (N1). These findings indicate that an efference copy from speech areas in prefrontal cortex is transmitted to auditory cortex, where it is used to suppress processing of anticipated speech sounds. About 100ms after N1, a subsequent auditory cortical component (P2) was not suppressed during talking. The combined N1 and P2 effects suggest that although sensory processing is suppressed as reflected in N1, perceptual gaps may be filled as reflected in the lack of P2 suppression, explaining the discrepancy between sensory suppression and preserved sensory experiences. These findings, coupled with the coherence between relevant brain regions before and during speech, provide new mechanistic understanding of the complex interactions between action planning and sensory processing that provide for differentiated tagging and monitoring of one's own speech, processes disrupted in neuropsychiatric disorders.	\N	\N
24424293	To assess the role of the efferent auditory system by inhibition of contralateral otoacoustic emission in dyslexic children with auditory processing disorders. The study sample was 34 children: 17 with dyslexia and 17 age-matched controls. Sensitive speech tests (low-pass filtered, time-compressed, distorted and dichotic) were performed to assess coexisting auditory processing disorder. Distortion-product otoacoustic emission (DPOAE) values were measured in basal condition and with contralateral broadband noise signal delivered via an earphone transducer at 60 dB SPL. The lower scores at sensitive speech testing confirmed the association of an auditory processing disorder in the dyslexic children. DPOAE values were significantly attenuated by contralateral inhibition only in the control group (p=0.001; dyslexics, p=0.19); attenuation was not significant at any frequency in the dyslexic group. The differences in DPOAE attenuation between the groups, although not statistically significant, suggest alterations in the auditory efferent system in the dyslexic population. These alterations may affect language perception. If confirmed in further studies with larger samples, these results could provide insight into a possible pathophysiological background of dyslexia.	\N	\N
24434131	Cochlear implantation provides children with a significant hearing loss the potential to engage in phonological processing via audition; however these children can still have poor or inadequately detailed mental (phonological) representations of speech and as such phonological awareness and reading difficulties. Heterogeneous participant profiles, particularly varying modes of communication have clouded the research regarding reading outcomes of children using a cochlear implant. The objective of this study was to explore the relationships between word reading and reading comprehension outcomes, and a range of variables of a relatively homogenous group of children using cochlear implants. Forty-seven oral communicating children using a cochlear implant and who had attended auditory-verbal therapy served as participants. They were administered a comprehensive battery of 10 different assessments covering 22 different tasks across the domains of speech perception, speech production, language, phonological processing and reading. Correlation and principal component analyses were used to examine the relationships between outcome areas. Audiologic and demographic variables were not significantly related to reading outcomes, with the exception of family size. Language and word reading were most strongly related to reading comprehension, while phonological awareness and language were most strongly related to word reading. It is proposed that the development of well-specified phonological representations might underlie these relationships. For oral communicating children using a cochlear implant, good reading outcomes are linked to better language and phonological processing abilities.	\N	\N
24437764	Preferences of concert hall acoustics are explored with preference mapping. The investigation is performed on previously gathered data from individual vocabulary profiling of nine concert halls and three pieces of symphonic music, namely, excerpts of compositions by Beethoven, Bruckner, and Mozart. Individual preferences are regressed onto a latent three-dimensional sensory space obtained by multiple factor analysis of descriptive sensory data. Overlaying individually estimated preference surfaces onto one another produces preference maps which illustrates both the overall preference of the stimuli as well as differences between individual listeners. A comparison of the maps between music motifs illustrates how each music signal affects the weighting of different acoustical qualities in preference judgments. Differences in preferences between individuals are pronounced in the excerpts of Beethoven and Bruckner, while the responses are more homogeneous for Mozart music motif. Overall, proximity is identified as the main aspect associated with preference, but also loudness, envelopment, and bass are important. A correlation analysis of objective parameters and subjective perceptions substantiates the importance of lateral sound energy for good concert hall acoustics. Particularly, the lateral early energy fraction at high frequencies is found to be associated with the perception of proximity, and hence, also with preference.	\N	\N
24437852	The purpose of this study was to determine the overall impact of early and late reflections on the intelligibility of reverberated speech by cochlear implant listeners. Two specific reverberation times were assessed. For each reverberation time, sentences were presented in three different conditions wherein the target signal was filtered through the early, late or entire part of the acoustic impulse response. Results obtained with seven cochlear implant listeners indicated that while early reflections neither enhanced nor reduced overall speech perception performance, late reflections severely reduced speech intelligibility in both reverberant conditions tested.	\N	\N
24453339	The temporal envelope of speech is an important cue contributing to speech intelligibility. Theories about the neural foundations of speech perception postulate that the left and right auditory cortices are functionally specialized in analyzing speech envelope information at different time scales: the right hemisphere is thought to be specialized in processing syllable rate modulations, whereas a bilateral or left hemispheric specialization is assumed for phoneme rate modulations. Recently, it has been found that this functional hemispheric asymmetry is different in individuals with language-related disorders such as dyslexia. Most studies were, however, performed in adults and school-aged children, and only a little is known about how neural auditory processing at these specific rates manifests and develops in very young children before reading acquisition. Yet, studying hemispheric specialization for processing syllable and phoneme rate modulations in preliterate children may reveal early neural markers for dyslexia. In the present study, human cortical evoked potentials to syllable and phoneme rate modulations were measured in 5-year-old children at high and low hereditary risk for dyslexia. The results demonstrate a right hemispheric preference for processing syllable rate modulations and a symmetric pattern for phoneme rate modulations, regardless of hereditary risk for dyslexia. These results suggest that, while hemispheric specialization for processing syllable rate modulations seems to be mature in prereading children, hemispheric specialization for phoneme rate modulation processing may still be developing. These findings could have important implications for the development of phonological and reading skills.	\N	\N
24456178	Spectral modulation detection (SMD) provides a psychoacoustic estimate of spectral resolution. The SMD threshold for an implanted ear is highly correlated with speech understanding and is thus a non-linguistic, psychoacoustic index of speech understanding. This measure, however, is time and equipment intensive and thus not practical for clinical use. Thus the purpose of the current study was to investigate the efficacy of a quick SMD task with the following three study aims: (1) to investigate the correlation between the long psychoacoustic, and quick SMD tasks, (2) to determine the test/retest variability of the quick SMD task, and (3) to evaluate the relationship between the quick SMD task and speech understanding. This study included a within-subjects, repeated-measures design. Seventy-six adult cochlear implant recipients participated. The results were as follows: (1) there was a significant correlation between the long psychoacoustic, and quick SMD tasks, (2) the test-retest variability of the quick SMD task was highly significant and, (3) there was a significant positive correlation between the quick SMD task and monosyllabic word recognition. The results of this study represent the direct clinical translation of a research-proven task of SMD into a quick, clinically feasible format.	\N	\N
24457086	Due to extensive variability in the phonetic realizations of words, there may be few or no proximal spectro-temporal cues that identify a word's onset or even its presence. Dilley and Pitt (2010) showed that the rate of context speech, distal from a to-be-recognized word, can have a sizeable effect on whether or not a word is perceived. This investigation considered whether there is a distinct role for distal rhythm in the disappearing word effect. Listeners heard sentences that had a grammatical interpretation with or without a critical function word (FW) and transcribed what they heard (e.g., are in Jill got quite mad when she heard there are birds can be removed and Jill got quite mad when she heard their birds is still grammatical). Consistent with a perceptual grouping hypothesis, participants were more likely to report critical FWs when distal rhythm (repeating ternary or binary pitch patterns) matched the rhythm in the FW-containing region than when it did not. Notably, effects of distal rhythm and distal rate were additive. Results demonstrate a novel effect of distal rhythm on the amount of lexical material listeners hear, highlighting the importance of distal timing information and providing new constraints for models of spoken word recognition.	\N	\N
24464088	Bimodal stimulation, or stimulation of a cochlear implant (CI) together with a contralateral hearing aid (HA), can improve speech perception in noise However, this benefit is variable, and some individuals even experience interference with bimodal stimulation. One contributing factor to this variability may be differences in binaural spectral integration (BSI) due to abnormal auditory experience. CI programming introduces interaural pitch mismatches, in which the frequencies allocated to the electrodes (and contralateral HA) differ from the electrically stimulated cochlear frequencies. Previous studies have shown that some, but not all, CI users adapt pitch perception to reduce this mismatch. The purpose of this study was to determine whether broadened BSI may also reduce the perception of mismatch. Interaural pitch mismatches and dichotic pitch fusion ranges were measured in 21 bimodal CI users. Seventeen subjects with wide fusion ranges also conducted a task to pitch match various fused electrode-tone pairs. All subjects showed abnormally wide dichotic fusion frequency ranges of 1-4 octaves. The fusion range size was weakly correlated with the interaural pitch mismatch, suggesting a link between broad binaural pitch fusion and large interaural pitch mismatch. Dichotic pitch averaging was also observed, in which a new binaural pitch resulted from the fusion of the original monaural pitches, even when the pitches differed by as much as 3-4 octaves. These findings suggest that abnormal BSI, indicated by broadened fusion ranges and spectral averaging between ears, may account for speech perception interference and nonoptimal integration observed with bimodal compared with monaural hearing device use.	\N	\N
24465675	Perception of our environment is a multisensory experience; information from different sensory systems like the auditory, visual and tactile is constantly integrated. Complex tasks that require high temporal and spatial precision of multisensory integration put strong demands on the underlying networks but it is largely unknown how task experience shapes multisensory processing. Long-term musical training is an excellent model for brain plasticity because it shapes the human brain at functional and structural levels, affecting a network of brain areas. In the present study we used magnetoencephalography (MEG) to investigate how audio-tactile perception is integrated in the human brain and if musicians show enhancement of the corresponding activation compared to non-musicians. Using a paradigm that allowed the investigation of combined and separate auditory and tactile processing, we found a multisensory incongruency response, generated in frontal, cingulate and cerebellar regions, an auditory mismatch response generated mainly in the auditory cortex and a tactile mismatch response generated in frontal and cerebellar regions. The influence of musical training was seen in the audio-tactile as well as in the auditory condition, indicating enhanced higher-order processing in musicians, while the sources of the tactile MMN were not influenced by long-term musical training. Consistent with the predictive coding model, more basic, bottom-up sensory processing was relatively stable and less affected by expertise, whereas areas for top-down models of multisensory expectancies were modulated by training.	\N	\N
24482186	Tinnitus is described as the perception of sound or noise in the absence of real acoustic stimulation. In the current absence of a cure for tinnitus, clinical management typically focuses on reducing the effects of co-morbid symptoms such as distress or hearing loss. Hearing loss is commonly co-morbid with tinnitus and so logic implies that amplification of external sounds by hearing aids will reduce perception of the tinnitus sound and the distress associated with it. To assess the effects of hearing aids specifically in terms of tinnitus benefit in patients with tinnitus and co-existing hearing loss. We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL); PubMed; EMBASE; CINAHL; Web of Science; Cambridge Scientific Abstracts; ICTRP and additional sources for published and unpublished trials. The date of the search was 19 August 2013. Randomised controlled trials and non-randomised controlled trials recruiting adults with subjective tinnitus and some degree of hearing loss, where the intervention involves amplification with hearing aids and this is compared to interventions involving other medical devices, other forms of standard or complementary therapy, or combinations of therapies, no intervention or placebo interventions. Three authors independently screened all selected abstracts. Two authors independently extracted data and assessed those potentially suitable studies for risk of bias. For studies meeting the inclusion criteria, we used the mean difference (MD) to compare hearing aids with other interventions and controls. One randomised controlled trial (91 participants) was included in this review. We judged the trial to have a low risk of bias for method of randomisation and outcome reporting, and an unclear risk of bias for other criteria. No non-randomised controlled trials meeting our inclusion criteria were identified. The included study measured change in tinnitus severity (primary measure of interest) using a tinnitus questionnaire measure, and change in tinnitus loudness (secondary measure of interest) on a visual analogue scale. Other secondary outcome measures of interest, namely change in the psychoacoustic characteristics of tinnitus, change in self reported anxiety, depression and quality of life, and change in neurophysiological measures, were not investigated in this study. The included study compared hearing aid use to sound generator use. The estimated effect on change in tinnitus loudness or severity as measured by the Tinnitus Handicap Inventory score was compatible with benefits for both hearing aids or sound generators but no difference was found between the two alternative treatments (MD -0.90, 95% confidence interval (CI) -7.92 to 6.12) (100-point scale); moderate quality evidence. No negative or adverse events were reported. The current evidence base for hearing aid prescription for tinnitus is limited. To be useful, future studies should make appropriate use of blinding and be consistent in their use of outcome measures. Whilst hearing aids are sometimes prescribed as part of tinnitus management, there is currently no evidence to support or refute their use as a more routine intervention for tinnitus.	\N	\N
24486809	Novel stimuli reliably attract attention, suggesting that novelty may disrupt performance when it is task-irrelevant. However, under certain circumstances novel stimuli can also elicit a general alerting response having beneficial effects on performance. In a series of experiments we investigated whether different aspects of novelty--stimulus novelty, contextual novelty, surprise, deviance, and relative complexity--lead to distraction or facilitation. We used a version of the visual oddball paradigm in which participants responded to an occasional auditory target. Participants responded faster to this auditory target when it occurred during the presentation of novel visual stimuli than of standard stimuli, especially at SOAs of 0 and 200 ms (Experiment 1). Facilitation was absent for both infrequent simple deviants and frequent complex images (Experiment 2). However, repeated complex deviant images did facilitate responses to the auditory target at the 200 ms SOA (Experiment 3). These findings suggest that task-irrelevant deviant visual stimuli can facilitate responses to an unrelated auditory target in a short 0-200 millisecond time-window after presentation. This only occurs when the deviant stimuli are complex relative to standard stimuli. We link our findings to the novelty P3, which is generated under the same circumstances, and to the adaptive gain theory of the locus coeruleus-norepinephrine system (Aston-Jones and Cohen, 2005), which may explain the timing of the effects.	\N	\N
24496290	Growing evidence suggests that children who are deaf and use cochlear implants (CIs) can communicate effectively using spoken language. Research has reported that age of implantation and length of experience with the CI play an important role in a predicting a child's linguistic development. In recent years, the increase in the number of children receiving bilateral CIs (BiCIs) has led to interest in new variables that may also influence the development of hearing, speech, and language abilities, such as length of bilateral listening experience and the length of time between the implantation of the two CIs. One goal of the present study was to determine how a cohort of children with BiCIs performed on standardized measures of language and nonverbal cognition. This study examined the relationship between performance on language and nonverbal intelligence quotient (IQ) tests and the ages at implantation of the first CI and second CI. This study also examined whether early bilateral activation is related to better language scores. Children with BiCIs (n = 39; ages 4 to 9 years) were tested on two standardized measures, the Test of Language Development and the Leiter International Performance Scale-Revised, to evaluate their expressive/receptive language skills and nonverbal IQ/memory. Hierarchical regression analyses were used to evaluate whether BiCI hearing experience predicts language performance. While large intersubject variability existed, on average, almost all the children with BiCIs scored within or above normal limits on measures of nonverbal cognition. Expressive and receptive language scores were highly variable, less likely to be above the normative mean, and did not correlate with Length of first CI Use, defined as length of auditory experience with one cochlear implant, or Length of second CI Use, defined as length of auditory experience with two cochlear implants. All children in the present study had BiCIs. Most IQ scores were either at or above that found in the general population of typically hearing children. However, there was greater variability in their performance on a standardized test of expressive and receptive language. This cohort of children, who are mainstreamed in schools at age-appropriate grades, whose mothers' education is high, and whose families' socioecononomic status is high, had, as a group, on average, language scores within the same range as the normative sample of hearing children. Further research identifying the predictors that contribute to the high variability in both expressive and receptive language scores in children with BiCIs will provide useful information that can aid in clinical management and decision making.	\N	\N
24497938	The vast majority of people experience involuntary musical imagery (INMI) or 'earworms'; perceptions of spontaneous, repetitive musical sound in the absence of an external source. The majority of INMI episodes are not bothersome, while some cause disruption ranging from distraction to anxiety and distress. To date, little is known about how the majority of people react to INMI, in particular whether evaluation of the experience impacts on chosen response behaviours or if attempts at controlling INMI are successful or not. The present study classified 1046 reports of how people react to INMI episodes. Two laboratories in Finland and the UK conducted an identical qualitative analysis protocol on reports of INMI reactions and derived visual descriptive models of the outcomes using grounded theory techniques. Combined analysis carried out across the two studies confirmed that many INMI episodes were considered neutral or pleasant, with passive acceptance and enjoyment being among the most popular response behaviours. A significant number of people, however, reported on attempts to cope with unwanted INMI. The most popular and effective behaviours in response to INMI were seeking out the tune in question, and musical or verbal distraction. The outcomes of this study contribute to our understanding of the aetiology of INMI, in particular within the framework of memory theory, and present testable hypotheses for future research on successful INMI coping strategies.	\N	\N
24506533	We examined infants' oscillatory brain activity during a live interaction with an adult who showed them novel objects. Activation in the alpha frequency range was assessed. Nine-month-old infants responded with desynchronization of alpha-band activity when looking at an object together with an adult during a social interaction involving eye contact. When infant and experimenter only looked at the object without engaging in eye contact, no such effect was observed. Results are interpreted in terms of activation of a generic semantic knowledge system induced by eye contact during a social interaction.	\N	\N
24518404	It was hypothesized that cochlear implant (CI) subjects would be able to correctly identify 1, 2, and 3 simultaneous pitches through direct electrical stimulation. We further hypothesized that the location on the implant array and the fundamental frequency of the pitches would have an impact on the performance. "They gave me back speech but not music" is a sentence commonly heard by CI subjects. One of the reasons is that in music, multiple streams are frequently played at the same time, which is an essential feature of harmony. Current CI speech processors do not allow CI users to perceive such complex polyphonic sounds. In the present study, the authors assessed the ability of CI subjects to perceive simultaneous modulation frequencies based on direct electrical stimulation. Ten CI subjects were asked to identify 1, 2, and 3 simultaneous pitches applied on different electrodes using sinusoidal amplitude modulation. All stimuli were loudness balanced before the actual identification task. Subjects were able to identify 1, 2, and 3 simultaneous pitches. The further the distance between the 2 electrodes, the better was the performance in the 2-pitch condition. The distance between the modulation frequencies had a significant effect on the performance in the 2-and 3-pitch condition. Subjects are able to identify complex polyphonic stimuli based on the number of active electrodes. The additional polyphonic rate pitch cue improves performance in some conditions.	\N	\N
24553776	Sounds emitted by different sources arrive at our ears as a mixture that must be disentangled before meaningful information can be retrieved. It is still a matter of debate whether this decomposition happens automatically or requires the listener's attention. These opposite positions partly stem from different methodological approaches to the problem. We propose an integrative approach that combines the logic of previous measurements targeting either auditory stream segregation (interpreting a mixture as coming from two separate sources) or integration (interpreting a mixture as originating from only one source). By means of combined behavioral and event-related potential (ERP) measures, our paradigm has the potential to measure stream segregation and integration at the same time, providing the opportunity to obtain positive evidence of either one. This reduces the reliance on zero findings (i.e., the occurrence of stream integration in a given condition can be demonstrated directly, rather than indirectly based on the absence of empirical evidence for stream segregation, and vice versa). With this two-way approach, we systematically manipulate attention devoted to the auditory stimuli (by varying their task relevance) and to their underlying structure (by delivering perceptual tasks that require segregated or integrated percepts). ERP results based on the mismatch negativity (MMN) show no evidence for a modulation of stream integration by attention, while stream segregation results were less clear due to overlapping attention-related components in the MMN latency range. We suggest future studies combining the proposed two-way approach with some improvements in the ERP measurement of sequential stream segregation.	\N	\N
24556905	The aim of this study was to investigate the efficacy of a direct acoustic cochlear implant (DACI) for speech understanding in noise in patients suffering from severe to profound mixed hearing loss (MHL) due to various etiologies compared to the preoperative best-aided condition. The study was performed at five tertiary referral centers in Europe (Belgium, Germany, Poland and Spain). Nineteen adult subjects with severe to profound MHL due to (advanced) otosclerosis, ear canal fibrosis, chronic otitis media, tympanosclerosis or previous cholesteatoma were implanted with a DACI (Codacs™ Investigational Device) combined with a conventional stapes prosthesis. Unaided and aided speech reception scores in quiet and in noise, preoperative and postoperative air and bone conduction thresholds and aided and unaided sound field thresholds were measured prospectively during the study. Subjective benefit analysis was determined through the Abbreviated Profile of Hearing Aid Benefit questionnaire. Quality of life was measured by the Health Utilities Index. All subjects were fitted preoperatively with hearing aids and/or a bone conduction implant on a headband before DACI implantation. This allows direct comparison between different hearing rehabilitation solutions. The mean speech reception threshold in noise improved significantly by 7.9 dB signal-to-noise ratio (SNR) after activation of the DACI compared to the preoperative best-aided condition. For all 19 subjects, a mean postoperative aided speech reception threshold of 2.6 dB SNR (standard deviation: 8.3 dB) was measured. On average, no significant shift in the bone conduction thresholds was noted 4-5 months after implantation. A mean sound field threshold improvement of 46 and 16 dB was measured compared to the preoperative unaided and best-aided condition, respectively. Speech perception tests in quiet showed a mean improvement of the word recognition scores by 65 and 48% at 65 dB SPL compared to the preoperative unaided and best-aided condition, respectively. In summary, DACI provides an effective improvement of the speech perception in noise compared to the best-aided condition in subjects suffering from severe to profound MHL.	\N	\N
24559662	The minimum time interval between two stimuli that can be reliably detected is called the gap detection threshold. The present study examines whether an unconscious state, natural sleep affects the gap detection threshold. Event-related potentials were recorded in 10 young adults while awake and during all-night sleep to provide an objective estimate of this threshold. These subjects were presented with 2, 4, 8 or 16ms gaps occurring in 1.5 duration white noise. During wakefulness, a significant N1 was elicited for the 8 and 16ms gaps. N1 was difficult to observe during stage N2 sleep, even for the longest gap. A large P2 was however elicited and was significant for the 8 and 16ms gaps. Also, a later, very large N350 was elicited by the 16ms gap. An N1 and P2 was significant only for the 16ms gap during REM sleep. ERPs to gaps occurring in noise segments can therefore be successfully elicited during natural sleep. The gap detection threshold is similar in the waking and sleeping states.	\N	\N
24561213	The present study investigated the joint impact of target-flanker similarity and of spatial frequency content on the crowding effect in letter identification. We presented spatial frequency filtered letters to neurologically intact non-dyslexic readers while manipulating target-flanker distance, target eccentricity and target-flanker confusability (letter similarity metric based on published letter confusion matrices). The results show that high target-flanker confusability magnifies crowding. They also reveal an intricate pattern of interactions of the spatial frequency content of the stimuli with target eccentricity, flanker distance and similarity. The findings are congruent with the notion that crowding results from the inappropriate pooling of target and flanker features and that this integration is more likely to match a response template at a subsequent decision stage with similar than dissimilar flankers. In addition, the evidence suggests that crowding from similar flankers is biased towards relatively high spatial frequencies and that crowding shifts towards lower spatial frequencies as target eccentricity is increased.	\N	\N
24566800	Learning in perceptual tasks is typically highly specific to the trained stimulus parameters. However, can learning be specific to a stimulus parameter that is perceptually indistinguishable from another? We assessed this question using a perceived sound location task in which the perceived sound location was created through either an interaural time difference (ITD) cue or an interaural level difference (ILD) cue. We used the same transient, broadband sound (clicks) for both cues, and after training on one of the cues, listeners switched cue mid-session. This allowed us to assess cue specificity or transfer when the subjectively unnoticed cue switch occurred. One group of listeners improved their ITD performance as a function of training, but deteriorated in performance when switching to ILD in mid training session. Another group of listeners started with ILD training; their improved performance level did not deteriorate as they switched to the ITD cue. This transfer asymmetry was not hypothesized, and we therefore extended our study with a second data collection. Both the training effect and the transfer asymmetry remained after the second data collection. Our results indicate (a) listeners can improve both their ITD and ILD performance for click sounds, extending previous findings on tones; (b) learning can be specific to a stimulus parameter that is indistinguishable from another, as ITD learning did not transfer to ILD performance; but (c) ILD learning can transfer to ITD performance. This transfer asymmetry may have occurred because of how ITD and ILD are coded in early brainstem areas.	\N	\N
24568205	The melodic contour of speech forms an important perceptual aspect of tonal and nontonal languages and an important limiting factor on the intelligibility of speech heard through a cochlear implant. Previous work exploring the neural correlates of speech comprehension identified a left-dominant pathway in the temporal lobes supporting the extraction of an intelligible linguistic message, whereas the right anterior temporal lobe showed an overall preference for signals clearly conveying dynamic pitch information [Johnsrude, I. S., Penhune, V. B., & Zatorre, R. J. Functional specificity in the right human auditory cortex for perceiving pitch direction. Brain, 123, 155-163, 2000; Scott, S. K., Blank, C. C., Rosen, S., & Wise, R. J. Identification of a pathway for intelligible speech in the left temporal lobe. Brain, 123, 2400-2406, 2000]. The current study combined modulations of overall intelligibility (through vocoding and spectral inversion) with a manipulation of pitch contour (normal vs. falling) to investigate the processing of spoken sentences in functional MRI. Our overall findings replicate and extend those of Scott et al. [Scott, S. K., Blank, C. C., Rosen, S., & Wise, R. J. Identification of a pathway for intelligible speech in the left temporal lobe. Brain, 123, 2400-2406, 2000], where greater sentence intelligibility was predominately associated with increased activity in the left STS, and the greatest response to normal sentence melody was found in right superior temporal gyrus. These data suggest a spatial distinction between brain areas associated with intelligibility and those involved in the processing of dynamic pitch information in speech. By including a set of complexity-matched unintelligible conditions created by spectral inversion, this is additionally the first study reporting a fully factorial exploration of spectrotemporal complexity and spectral inversion as they relate to the neural processing of speech intelligibility. Perhaps surprisingly, there was little evidence for an interaction between the two factors-we discuss the implications for the processing of sound and speech in the dorsolateral temporal lobes.	\N	\N
24576508	We investigated the effects of linguistic experience and language familiarity on the perception of audio-visual (A-V) synchrony in fluent speech. In Experiment 1, we tested a group of monolingual Spanish- and Catalan-learning 8-month-old infants to a video clip of a person speaking Spanish. Following habituation to the audiovisually synchronous video, infants saw and heard desynchronized clips of the same video where the audio stream now preceded the video stream by 366, 500, or 666 ms. In Experiment 2, monolingual Catalan and Spanish infants were tested with a video clip of a person speaking English. Results indicated that in both experiments, infants detected a 666 and a 500 ms asynchrony. That is, their responsiveness to A-V synchrony was the same regardless of their specific linguistic experience or familiarity with the tested language. Compared to previous results from infant studies with isolated audiovisual syllables, these results show that infants are more sensitive to A-V temporal relations inherent in fluent speech. Furthermore, the absence of a language familiarity effect on the detection of A-V speech asynchrony at eight months of age is consistent with the broad perceptual tuning usually observed in infant response to linguistic input at this age.	\N	\N
24581119	Music conveys emotion by manipulating musical structures, particularly musical mode- and tempo-impact. The neural correlates of musical mode and tempo perception revealed by electroencephalography (EEG) have not been adequately addressed in the literature. This study used independent component analysis (ICA) to systematically assess spatio-spectral EEG dynamics associated with the changes of musical mode and tempo. Empirical results showed that music with major mode augmented delta-band activity over the right sensorimotor cortex, suppressed theta activity over the superior parietal cortex, and moderately suppressed beta activity over the medial frontal cortex, compared to minor-mode music, whereas fast-tempo music engaged significant alpha suppression over the right sensorimotor cortex. The resultant EEG brain sources were comparable with previous studies obtained by other neuroimaging modalities, such as functional magnetic resonance imaging (fMRI) and positron emission tomography (PET). In conjunction with advanced dry and mobile EEG technology, the EEG results might facilitate the translation from laboratory-oriented research to real-life applications for music therapy, training and entertainment in naturalistic environments.	\N	\N
24581190	The use of adequate assessment tools in health care is crucial for the management of care. The lack of specific tools in Portugal for assessing the performance of children who use cochlear implants motivated the translation and adaptation of the EARS (Evaluation of Auditory Responses to Speech) test battery into European Portuguese. This test battery is today one of the most commonly used by (re)habilitation teams of deaf children who use cochlear implants worldwide. The goal to be achieved with the validation of EARS was to provide (re)habilitation teams an instrument that enables: (i) monitoring the progress of individual (re)habilitation, (ii) managing a (re)habilitation program according to objective results, comparable between different (re)habilitation teams, (iii) obtaining data that can be compared with the results of international teams, and (iv) improving engagement and motivation of the family and other professionals from local teams. For the test battery translation and adaptation process, the adopted procedures were the following: (i) translation of the English version into European Portuguese by a professional translator, (ii) revision of the translation performed by an expert panel, including doctors, speech-language pathologists and audiologists, (iii) adaptation of the test stimuli by the team's speechlanguage pathologist, and (iv) further review by the expert panel. For each of the tests that belong to the EARS battery, the introduced adaptations and adjustments are presented, combining the characteristics and objectives of the original tests with the linguistic and cultural specificities of the Portuguese population. The difficulties that have been encountered during the translation and adaptation process and the adopted solutions are discussed. Comparisons are made with other versions of the EARS battery. We defend that the translation and the adaptation process followed for the EARS test battery into European Portuguese was correctly conducted, respecting the characteristics of the original instruments and adapting the test stimuli to the linguistic and cultural reality of the Portuguese population, thus meeting the goals that have been set.	\N	\N
24581551	There is evidence that people with psychosis display a "jump-to-conclusions" (JTC) reasoning style, and that this bias may be specific to delusions. A "jump-to-perceptions" (JTP) cognitive bias has also been found and is typically linked to hallucinations. However, there is some evidence for an association between JTP and delusions, and its specificity to hallucinations remains unclear. It has been suggested that these biases are related and products of shared cognitive processes. This study examined the symptom specificity of JTC and JTP, and the relationship between them, in a sample of 98 individuals with delusions divided into 'hallucinators' (n=51) and 'non-hallucinators' (n=47). Biases were assessed using the beads task and visual and auditory perceptual tasks. As predicted, both groups demonstrated a JTC bias, but the 'hallucinators' showed a more pronounced JTP style in both modalities. The presence of JTC and JTP biases did not co-occur: making a decision on the beads task after two or fewer draws was not related to visual JTP, and was associated with a less marked JTP bias in the auditory perceptual task. No differences were found in JTP or JTC between participants with and without a schizophrenia diagnosis. JTP, but not JTC, was associated with the presence of hallucinations. These findings suggest that the JTC and JTP biases show specificity to delusions and hallucinations, respectively, and not to diagnosis. There was no evidence that they are the product of shared cognitive processes, further supporting their specificity.	\N	\N
24597272	Listeners find it relatively difficult to recognize words that are similar-sounding to other known words. In contrast, when asked to identify spoken nonwords, listeners perform better when the nonwords are similar to many words in their language. These effects of sound similarity have been assessed in multiple ways, and both sublexical (phonotactic probability) and lexical (neighborhood) effects have been reported, leading to models that incorporate multiple stages of processing. One prediction that can be derived from these models is that there may be differences among individuals in the size of these similarity effects as a function of working memory abilities. This study investigates how item-individual characteristics of nonwords (both phonotactic probability and neighborhood density) interact with listener-individual characteristics (such as cognitive abilities and hearing sensitivity) in the perceptual identification of nonwords. A set of nonwords was used in which neighborhood density and phonotactic probability were not correlated. In our data, neighborhood density affected identification more reliably than did phonotactic probability. The first study, with young adults, showed that higher neighborhood density particularly benefits nonword identification for those with poorer attention-switching control. This suggests that it may be easier to focus attention on a novel item if it activates and receives support from more similar-sounding neighbors. A similar study on nonword identification with older adults showed increased neighborhood density effects for those with poorer hearing, suggesting that activation of long-term linguistic knowledge is particularly important to back up auditory representations that are degraded as a result of hearing loss.	\N	\N
24603717	Objective identification and description of mimicked calls is a primary component of any study on avian vocal mimicry but few studies have adopted a quantitative approach. We used spectral feature representations commonly used in human speech analysis in combination with various distance metrics to distinguish between mimicked and non-mimicked calls of the greater racket-tailed drongo, Dicrurus paradiseus and cross-validated the results with human assessment of spectral similarity. We found that the automated method and human subjects performed similarly in terms of the overall number of correct matches of mimicked calls to putative model calls. However, the two methods also misclassified different subsets of calls and we achieved a maximum accuracy of ninety five per cent only when we combined the results of both the methods. This study is the first to use Mel-frequency Cepstral Coefficients and Relative Spectral Amplitude - filtered Linear Predictive Coding coefficients to quantify vocal mimicry. Our findings also suggest that in spite of several advances in automated methods of song analysis, corresponding cross-validation by humans remains essential.	\N	\N
24604542	Two experiments were conducted to study effects of modality, temporal position, and their interaction on comparisons of successive stimuli. In Experiment 1, intramodal (tone-tone and line-line) and crossmodal (tone-line and line-tone) stimulus pairs, with two interstimulus intervals (ISIs), 400 and 2,000 ms, were presented. Participants indicated which stimulus was the "stronger." Time-order errors (TOEs) were assessed using the D% measure and were found in all types of pairs. Variation in TOEs across conditions was well accounted for by changes in parameters (stimulus weights, reference levels) in an extended version of Hellström's sensation weighting (SW) model. With an ISI of 2,000 ms, the first stimulus had a lower weight (less impact on the response) than did the second stimulus. More negative TOEs were found with the longer ISI in all pair types except tone-line. In Experiment 2, participants indicated which of two lines was the longer or which of two tones was the louder. An intra- or crossmodal anchor, or no anchor, was interpolated between the stimuli. Anchoring tended to reduce the weight of the first stimulus, suggesting interference with memory, and to yield negative TOEs. Intramodal anchors yielded reduced weights of both stimuli, most dramatically for tones, suggesting an additional effect of stimulus interference. Response times decreased with crossmodal anchors. For line-line pairs, strong negative TOEs were found. In both experiments, the variation in TOE across conditions was well accounted for by the SW model.	\N	\N
24606282	An experiment was carried out to determine whether the level of the speech fluency disorder can be estimated by means of automatic acoustic measurements. These measures analyze, for example, the amount of silence in a recording or the number of abrupt spectral changes in a speech signal. All the measures were designed to take into account symptoms of stuttering. In the experiment, 118 audio recordings of read speech by Czech native speakers were employed. The results indicate that the human-made rating of the speech fluency disorder in read speech can be predicted on the basis of automatic measurements. The number of abrupt spectral changes in the speech segments turns out to be the most appropriate measure to describe the overall speech performance. The results also imply that there are measures with good results describing partial symptoms (especially fixed postures without audible airflow).	\N	\N
24611258	Previous researchers have found that participants associate higher frequencies with locations that are higher in space and lower frequencies with lower locations, creating a phenomenological-spatial association for the frequency of auditory tones. With such an association, the frequency of an auditory tone could potentially bias movements along multiple axes. This hypothesis was tested. In four experiments, nine frequencies (250-1,250 Hz) were binaurally presented to blindfolded participants (n = 10, 12, 20, & 9; M age = 22 yr.) who indicated the perceived location of the stimuli on a measurement scale oriented in the vertical, the horizontal (Experiment 1), or depth dimension (Experiment 2). In Experiment 3, participants were asked to indicate the perceived location of the frequencies on a two-dimensional vertical board located in front of them. In Experiment 4, participants indicated the perceived location in three-dimensional space. An optoelectronic device recorded at all locations. Analyses of constant error indicated a spatial association in the vertical, horizontal, and depth dimensions when responses were restricted to only one dimension (Experiments 1 & 2). Higher frequencies were perceived to be located higher, farther to the right, and farther away from the body than lower frequencies. However, this spatial association was only exhibited in the vertical dimension when the responses were unconstrained in two dimensions (vertical and horizontal; Experiment 3) and all three dimensions (Experiment 4). Although this spatial association is a robust phenomenon, it appears that the association only biases actions when indicating perceived locations in the vertical dimension during unconstrained responses.	\N	\N
24616980	To investigate the changes of electrode impedance, THR/MCL values, and dynamic range (DR) in Combi 40+ cochlear implant after implantation. A respective study was carried out collecting 20 consecutively implanted children's electrode impedances, THR/MCL values, and DR at seven time point during the first three years after implantation. Their variation and correlations were analyzed. Overall, electrode impedances were lowest during the operation, and significantly rise to the highest at the first stimulation, then followed by a gradual decrease. After three months, electrode impedance of apical and medial cochlear segment were basically stable, while that of the basal segment was gradually increased. Dynamic range (DR) of apical and medial group electrode increased early after the operation and showed a stabilization from the second year, whereas that of basal group have a downward trend since the first year. However, the electric charge of each group increased significantly after three months, and then become stable after first year. Otherwise, a stronger negative rectilinear correlation was found between impedance changes with DR than with THR/MCL level. The electrode impedances vary clue to different electrode position. Measuring the electrode impedance can effectively evaluate the working status of Combi C40+ cochlear implant. The dynamic range of the electrode was negatively correlated with the impedances, which made it possible to predict the width of the dynamic range by measuring the impedance 3 or 6 months after operation.	\N	\N
24622027	The safety of implanting a titanium microactuator into the lateral wall of cat scala tympani was assessed by comparing preoperative and postoperative auditory brainstem response (ABR) thresholds for 1 to 3 months. The safety of directly stimulating cochlear perilymph with an implantable hearing system requires maintaining preoperative hearing levels. This cat study is an essential step in the development of the next generation of fully implantable hearing devices for humans. Following GLP surgical standards, a 1-mm cochleostomy was drilled into the lateral wall of the scala tympani, and a nonfunctioning titanium anchor/microactuator assembly was inserted in 8 cats. The scala media was damaged in the 1 cat. ABR thresholds with click and 4- and 8-kHz stimuli were measured preoperatively and compared with postoperative thresholds at 1, 2, and 3 months. Nonimplanted ear thresholds were also measured to establish statistical significance for threshold shifts (>28.4 dB). Two audiologists independently interpreted thresholds. Postoperatively, 7 cats implanted in the scala tympani demonstrated no significant ABR threshold shift for click stimulus; one shifted ABR thresholds to 4- and 8-kHz stimuli. The eighth cat, with surgical damage to the scala media, maintained stable click threshold but had a significant shift to 4- and 8-kHz stimuli. This cat study provides no evidence of worsening hearing thresholds after fenestration of the scala tympani and insertion of a titanium anchor/microactuator, provided there is no surgical trauma to the scala media and the implanted device is securely anchored in the cochleostomy. These 2 issues have been resolved in the development of a fully implantable hearing system for humans. The long-term hearing stability (combined with histologic studies) reaffirm that the microactuator is well tolerated by the cat cochlea.	\N	\N
24622351	Pure-tone auditory thresholds in children are below the standardized hearing threshold levels described by ). The development of hearing ability in Chinese and German children at different ages is analyzed and compared with data in the literature. Extended high frequencies above 8 kHz are included due to their vulnerability to noise. Ninety-one children in China and 197 children at a typical primary school in Germany underwent audiometric tests at 17 frequencies ranging from 125 Hz to 16 kHz. To analyze effects of age the children were assessed in age groups of 6 to 9, 9 to 12, and 13 to 16 years of age. Children in China and Germany have the poorest hearing sensitivity at low frequencies (below 1 kHz) and the best sensitivity at the extended high frequencies above 8 kHz. The mean deviations (both ears) from the standard thresholds for adults 18 to 25 years of age, averaged over all frequencies, are 6.7 dB for Chinese and 7.1 dB for German children in the youngest age groups. In the Chinese age group of 9- to 12-year olds the averaged threshold is 4.5 dB and for the same German age group 3.6 dB. For the Chinese age group of 13- to 16-year olds the averaged threshold is 3.3 dB. The improvements of the older German age group compared with the younger are significant at p < 0.05 and are nearly twice as high compared with the comparable Chinese age groups. Age-dependent improvements of hearing ability are evident in children and should be considered in evaluating audiometric test results. Audiometric tests in the extended high-frequency range could be used as an early warning system for future degeneration of hearing ability.	\N	\N
24623783	The earliest stages of cortical processing of speech sounds take place in the auditory cortex. Transcranial magnetic stimulation (TMS) studies have provided evidence that the human articulatory motor cortex contributes also to speech processing. For example, stimulation of the motor lip representation influences specifically discrimination of lip-articulated speech sounds. However, the timing of the neural mechanisms underlying these articulator-specific motor contributions to speech processing is unknown. Furthermore, it is unclear whether they depend on attention. Here, we used magnetoencephalography and TMS to investigate the effect of attention on specificity and timing of interactions between the auditory and motor cortex during processing of speech sounds. We found that TMS-induced disruption of the motor lip representation modulated specifically the early auditory-cortex responses to lip-articulated speech sounds when they were attended. These articulator-specific modulations were left-lateralized and remarkably early, occurring 60-100 ms after sound onset. When speech sounds were ignored, the effect of this motor disruption on auditory-cortex responses was nonspecific and bilateral, and it started later, 170 ms after sound onset. The findings indicate that articulatory motor cortex can contribute to auditory processing of speech sounds even in the absence of behavioral tasks and when the sounds are not in the focus of attention. Importantly, the findings also show that attention can selectively facilitate the interaction of the auditory cortex with specific articulator representations during speech processing.	\N	\N
24627167	In research investigating Stroop or Simon effects, data are typically analyzed at the level of mean response time (RT), with results showing faster responses for compatible than for incompatible trials. However, this analysis provides only limited information as it glosses over the shape of the RT distributions and how they may differ across tasks and experimental conditions. These limitations have encouraged the analysis of RT distributions using delta plots. In the present review, we aim to bring together research on distributional properties of auditory and visual interference effects. Extending previous reviews on distributional properties of the Simon effect, we additionally review studies reporting distributional analyses of Stroop effects. We show that distributional analyses of sequential effects (i.e., taking into account congruency of the previous trial) capture important similarities and differences of interference effects across tasks (Simon, Stroop) as well as across sensory modalities, despite some challenges associated to this approach.	\N	\N
24627209	In multisensory research, faster responses are commonly observed when multimodal stimuli are presented, as compared to unimodal target presentations. This so-called redundant-signals effect can be explained by several frameworks, including separate-activation and coactivation models. The redundant-signals effect has been investigated in a large number of studies; however, most of those studies have been limited to the rejection of separate-activation models. Coactivation models have been analyzed in only a few studies, primarily using simple response tasks. Here, we investigated the mechanism of multisensory integration underlying go/no-go and choice responses to redundant auditory-visual stimuli. In the present study, the mean and variance of response times, as well as the accuracy rates of go/no-go and choice responses, were used to test a coactivation model based on the linear superposition of diffusion processes (Schwarz, 1994) within two absorbing barriers. The diffusion superposition model accurately describes the means and variances of response times as well as the proportions of correct responses observed in the two tasks. Linear superposition thus seems to be a general principle in the integration of redundant information provided by different sensory channels, and is not restricted to simple responses. The results connect existing theories of multisensory integration with theories on choice behavior.	\N	\N
24632322	Two experiments investigated the cognitive skills that underlie children's susceptibility to semantic and phonological false memories in the Deese/Roediger-McDermott procedure (Deese, 1959; Roediger & McDermott, 1995). In Experiment 1, performance on the Verbal Similarities subtest of the British Ability Scales (BAS) II (Elliott, Smith, & McCulloch, 1997) predicted correct and false recall of semantic lures. In Experiment 2, performance on the Yopp-Singer Test of Phonemic Segmentation (Yopp, 1988) did not predict correct recall, but inversely predicted the false recall of phonological lures. Auditory short-term memory was a negative predictor of false recall in Experiment 1, but not in Experiment 2. The findings are discussed in terms of the formation of gist and verbatim traces as proposed by fuzzy trace theory (Reyna & Brainerd, 1998) and the increasing automaticity of associations as proposed by associative activation theory (Howe, Wimmer, Gagnon, & Plumpton, 2009).	\N	\N
24633379	In order to acquire language, children require speech input. The prosody of the speech input plays an important role. In most cultures adults modify their code when communicating with children. Compared to normal speech this code differs especially with regard to prosody. For this review a selective literature search in PubMed and Scopus was performed. Prosodic characteristics are a key feature of spoken language. By analysing prosodic features, children gain knowledge about underlying grammatical structures. Child-directed speech (CDS) is modified in a way that meaningful sequences are highlighted acoustically so that important information can be extracted from the continuous speech flow more easily. CDS is said to enhance the representation of linguistic signs. Taking into consideration what has previously been described in the literature regarding the perception of suprasegmentals, CDS seems to be able to support language acquisition due to the correspondence of prosodic and syntactic units. However, no findings have been reported, stating that the linguistically reduced CDS could hinder first language acquisition.	\N	\N
24635583	The attentional blink (AB) refers to the decline in report accuracy of a second target (T2) when presented shortly after a first target (T1) in a rapid serial visual presentation (RSVP) of distractors. It is known that masking T1 increases the magnitude of the AB, and masking a single target (equivalent to T1) in a RSVP stream attenuates the P3 to the target in correct trials. The major purpose of the present study was to clarify how these two effects may be integrated. An intervening distractor was presented at lag 1 (T1+1), at lag 2 (T1+2), or at neither of these two lags (no distractor). T2 was always presented at lag 3, as the last item in the stream. The P3 to T1 was attenuated and the P3 to T2 delayed in the T1+1 condition compared to the two other distractor conditions. These results clearly show that masking T1 attenuates the P3 to T1 and delays the P3 to T2 in the AB. Implications for extant theories of the AB are discussed.	\N	\N
24637103	Processing local elements of hierarchical patterns at a superior level and independently from an intact global influence is a well-established characteristic of autistic visual perception. However, whether this confirmed finding has an equivalent in the auditory modality is still unknown. To fill this gap, 18 autistics and 18 typical participants completed a melodic decision task where global and local level information can be congruent or incongruent. While focusing either on the global (melody) or local level (group of notes) of hierarchical auditory stimuli, participants have to decide whether the focused level is rising or falling. Autistics showed intact global processing, a superior performance when processing local elements and a reduced global-to-local interference compared to typical participants. These results are the first to demonstrate that autistic processing of auditory hierarchical stimuli closely parallels processing of visual hierarchical stimuli. When analyzing complex auditory information, autistic participants present a local bias and a more autonomous local processing, but not to the detriment of global processing.	\N	\N
24639401	Blind people rely more on vocal cues when they recognize a person's identity than sighted people. Indeed, a number of studies have reported better voice recognition skills in blind than in sighted adults. The present functional magnetic resonance imaging study investigated changes in the functional organization of neural systems involved in voice identity processing following congenital blindness. A group of congenitally blind individuals and matched sighted control participants were tested in a priming paradigm, in which two voice stimuli (S1, S2) were subsequently presented. The prime (S1) and the target (S2) were either from the same speaker (person-congruent voices) or from two different speakers (person-incongruent voices). Participants had to classify the S2 as either a old or a young person. Person-incongruent voices (S2) compared with person-congruent voices elicited an increased activation in the right anterior fusiform gyrus in congenitally blind individuals but not in matched sighted control participants. In contrast, only matched sighted controls showed a higher activation in response to person-incongruent compared with person-congruent voices (S2) in the right posterior superior temporal sulcus. These results provide evidence for crossmodal plastic changes of the person identification system in the brain after visual deprivation.	\N	\N
24642285	We used magnetoencephalography (MEG) to examine brain activity related to the maintenance of non-verbal pitch information in auditory short-term memory (ASTM). We focused on brain activity that increased with the number of items effectively held in memory by the participants during the retention interval of an auditory memory task. We used very simple acoustic materials (i.e., pure tones that varied in pitch) that minimized activation from non-ASTM related systems. MEG revealed neural activity in frontal, temporal, and parietal cortices that increased with a greater number of items effectively held in memory by the participants during the maintenance of pitch representations in ASTM. The present results reinforce the functional role of frontal and temporal cortices in the retention of pitch information in ASTM. This is the first MEG study to provide both fine spatial localization and temporal resolution on the neural mechanisms of non-verbal ASTM for pitch in relation to individual differences in the capacity of ASTM. This research contributes to a comprehensive understanding of the mechanisms mediating the representation and maintenance of basic non-verbal auditory features in the human brain.	\N	\N
24655365	Previous studies have shown that in semi-spontaneous speech, individuals with Broca's and anomic aphasia produce relatively many direct speech constructions. It has been claimed that in 'healthy' communication direct speech constructions contribute to the liveliness, and indirectly to the comprehensibility, of speech. To examine the effects of the occurrence of direct speech constructions on the perceived liveliness and speech comprehensibility of narratives produced by individuals with and without aphasia. Thirty-seven naive listeners rated 30 speech fragments with and without direct speech from ten speakers with and ten speakers without aphasia. The fragments originated from semi-structured interviews. The raters scored the perceived liveliness and the perceived comprehensibility of these fragments. For both groups of speakers, fragments containing direct speech constructions received higher scores for liveliness than fragments without direct speech constructions. However, no effect of direct speech was found on perceived comprehensibility. This is the first research to demonstrate that communication is perceived as more lively when it contains direct speech than when it does not, but yet is not more comprehensible. Individuals with Broca's and anomic aphasia are known to produce regularly direct speech constructions in elicited narratives. Given that liveliness is known to increase listeners' involvement and to help listeners stay focused, we suggest that this relative increase in direct speech by aphasic speakers may reflect a strategy to increase not only the liveliness of their discourse, but also listener focus and involvement.	\N	\N
24658600	Extended stabilization of gaze leads to disappearance of dim visual targets presented peripherally. This phenomenon, known as Troxler fading, is thought to result from neuronal adaptation. Intense targets also disappear intermittently when surrounded by a moving pattern (the "mask"), a phenomenon known as motion-induced blindness (MIB). The similar phenomenology and dynamics of these disappearances may suggest that also MIB is, likewise, solely due to adaptation, which may be amplified by the presence of the mask. Here we directly compared the dependence of both phenomena on target contrast. Observers reported the disappearance and reappearance of a target of varying intensity (contrast levels: 8%-80%). MIB was induced by adding a mask that moved at one of various different speeds. The results revealed a lawful effect of contrast in both MIB and Troxler fading, but with opposite trends. Increasing target contrast increased (doubled) the rate of disappearance events for MIB, but decreased the disappearance rate to half in Troxler fading. The target mean invisible period decreased equally strongly with target contrast in MIB and in Troxler fading. The results suggest that both MIB and Troxler are equally affected by contrast adaptation, but that the rate of MIB is governed by an additional mechanism, possibly involving antagonistic processes between neuronal populations processing target and mask. Our results link MIB to other bi-stable visual phenomena that involve neuronal competition (such as binocular rivalry), which exhibit an analogous dependency on the strength of the competing stimulus components.	\N	\N
24658601	The goal of this study was to create and validate a new set of sentence lists that could be used to evaluate the speech-perception abilities of listeners with hearing loss in cases where adult materials are inappropriate due to difficulty level or content. The authors aimed to generate a large number of sentence lists with an equivalent level of difficulty for the evaluation of performance over time and across conditions. The original Pediatric AzBio sentence corpus included 450 sentences recorded from one female talker. All sentences included in the corpus were successfully repeated by kindergarten and first-grade students with normal hearing. The mean intelligibility of each sentence was estimated by processing each sentence through a cochlear implant simulation and calculating the mean percent correct score achieved by 15 normal-hearing listeners. After sorting sentences by mean percent correct scores, 320 sentences were assigned to 16 lists of equivalent difficulty. List equivalency was then validated by presenting all sentence lists, in a novel random order, to adults and children with hearing loss. A final-validation stage examined single-list comparisons from adult and pediatric listeners tested in research or clinical settings. The results of the simulation study allowed for the creation of 16 lists of 20 sentences. The average intelligibility of each list ranged from 78.4 to 78.7%. List equivalency was then validated, when the results of 16 adult cochlear implant users and 9 pediatric hearing aid and cochlear implant users revealed no significant differences across lists. The binomial distribution model was used to account for the inherent variability observed in the lists. This model was also used to generate 95% confidence intervals for one and two list comparisons. A retrospective analysis of 361 instances from 78 adult cochlear implant users and 48 instances from 36 pediatric cochlear implant users revealed that the 95% confidence intervals derived from the model captured 94% of all responses (385 of 409). The cochlear implant simulation was shown to be an effective method for estimating the intelligibility of individual sentences for use in the evaluation of cochlear implant users. Furthermore, the method used for constructing equivalent sentence lists and estimating the inherent variability of the materials has also been validated. Thus, the AzBio Pediatric Sentence Lists are equivalent and appropriate for the assessment of speech-understanding abilities of children with hearing loss as well as adults for whom performance on AzBio sentences is near the floor.	\N	\N
24671776	Learning about objects often requires making arbitrary associations among multisensory properties, such as the taste and appearance of a food or the face and voice of a person. However, the multisensory properties of individual objects usually are statistically constrained, such that some properties are more likely to co-occur than others, on the basis of their category. For example, male faces are more likely to co-occur with characteristically male voices than with female voices. Here, we report evidence that these natural multisensory statistics play a critical role in the learning of novel, arbitrary associative pairs. In Experiment 1, we found that learning of pairs consisting of human voices and gender-congruent faces was superior to learning of pairs consisting of human voices and gender-incongruent faces or of pairs consisting of human voices and pictures of inanimate objects (plants and rocks). In Experiment 2, we found that this "categorical congruency" advantage extended to nonhuman stimuli, as well-namely, to pairs of class-congruent animal pictures and vocalizations (e.g., dogs and barks) versus class-incongruent pairs (e.g., dogs and bird chirps). These findings suggest that associating multisensory properties that are statistically consistent with the various objects that we encounter in our daily lives is a privileged form of learning.	\N	\N
24686722	PURPOSE Several acoustic cues specify any single phonemic contrast. Nonetheless, adult, native speakers of a language share weighting strategies, showing preferential attention to some properties over others. Cochlear implant (CI) signal processing disrupts the salience of some cues: In general, amplitude structure remains readily available, but spectral structure less so. This study asked how well speech recognition is supported if CI users shift attention to salient cues not weighted strongly by native speakers. METHOD Twenty adults with CIs participated. The /bɑ/-/wɑ/ contrast was used because spectral and amplitude structure varies in correlated fashion for this contrast. Adults with normal hearing weight the spectral cue strongly but the amplitude cue negligibly. Three measurements were made: labeling decisions, spectral and amplitude discrimination, and word recognition. RESULTS Outcomes varied across listeners: Some weighted the spectral cue strongly, some weighted the amplitude cue, and some weighted neither. Spectral discrimination predicted spectral weighting. Spectral weighting explained the most variance in word recognition. Age of onset of hearing loss predicted spectral weighting but not unique variance in word recognition. CONCLUSION The weighting strategies of listeners with normal hearing likely support speech recognition best, so efforts in implant design, fitting, and training should focus on developing those strategies.	\N	\N
24687127	The purpose of this research was to compare the perception of Japanese vowel length contrasts by 4 groups of listeners who differed in their familiarity with length contrasts in their first language (L1; i.e., American English, Italian, Japanese, and Thai). Of the 3 nonnative groups, native Thai listeners were expected to outperform American English and Italian listeners, because vowel length is contrastive in their L1. Native Italian listeners were expected to demonstrate a higher level of accuracy for length contrasts than American English listeners, because the former are familiar with consonant (but not vowel) length contrasts (i.e., singleton vs. geminate) in their L1. A 2-alternative forced-choice AXB discrimination test that included 125 trials was administered to all the participants, and the listeners' discrimination accuracy (d') was reported. As expected, Japanese listeners were more accurate than all 3 nonnative groups in their discrimination of Japanese vowel length contrasts. The 3 nonnative groups did not differ from one another in their discrimination accuracy despite varying experience with length contrasts in their L1. Only Thai listeners were more accurate in their length discrimination when the target vowel was long than when it was short. Being familiar with vowel length contrasts in L1 may affect the listeners' cross-language perception, but it does not guarantee that their L1 experience automatically results in efficient processing of length contrasts in unfamiliar languages. The extent of success may be related to how length contrasts are phonetically implemented in listeners' L1.	\N	\N
24690415	When musical notes are combined to make a chord, the closeness of fit of the combined spectrum to a single harmonic series (the 'harmonicity' of the chord) predicts the perceived consonance (how pleasant and stable the chord sounds; McDermott, Lehr, & Oxenham, 2010). The distinction between consonance and dissonance is central to Western musical form. Harmonicity is represented in the temporal firing patterns of populations of brainstem neurons. The current study investigates the role of brainstem temporal coding of harmonicity in the perception of consonance. Individual preference for consonant over dissonant chords was measured using a rating scale for pairs of simultaneous notes. In order to investigate the effects of cochlear interactions, notes were presented in two ways: both notes to both ears or each note to different ears. The electrophysiological frequency following response (FFR), reflecting sustained neural activity in the brainstem synchronised to the stimulus, was also measured. When both notes were presented to both ears the perceptual distinction between consonant and dissonant chords was stronger than when the notes were presented to different ears. In the condition in which both notes were presented to the both ears additional low-frequency components, corresponding to difference tones resulting from nonlinear cochlear processing, were observable in the FFR effectively enhancing the neural harmonicity of consonant chords but not dissonant chords. Suppressing the cochlear envelope component of the FFR also suppressed the additional frequency components. This suggests that, in the case of consonant chords, difference tones generated by interactions between notes in the cochlea enhance the perception of consonance. Furthermore, individuals with a greater distinction between consonant and dissonant chords in the FFR to individual harmonics had a stronger preference for consonant over dissonant chords. Overall, the results provide compelling evidence for the role of neural temporal coding in the perception of consonance, and suggest that the representation of harmonicity in phase locked neural firing drives the perception of consonance.	\N	\N
24701988	Studies of facial affect recognition by people with traumatic brain injury (TBI) have shown this to be a significant problem. Vocal affect recognition also appears to be challenging for this population, but little is known about the degree to which one modality is impaired compared to the other. This study compared facial and vocal affect recognition of high and low intensity emotion expressions in people with moderate-to-severe TBI. The Diagnostic Analysis of Nonverbal Accuracy-2 (Adult Faces; Voices) was administered to 203 participants with TBI. Adults with TBI identified vocal emotion expressions with greater accuracy than facial emotion expressions. Facial affect recognition impairment was identified in 34% of participants, 22% were classified as having vocal affect recognition impairment and 15% showed impairment in both modalities. Participants were significantly less accurate at identifying low vs high intensity emotion expressions in both modalities. Happy facial expressions were significantly better identified than all other emotions. Errors were distributed across the emotion categories for vocal expressions. The degree of facial affect impairment was significantly greater than vocal affect impairment in this sample of people with moderate-to-severe TBI. Low intensity emotion expressions were particularly problematic and an advantage for positively valenced facial emotion expressions was indicated.	\N	\N
24702433	In this paper, the authors analyze the auditory rehabilitation after cochlear implantation in adults with hearing impairment after head trauma, comparing their performance with that of other cochlear implant (CI) adult users who have post-lingual hearing impairment with other etiologies. The participants were divided into two groups: group 1 (N = 14) composed of CI adult users who have acquired severe to profound hearing loss after head trauma; group 2 (N = 231) composed of CI adult users who have severe to profound hearing loss from other etiologies. Performance was assessed using the following tests: tonal audiometry, speech audiometry, consonantal phonemes identification test, 100 words test, 100 words through the telephone test, monosyllables test, numbers test, sentences test, and sentences through the telephone test. Average results from group 1 were lower when compared with those of group 2 in all the tests used. No statistically significant difference was found for most tests. Statistically significant difference was found for consonantal phonemes identification test, 100 words through the telephone test, monosyllables test (when analyzed regarding the phonemes correctly repeated), and sentences through the telephone test. The performance of the group of CI adult users who have acquired hearing impairment after head trauma was globally lower than that observed on the group of hearing impairment with other etiologies. However, the difference was not statistically significant for most tests. Despite this difference in performance, the results from the group of CI adult users who have acquired hearing impairment after head trauma show the effectiveness of auditory rehabilitation through cochlear implantation in these situations.	\N	\N
24703829	Exploding head syndrome is characterized by the perception of abrupt, loud noises when going to sleep or waking up. They are usually painless, but associated with fear and distress. In spite of the fact that its characteristic symptomatology was first described approximately 150 y ago, exploding head syndrome has received relatively little empirical and clinical attention. Therefore, a comprehensive review of the scientific literature using Medline, PsycINFO, Google Scholar, and PubMed was undertaken. After first discussing the history, prevalence, and associated features, the available polysomnography data and five main etiological theories for exploding head syndrome are summarized. None of these theories has yet reached dominance in the field. Next, the various methods used to assess and treat exploding head syndrome are discussed, as well as the limited outcome data. Finally, recommendations for future measure construction, treatment options, and differential diagnosis are provided.	\N	\N
24707789	Syntactic priming occurs when structural information from one sentence influences processing of a subsequently encountered sentence (Bock, 1986; Ledoux et al., 2007). This article reports 2 eye-tracking experiments investigating the effects of a prime sentence on the processing of a target sentence that shared aspects of syntactic form. The experiments were designed to determine the degree to which lexical overlap between prime and target sentences produced larger effects, comparable to the widely observed "lexical boost" in production experiments (Pickering & Branigan, 1998; Pickering & Ferreira, 2008). The current experiments showed that priming effects during online comprehension were in fact larger when a verb was repeated across the prime and target sentences (see also Tooley et al., 2009). The finding of larger priming effects with lexical repetition supports accounts under which syntactic form representations are connected to individual lexical items (e.g., Tomasello, 2003; Vosse & Kempen, 2000, 2009).	\N	\N
24708425	Visual illusions can reveal unconscious representations and processes at work in perception. Here we report a robust illusion that involves the misperception of moving, partially occluded objects. When a dynamically occluded object is seen through 2 misaligned apertures, the object appears misaligned in the direction of the apertures, creating the Aperture Capture Illusion. Specifically, when part of a dynamically occluded object disappears behind an occluding surface and then another part of the object comes into view immediately afterward, the 2 parts appear misaligned in the direction of the offset of the apertures through which they were seen. This illusion can be nulled: Separating the 2 object parts to increase the time interval between their appearance produced the percept of alignment. The ability to null the illusion in this manner demonstrates that dynamically occluded regions of moving objects continue to persist in perceptual awareness but, we argue, are perceived to move at a slower velocity than visible regions. We report 7 experiments establishing the existence of the illusion and ruling out several classes of explanation for it. We interpret the illusion and the ability to nullify it within the context of Palmer, Kellman, and Shipley's (2006) theory of spatiotemporal object formation.	\N	\N
24719237	A briefly flashed target stimulus can become "invisible" when immediately followed by a mask-a phenomenon known as backward masking, which constitutes a major tool in the cognitive sciences. One form of backward masking is termed metacontrast masking. It is generally assumed that in metacontrast masking, the mask suppresses activity on which the conscious perception of the target relies. This assumption biases conclusions when masking is used as a tool-for example, to study the independence between perceptual detection and motor reaction. This is because other models can account for reduced perceptual performance without requiring suppression mechanisms. In this study, we used signal detection theory to test the suppression model against an alternative view of metacontrast masking, referred to as the summation model. This model claims that target- and mask-related activations fuse and that the difficulty in detecting the target results from the difficulty to discriminate this fused response from the response produced by the mask alone. Our data support this alternative view. This study is not a thorough investigation of metacontrast masking. Instead, we wanted to point out that when a different model is used to account for the reduced perceptual performance in metacontrast masking, there is no need to postulate a dissociation between perceptual and motor responses to account for the data. Metacontrast masking, as implemented in the Fehrer-Raab situation, therefore is not a valid method to assess perceptual-motor dissociations.	\N	\N
24728649	Recent findings have suggested that transient attention can be triggered at two locations simultaneously. However, it is unclear whether doing so reduces the effect of attention at each attended location. In two experiments, we explored the consequences of dividing attention. In the first experiment, we compared the effects of one or two cues against an uncued baseline to determine the consequences of dividing attention in a paradigm with four rapid serial visual presentation (RSVP) streams. The results indicated that two simultaneous cues increase the accuracy of reporting two targets by almost the same amount as a single cue increases the report of a single target. These results suggest that when attention is divided between multiple locations, the attentional benefit at each location is not reduced in proportion to the total number of cues. A consequent prediction of this finding is that the identification of two RSVP targets should be better when they are presented simultaneously rather than sequentially. In a second experiment, we verified this prediction by finding evidence of lag-0 sparing: Two targets presented simultaneously in different locations were reported more easily than two targets separated by 100 ms. These findings argue against a biased-competition theory of attention. We suggest that visual attention, as triggered by a cue or target, is better described by a convergent gradient-field attention model.	\N	\N
24728874	In autism spectrum disorders (ASD), social motivation theories suggest that the core social communication problems seen in children with ASD arise from diminished responsiveness to social reward. Although clinical and experimental data support these theories, the extent to which the reward deficit in ASD is unique for social rewards remains unclear. With the present investigation, we aimed to provide insight into the degree to which sociality as well as familiarity of reward incentives impact motivated goal-directed behavior in children with ASD. To do so, we directly compared the influence of familiar versus unfamiliar social reward relative to nonsocial, monetary reward in children with ASD relative to age- and IQ-matched typically developing controls (TDC) using a visual and auditory incentive go/nogo task with reward contingencies for successful response inhibitions. We found that children with ASD responded stronger to visual familiar and unfamiliar social reward as well as to nonsocial, monetary reward than TDC. While the present data are at odds with predictions made by social motivation theories, individual variations beyond clinical diagnosis, such as reward exposure across various social settings, help explain the pattern of results. The findings of this study stress the necessity for additional research on intra-individual as well as environmental factors that contribute to social reward responsiveness in individuals with ASD versus other neuropsychiatric disorders such as ADHD or conduct disorder.	\N	\N
24732070	Human subjects performed in several behavioral conditions requiring, or not requiring, selective attention to visual stimuli. Specifically, the attentional task was to recognize strings of digits that had been presented visually. A nonlinear version of the stimulus-frequency otoacoustic emission (SFOAE), called the nSFOAE, was collected during the visual presentation of the digits. The segment of the physiological response discussed here occurred during brief silent periods immediately following the SFOAE-evoking stimuli. For all subjects tested, the physiological-noise magnitudes were substantially weaker (less noisy) during the tasks requiring the most visual attention. Effect sizes for the differences were >2.0. Our interpretation is that cortico-olivo influences adjusted the magnitude of efferent activation during the SFOAE-evoking stimulation depending upon the attention task in effect, and then that magnitude of efferent activation persisted throughout the silent period where it also modulated the physiological noise present. Because the results were highly similar to those obtained when the behavioral conditions involved auditory attention, similar mechanisms appear to operate both across modalities and within modalities. Supplementary measurements revealed that the efferent activation was spectrally global, as it was for auditory attention.	\N	\N
24746946	Action representations associated with object use may be incidentally activated during visual object processing, and the time course of such activations may be influenced by lexical-semantic context (e.g., Lee, Middleton, Mirman, Kalénine, & Buxbaum (2012). Journal of Experimental Psychology: Human Perception and Performance, 39(1), 257-270). In this study we used the "visual world" eye-tracking paradigm to examine whether a deficit in producing skilled object-use actions (apraxia) is associated with abnormalities in incidental activation of action information, and assessed the neuroanatomical substrates of any such deficits. Twenty left hemisphere stroke patients, ten of whom were apraxic, performed a task requiring identification of a named object in a visual display containing manipulation-related and unrelated distractor objects. Manipulation relationships among objects were not relevant to the identification task. Objects were cued with neutral ("S/he saw the…."), or action-relevant ("S/he used the….") sentences. Non-apraxic participants looked at use-related non-target objects significantly more than at unrelated non-target objects when cued both by neutral and action-relevant sentences, indicating that action information is incidentally activated. In contrast, apraxic participants showed delayed activation of manipulation-based action information during object identification when cued by neutral sentences. The magnitude of delayed activation in the neutral sentence condition was reliably predicted by lower scores on a test of gesture production to viewed objects, as well as by lesion loci in the inferior parietal and posterior temporal lobes. However, when cued by a sentence containing an action verb, apraxic participants showed fixation patterns that were statistically indistinguishable from non-apraxic controls. In support of grounded theories of cognition, these results suggest that apraxia and temporal-parietal lesions may be associated with abnormalities in incidental activation of action information from objects. Further, they suggest that the previously-observed facilitative role of action verbs in the retrieval of object-related action information extends to participants with apraxia.	\N	\N
24746955	Selective attention to phonology, i.e., the ability to attend to sub-syllabic units within spoken words, is a critical precursor to literacy acquisition. Recent functional magnetic resonance imaging evidence has demonstrated that a left-lateralized network of frontal, temporal, and posterior language regions, including the visual word form area, supports this skill. The current event-related potential (ERP) study investigated the temporal dynamics of selective attention to phonology during spoken word perception. We tested the hypothesis that selective attention to phonology dynamically modulates stimulus encoding by recruiting left-lateralized processes specifically while the information critical for performance is unfolding. Selective attention to phonology was captured by manipulating listening goals: skilled adult readers attended to either rhyme or melody within auditory stimulus pairs. Each pair superimposed rhyming and melodic information ensuring identical sensory stimulation. Selective attention to phonology produced distinct early and late topographic ERP effects during stimulus encoding. Data-driven source localization analyses revealed that selective attention to phonology led to significantly greater recruitment of left-lateralized posterior and extensive temporal regions, which was notably concurrent with the rhyme-relevant information within the word. Furthermore, selective attention effects were specific to auditory stimulus encoding and not observed in response to cues, arguing against the notion that they reflect sustained task setting. Collectively, these results demonstrate that selective attention to phonology dynamically engages a left-lateralized network during the critical time-period of perception for achieving phonological analysis goals. These findings suggest a key role for selective attention in on-line phonological computations. Furthermore, these findings motivate future research on the role that neural mechanisms of attention may play in phonological awareness impairments thought to underlie developmental reading disabilities.	\N	\N
24751993	Voice pitch is an important information-bearing component of language that is subject to experience dependent plasticity at both early cortical and subcortical stages of processing. We have already demonstrated that pitch onset component (Na) of the cortical pitch response (CPR) is sensitive to flat pitch and its salience … CPR responses from Chinese listeners were elicited by three citation forms varying in pitch acceleration and duration. Results showed that the pitch onset component (Na) was invariant to changes in acceleration. In contrast, Na–Pb and Pb–Nb showed a systematic decrease in the interpeak latency and decrease in amplitude with increase in pitch acceleration that followed the time course of pitch change across the three stimuli. A strong correlation with pitch acceleration was observed for these two components only – a putative index of pitch-relevant neural activity associated with the more rapidly-changing portions of the pitch contour. Pc–Nc marks unambiguously the stimulus offset … and their functional roles as related to sensory and cognitive properties of the stimulus. [Corrected]	\N	\N
24754984	To retrospectively analyze the auditory and speech development of young children with bilateral congenital aural atresia after using bone-anchored hearing aid (BAHA) softband. From August 2010 to January 2013, a total of 12 patients aged at a range of 3 months to 6 years with bilateral aural atresia using BAHA softband were divided into under 4-year-old group (n = 7, an average age of 14 months) and over 4-year-old group (n = 5, an average age of 77 months). The air and bone auditory thresholds of the under 4-year-old group were assessed by auditory brainstem response (ABR). The Infant-Toddler Meaningful Auditory Integration Scale (IT-MAIS) was used to evaluate early auditory development.Soundfield pure tone audiometry (PTA) was applied in the over 4-year-old group. The Standard Chinese lexical neighborhood test (LNT) was conducted to evaluate the speech discrimination scores unaided and aided for 6, 12 and 24 months. For the under 4-year-old group, the unaided air and bone conduction hearing thresholds were 70-90(73 ± 12) and 15-25(21 ± 4) dB nHL respectively.IT-MAIS score improved significantly after using softband for 6 months in comparisons with unaided situations. The average hearing threshold of patients in the over 4-year-old group was (63 ± 6) dB HL unaided versus (31 ± 4)dB HL aided. The average decline in pure-tone threshold was (32 ± 3)dB HL with BAHA softbands and LNT demonstrated improvements in the speech discrimination score. The differences of paired comparison were significant (all P < 0.05). The hearing ability of children with bilateral congenital aural atresia improves significantly after using BAHA softband. And its application at a young age can guarantee a relatively normal hearing development and avoid oral communication impairment.	\N	\N
24764068	The effects on multisensory integration have rarely been examined in amblyopia. The McGurk effect is a well-established audiovisual illusion that is manifested when an auditory phoneme is presented concurrently with an incongruent visual phoneme. Visually healthy viewers will hear a phoneme that does not match the actual auditory stimulus, having been perceptually influenced by the visual phoneme. This study examines audiovisual integration in adults with amblyopia. Twenty-two subjects with amblyopia and 25 visually healthy controls participated. Participants viewed videos of combinations of visual and auditory phonemes, and were asked to report what they heard. Some videos had congruent video and audio (control), whereas others had incongruent video and audio (McGurk). The McGurk effect is strongest when the visual phoneme dominates over the audio phoneme, resulting in low auditory accuracy on the task. Adults with amblyopia demonstrated a weaker McGurk effect than visually healthy controls (P = 0.01). The difference was greatest when viewing monocularly with the amblyopic eye, and it was also evident when viewing binocularly or monocularly with the fellow eye. No correlations were found between the strength of the McGurk effect and either visual acuity or stereoacuity in subjects with amblyopia. Subjects with amblyopia and controls showed a similar response pattern to different speakers and syllables, and subjects with amblyopia consistently demonstrated a weaker effect than controls. Abnormal visual experience early in life can have negative consequences for audiovisual integration that persists into adulthood in people with amblyopia.	\N	\N
24770403	To clarify the responsible gene for a family associated with hearing loss but having no well-known mitochondrial mutations. A Japanese family showing late-onset, progressive, and ski-sloping sensorineural hearing loss. Whole mitochondrial genome sequencing identified the 1673T>C mutation, a novel mitochondrial DNA mutation in the 16S ribosomal RNA gene. Whole mitochondrial genome sequencing is a powerful tool to identify the responsible gene for plausible mitochondrially inherited families. This is additional evidence that mitochondrial gene mutations may cause late-onset, progressive, and ski-sloping sensorineural hearing loss.	\N	\N
24778251	Although it is well accepted that the speech motor system (SMS) is activated during speech perception, the functional role of this activation remains unclear. Here we test the hypothesis that the redundant motor activation contributes to categorical speech perception under adverse listening conditions. In this functional magnetic resonance imaging study, participants identified one of four phoneme tokens (/ba/, /ma/, /da/, or /ta/) under one of six signal-to-noise ratio (SNR) levels (-12, -9, -6, -2, 8 dB, and no noise). Univariate and multivariate pattern analyses were used to determine the role of the SMS during perception of noise-impoverished phonemes. Results revealed a negative correlation between neural activity and perceptual accuracy in the left ventral premotor cortex and Broca's area. More importantly, multivoxel patterns of activity in the left ventral premotor cortex and Broca's area exhibited effective phoneme categorization when SNR ≥ -6 dB. This is in sharp contrast with phoneme discriminability in bilateral auditory cortices and sensorimotor interface areas (e.g., left posterior superior temporal gyrus), which was reliable only when the noise was extremely weak (SNR > 8 dB). Our findings provide strong neuroimaging evidence for a greater robustness of the SMS than auditory regions for categorical speech perception in noise. Under adverse listening conditions, better discriminative activity in the SMS may compensate for loss of specificity in the auditory system via sensorimotor integration.	\N	\N
24778384	The activation of listener's motor system during speech processing was first demonstrated by the enhancement of electromyographic tongue potentials as evoked by single-pulse transcranial magnetic stimulation (TMS) over tongue motor cortex. This technique is, however, technically challenging and enables only a rather coarse measurement of this motor mirroring. Here, we applied TMS to listeners' tongue motor area in association with ultrasound tissue Doppler imaging to describe fine-grained tongue kinematic synergies evoked by passive listening to speech. Subjects listened to syllables requiring different patterns of dorso-ventral and antero-posterior movements (/ki/, /ko/, /ti/, /to/). Results show that passive listening to speech sounds evokes a pattern of motor synergies mirroring those occurring during speech production. Moreover, mirror motor synergies were more evident in those subjects showing good performances in discriminating speech in noise demonstrating a role of the speech-related mirror system in feed-forward processing the speaker's ongoing motor plan.	\N	\N
24779648	This study used event-related potentials (ERPs) to investigate discourse-coherence processing. Because there are scant data on ERP indices of discourse coherence in typical adults, it is important to study a non-clinical population before examining clinical populations. Twelve adults listened to a story with sentences in a coherent versus incoherent order. Sequences of nonsense syllables served as a control. ERPs in the 200-400 ms time window, reflecting phonological and lexical processing, and in the 600-900 ms time window, reflecting later discourse processing for integration, were investigated. Results revealed a right anterior and posterior positivity that was greater for coherent than for incoherent discourse during the 600-900 ms time window. These findings point to an index of discourse coherence and further suggest that ERPs can be used as a clinical tool to study discourse-processing disorders in populations with brain damage, such as aphasia and traumatic brain injury.	\N	\N
24793771	Auditory filter theory dictates a physiological compromise between frequency and temporal resolution of cochlear signal processing. We examined neurophysiological correlates of these spectrotemporal tradeoffs in the human auditory system using auditory evoked brain potentials and psychophysical responses. Temporal resolution was assessed using scalp-recorded auditory brainstem responses (ABRs) elicited by paired clicks. The inter-click interval (ICI) between successive pulses was parameterized from 0.7 to 25 ms to map ABR amplitude recovery as a function of stimulus spacing. Behavioral frequency difference limens (FDLs) and auditory filter selectivity (Q10 of psychophysical tuning curves) were obtained to assess relations between behavioral spectral acuity and electrophysiological estimates of temporal resolvability. Neural responses increased monotonically in amplitude with increasing ICI, ranging from total suppression (0.7 ms) to full recovery (25 ms) with a temporal resolution of ∼3-4 ms. ABR temporal thresholds were correlated with behavioral Q10 (frequency selectivity) but not FDLs (frequency discrimination); no correspondence was observed between Q10 and FDLs. Results suggest that finer frequency selectivity, but not discrimination, is associated with poorer temporal resolution. The inverse relation between ABR recovery and perceptual frequency tuning demonstrates a time-frequency tradeoff between the temporal and spectral resolving power of the human auditory system.	\N	\N
24795958	This study investigates how speed of motion is processed in language. In three eye-tracking experiments, participants were presented with visual scenes and spoken sentences describing fast or slow events (e.g., The lion ambled/dashed to the balloon). Results showed that looking time to relevant objects in the visual scene was affected by the speed of verb of the sentence, speaking rate, and configuration of a supporting visual scene. The results provide novel evidence for the mental simulation of speed in language and show that internal dynamic simulations can be played out via eye movements toward a static visual scene.	\N	\N
24801737	Two experiments used the progressive demasking (PD) task to examine age differences in the ability to inhibit higher frequency competitors during the process of identifying a visually degraded word. In Experiment 1, older adults exhibited a larger inhibitory neighborhood frequency effect (i.e., slower identification of words with many higher frequency competitors) than younger adults, but additional analyses indicated that this difference could be explained by general slowing rather than a deficit in inhibitory abilities. In Experiment 2, a primed version of the PD task was used to promote hypothesis testing by semantically priming the target word (e.g., cry-weep) or a higher frequency competitor of the target (e.g, day-weep) prior to the onset of the demasking sequence. Although older adults were more likely to make identification errors consistent with an inhibitory deficit (e.g., identifying weep as week), these errors were infrequent overall and there was no corresponding evidence of a larger interference effect in the older adults' identification latencies. Taken together, performance in these two tasks provides little evidence of reduced inhibitory functioning in older adults. The implications for the inhibitory deficit hypothesis of cognitive aging and directions for future are discussed.	\N	\N
24807850	The Finnish Matrix Test is the first sentence test in noise for the Finnish language. It was developed according to the HearCom standards and provides reliable speech intelligibility measurements with highly comparable results with the other international matrix tests. The aim of the study was to develop an accurate speech intelligibility test in noise for the Finnish language that is comparable across different languages. We chose a matrix sentence test, which comprises a base matrix of 10 names, verbs, numerals, adjectives and nouns. Test lists were formed from this matrix quasi randomly, providing test sentences of the same syntactical structure. The speech material corresponds to everyday spoken language and the phoneme distribution is representative of the Finnish language. The test was optimized by determining the speech recognition thresholds of the individual words and subsequently by applying level corrections of up to ±3 dB. Evaluation measurements were performed to check the equivalence of the different test lists with respect to speech intelligibility and to provide reference values for further clinical applications. After training, the mean speech recognition threshold (SRT) and the slope of the final test lists were -10.1 ± 0.1 dB signal-to-noise-ratio (SNR)and 16.7 ± 1.2%/dB, respectively (measurements at constant level; inter-list variability). The mean SRT and the slope of the test subjects were -10.1 ± 0.7 dB SNR and 17.5 ± 2.2%/dB (measurements at constant level; inter-subject variability). The expected SRT range for normal-hearing young adults for adaptive measurements is -9.7 ± 0.7 dB SNR.	\N	\N
24814580	The goal of the present research was to provide direct evidence for the cross-language interaction of phonologies at the sub-lexical level by using the masked onset priming paradigm. More specifically, we investigated whether there is a cross-language masked onset priming effect (MOPE) with L2 (English) primes and L1 (Russian) targets and whether it is modulated by the orthographic similarity of primes and targets. Primes and targets had onsets that overlapped either only phonologically, only orthographically, both phonologically and orthographically, or did not have any overlap. Phonological overlap, but not orthographic overlap, between primes and targets led to faster naming latencies. In contrast, the ERP data provided evidence for effects of both phonological and orthographic overlap. Finally, the time-course of phonological and orthographic processing for our bilinguals mirrored the time-course previously reported for monolinguals in the ERP data. These results provide evidence for shared representations at the sub-lexical level for a bilingual's two languages.	\N	\N
24815281	Reduced spectral resolution negatively impacts speech perception, particularly perception of vowels and consonant place. This study assessed impact of number of spectral channels on vowel discrimination by 6-month-old infants with normal hearing by comparing three listening conditions: Unprocessed speech, 32 channels, and 16 channels. Auditory stimuli (/ti/ and /ta/) were spectrally reduced using a noiseband vocoder and presented to infants with normal hearing via visual habituation. Results supported a significant effect of number of channels on vowel discrimination by 6-month-old infants. No differences emerged between unprocessed and 32-channel conditions in which infants looked longer during novel stimulus trials (i.e., discrimination). The 16-channel condition yielded a significantly different pattern: Infants demonstrated no significant difference in looking time to familiar vs novel stimulus trials, suggesting infants cannot discriminate /ti/ and /ta/ with only 16 channels. Results support effects of spectral resolution on vowel discrimination. Relative to published reports, young infants need more spectral detail than older children and adults to perceive spectrally degraded speech. Results have implications for development of perception by infants with hearing loss who receive auditory prostheses.	\N	\N
24828221	There are many clinically available tests for the assessment of auditory processing skills in children and adults. However, there is limited data available on the maturational effects on the performance on these tests. The current study investigated maturational effects on auditory processing abilities using three psychophysical measures: temporal modulation transfer function (TMTF), iterated ripple noise (IRN) perception, and spectral ripple discrimination (SRD). A cross-sectional study. Three groups of subjects were tested: 10 adults (18-30 yr), 10 older children (12-18 yr), and 10 young children (8-11 yr) Temporal envelope processing was measured by obtaining thresholds for amplitude modulation detection as a function of modulation frequency (TMTF; 4, 8, 16, 32, 64, and 128 Hz). Temporal fine structure processing was measured using IRN, and spectral processing was measured using SRD. The results showed that young children had significantly higher modulation thresholds at 4 Hz (TMTF) compared to the other two groups and poorer SRD scores compared to adults. The results on IRN did not differ across groups. The results suggest that different aspects of auditory processing mature at different age periods and these maturational effects need to be considered while assessing auditory processing in children.	\N	\N
24838018	The multisensory response enhancement (MRE), occurring when the response to a visual target integrated with a spatially congruent sound is stronger than the response to the visual target alone, is believed to be mediated by the superior colliculus (SC) (Stein & Meredith, 1993). Here, we used a focused attention paradigm to show that the spatial congruency effect occurs with red (SC-effective) but not blue (SC-ineffective) visual stimuli, when presented with spatially congruent sounds. To isolate the chromatic component of SC-ineffective targets and to demonstrate the selectivity of the spatial congruency effect we used the random luminance modulation technique (Experiment 1) and the tritanopic technique (Experiment 2). Our results indicate that the spatial congruency effect does not require the distribution of attention over different sensory modalities and provide correlational evidence that the SC mediates the effect.	\N	\N
24842067	Auditory feedback plays an important role in children's speech development by providing the child with information about speech outcomes that is used to learn and fine-tune speech motor plans. The use of auditory feedback in speech motor learning has been extensively studied in adults by examining oral motor responses to manipulations of auditory feedback during speech production. Children are also capable of adapting speech motor patterns to perceived changes in auditory feedback; however, it is not known whether their capacity for motor learning is limited by immature auditory-perceptual abilities. Here, the link between speech perceptual ability and the capacity for motor learning was explored in two groups of 5- to 7-year-old children who underwent a period of auditory perceptual training followed by tests of speech motor adaptation to altered auditory feedback. One group received perceptual training on a speech acoustic property relevant to the motor task while a control group received perceptual training on an irrelevant speech contrast. Learned perceptual improvements led to an enhancement in speech motor adaptation (proportional to the perceptual change) only for the experimental group. The results indicate that children's ability to perceive relevant speech acoustic properties has a direct influence on their capacity for sensory-based speech motor adaptation.	\N	\N
24850915	Many everyday skilled actions depend on moving in time with signals that are embedded in complex auditory streams (e.g. musical performance, dancing or simply holding a conversation). Such behaviour is apparently effortless; however, it is not known how humans combine auditory signals to support movement production and coordination. Here, we test how participants synchronize their movements when there are potentially conflicting auditory targets to guide their actions. Participants tapped their fingers in time with two simultaneously presented metronomes of equal tempo, but differing in phase and temporal regularity. Synchronization therefore depended on integrating the two timing cues into a single-event estimate or treating the cues as independent and thereby selecting one signal over the other. We show that a Bayesian inference process explains the situations in which participants choose to integrate or separate signals, and predicts motor timing errors. Simulations of this causal inference process demonstrate that this model provides a better description of the data than other plausible models. Our findings suggest that humans exploit a Bayesian inference process to control movement timing in situations where the origin of auditory signals needs to be resolved.	\N	\N
24851348	Learning and discovery seem often to begin with noting patterns. Human infants are skilled at pattern detection, even patterns only definable at an abstract level, which is key to their acquisition of complex knowledge systems such as language and music. However, research examining infants' abstract rule learning has generated inconsistent results. We propose that apparent domain differences in infants' abstract rule learning may be the result of extraneous stimulus variation and discrepancies in the methodologies employed across studies probing this skill. We discuss how a behavioral methodology indexing infants' online learning would be valuable in furthering understanding of infants' (as well as adults') abstract rule learning and its neurophysiological concomitants. We outline current research aimed at developing such an index, and we propose future research, pairing such techniques with neurophysiological methods, aimed at shining more light on human skill at discovering structure.	\N	\N
24856208	Human early visual cortex was traditionally thought to process simple visual features such as orientation, contrast, and spatial frequency via feedforward input from the lateral geniculate nucleus (e.g., [1]). However, the role of nonretinal influence on early visual cortex is so far insufficiently investigated despite much evidence that feedback connections greatly outnumber feedforward connections [2-5]. Here, we explored in five fMRI experiments how information originating from audition and imagery affects the brain activity patterns in early visual cortex in the absence of any feedforward visual stimulation. We show that category-specific information from both complex natural sounds and imagery can be read out from early visual cortex activity in blindfolded participants. The coding of nonretinal information in the activity patterns of early visual cortex is common across actual auditory perception and imagery and may be mediated by higher-level multisensory areas. Furthermore, this coding is robust to mild manipulations of attention and working memory but affected by orthogonal, cognitively demanding visuospatial processing. Crucially, the information fed down to early visual cortex is category specific and generalizes to sound exemplars of the same category, providing evidence for abstract information feedback rather than precise pictorial feedback. Our results suggest that early visual cortex receives nonretinal input from other brain areas when it is generated by auditory perception and/or imagery, and this input carries common abstract information. Our findings are compatible with feedback of predictive information to the earliest visual input level (e.g., [6]), in line with predictive coding models [7-10].	\N	\N
24858108	Rapidly approaching (looming) sounds are ecologically salient stimuli that are perceived as nearer than they are due to overestimation of their loudness change and underestimation of their distance (Neuhoff, 1998; Seifritz et al., 2002). Despite evidence for crossmodal influence by looming sounds onto visual areas (Romei, Murray, Cappe, & Thut, 2009, 2013; Tyll et al., 2013), it is unknown whether such sounds bias visual percepts in similar ways. Nearer objects appear to be larger and brighter than distant objects. If looming sounds impact visual processing, then visual stimuli paired with looming sounds should be perceived as brighter and larger, even when the visual stimuli do not provide motion cues, i.e. are static. In Experiment 1 we found that static visual objects paired with looming tones (but not static or receding tones) were perceived as larger and brighter than their actual physical properties, as if they appear closer to the observer. In a second experiment, we replicate and extend the findings of Experiment 1. Crucially, we did not find evidence of such bias by looming sounds when visual processing was disrupted via masking or when catch trials were presented, ruling out simple response bias. Finally, in a third experiment we found that looming tones do not bias visual stimulus characteristics that do not carry visual depth information such as shape, providing further evidence that they specifically impact in-depth visual processing. We conclude that looming sounds impact visual perception through a mechanism transferring in-depth sound motion information onto the relevant in-depth visual dimensions (such as size and luminance but not shape) in a crossmodal remapping of information for a genuine, evolutionary advantage in stimulus detection.	\N	\N
24869445	Two studies examined adult cochlear implant (CI) users' ability to match auditory rhythms occurring in music to visual rhythms occurring in dance (Cha Cha, Slow Swing, Tango and Jive). In Experiment 1, adults CI users (n = 10) and hearing controls matched a music excerpt to choreographed dance sequences presented as silent videos. In Experiment 2, participants matched a silent video of a dance sequence to music excerpts. CI users were successful in detecting timing congruencies across music and dance at well above-chance levels suggesting that they were able to process distinctive auditory and visual rhythm patterns that characterized each style. However, they were better able to detect cross-modal timing congruencies when the reference was an auditory rhythm than when the reference was a visual rhythm. Learning strategies that encourage cross-modal learning of musical rhythms may have applications in developing novel rehabilitative strategies to enhance music perception and appreciation outcomes of child implant users.	\N	\N
24872325	In the present study we investigate the rules governing the perception of audiovisual synchrony within spatio-temporally cluttered visual environments. Participants viewed a ring of 19 discs modulating in luminance while hearing an amplitude modulating tone. Each disc modulated with a unique temporal phase (40 ms intervals), with only one synchronized to the tone. Participants searched for the synchronised disc whose spatial location varied randomly across trials. Square-wave modulation facilitated search: the synchronized disc was frequently chosen, with tight response distributions centred near zero-phase lag. In the sinusoidal condition responses were equally distributed over the 19 discs regardless of phase. To investigate whether subjective synchrony in the square-wave condition was limited by spatial or temporal factors we repeated the experiment with either reduced spatial density (9 discs) or temporal density (80 ms phase intervals). Reduced temporal density greatly facilitated synchrony perception but left the synchrony bandwidth unchanged, while no influence of spatial density was found. We conclude that audio-visual synchrony is not strongly constrained by the spatial or temporal density of the visual display, but by a temporal window within which audio-visual events are perceived as synchronous, with a full bandwidth of ~185 ms.	\N	\N
24878593	One of the main issues within the field of social robotics is to endow robots with the ability to direct attention to people with whom they are interacting. Different approaches follow bio-inspired mechanisms, merging audio and visual cues to localize a person using multiple sensors. However, most of these fusion mechanisms have been used in fixed systems, such as those used in video-conference rooms, and thus, they may incur difficulties when constrained to the sensors with which a robot can be equipped. Besides, within the scope of interactive autonomous robots, there is a lack in terms of evaluating the benefits of audio-visual attention mechanisms, compared to only audio or visual approaches, in real scenarios. Most of the tests conducted have been within controlled environments, at short distances and/or with off-line performance measurements. With the goal of demonstrating the benefit of fusing sensory information with a Bayes inference for interactive robotics, this paper presents a system for localizing a person by processing visual and audio data. Moreover, the performance of this system is evaluated and compared via considering the technical limitations of unimodal systems. The experiments show the promise of the proposed approach for the proactive detection and tracking of speakers in a human-robot interactive framework.	\N	\N
24880672	To assess treatment outcomes via acoustic voice laboratory measurements before and after intervention in patients with common voice problems and Determine if outcome sensitivity of certain voice laboratory measures varies with disorder type. Retrospective and single-blinded. In this study, 40 patients with a single voice disorder diagnosis of either benign vocal fold lesions (lesions), primary muscle tension dysphonia (MTD-1), vocal fold atrophy (atrophy) or unilateral vocal fold paralysis (UVFP) underwent baseline testing, a single intervention-type (phonosurgery/voice therapy), and follow-up testing at uniform time points. Ten patients per diagnosis group were analyzed before and after treatment. Time- and frequency-based acoustic measures taken from vowels and sentences as well as patient-perceptual analysis (Voice Handicap Index-10) were reviewed. Statistically significant improvements were observed for three of four groups. Patients with muscle tension dysphonia displayed an improvement in Cepstral Spectral Index of Dysphonia speech (CSID) (P < 0.05). Patients with lesions had improved Voice Handicap Index-10 (P < 0.05), cepstral peak prominence (CPP) vowel standard deviation (P < 0.05), and CPP speech (P < 0.05). Patients with atrophy did not demonstrate significant improvement in any measure. Patients with unilateral vocal fold paralysis showed an improvement in CSID speech (P < 0.05) and CPP speech (P < 0.05). In addition, strong effect sizes were observed for many of the acoustic parameters studied. For all groups except atrophy, treatment was successful in improving patient perception of voice handicap and/or some acoustic voice parameters. A disorder-specific response to frequency-based acoustic measures was found.	\N	\N
24887110	Age-related hearing loss (presbycusis) is a common human disorder, affecting one in three Americans aged 60 and over. Previous studies have shown that presbyacusis is associated with a loss of non-sensory cells in the cochlear lateral wall. Sox10 is a transcription factor crucial to the development and maintenance of neural crest-derived cells including some non-sensory cell types in the cochlea. Mutations of the Sox10 gene are known to cause various combinations of hearing loss and pigmentation defects in humans. This study investigated the potential relationship between Sox10 gene expression and pathological changes in the cochlear lateral wall of aged CBA/CaJ mice and human temporal bones from older donors. Cochlear tissues prepared from young adult (1-3 month-old) and aged (2-2.5 year-old) mice, and human temporal bone donors were examined using quantitative immunohistochemical analysis and transmission electron microscopy. Cells expressing Sox10 were present in the stria vascularis, outer sulcus and spiral prominence in mouse and human cochleas. The Sox10(+) cell types included marginal and intermediate cells and outer sulcus cells, including those that border the scala media and those extending into root processes (root cells) in the spiral ligament. Quantitative analysis of immunostaining revealed a significant decrease in the number of Sox10(+) marginal cells and outer sulcus cells in aged mice. Electron microscopic evaluation revealed degenerative alterations in the surviving Sox10(+) cells in aged mice. Strial marginal cells in human cochleas from donors aged 87 and older showed only weak immunostaining for Sox10. Decreases in Sox10 expression levels and a loss of Sox10(+) cells in both mouse and human aged ears suggests an important role of Sox10 in the maintenance of structural and functional integrity of the lateral wall. A loss of Sox10(+) cells may also be associated with a decline in the repair capabilities of non-sensory cells in the aged ear.	\N	\N
24893743	RTs in conversation, with average gaps of 200 msec and often less, beat standard RTs, despite the complexity of response and the lag in speech production (600 msec or more). This can only be achieved by anticipation of timing and content of turns in conversation, about which little is known. Using EEG and an experimental task with conversational stimuli, we show that estimation of turn durations are based on anticipating the way the turn would be completed. We found a neuronal correlate of turn-end anticipation localized in ACC and inferior parietal lobule, namely a beta-frequency desynchronization as early as 1250 msec, before the end of the turn. We suggest that anticipation of the other's utterance leads to accurately timed transitions in everyday conversations.	\N	\N
24897885	Twenty-four Japanese undergraduate pairs (12 male and 12 female pairs) participated as witnesses to a simulated criminal event. Although the witness pairs watched the same video together, through wireless headphones they experienced two different auditory versions with four differing items without being aware of the discrepancies. After the presentation, the witnesses were led to discuss six items, including two critical ones they had heard differently and another four they had heard in common. Witness memory performance was assessed individually with multiple-choice questionnaires in three sessions: before the discussion, after the discussion, and 1 week later. The results showed that participants tended to conform to their co-witness more often on the discussed items than on the not-discussed items. Source monitoring analyses on the four critical items revealed that even those participants who conformed were mostly cognizant of the source of their information just after the discussion, but they were prone to source-monitoring errors a week later.	\N	\N
24904404	Auditory perception and auditory imagery have been shown to activate overlapping brain regions. We hypothesized that these phenomena also share a common underlying neural representation. To assess this, we used electrocorticography intracranial recordings from epileptic patients performing an out loud or a silent reading task. In these tasks, short stories scrolled across a video screen in two conditions: subjects read the same stories both aloud (overt) and silently (covert). In a control condition the subject remained in a resting state. We first built a high gamma (70-150 Hz) neural decoding model to reconstruct spectrotemporal auditory features of self-generated overt speech. We then evaluated whether this same model could reconstruct auditory speech features in the covert speech condition. Two speech models were tested: a spectrogram and a modulation-based feature space. For the overt condition, reconstruction accuracy was evaluated as the correlation between original and predicted speech features, and was significant in each subject (p < 10(-5); paired two-sample t-test). For the covert speech condition, dynamic time warping was first used to realign the covert speech reconstruction with the corresponding original speech from the overt condition. Reconstruction accuracy was then evaluated as the correlation between original and reconstructed speech features. Covert reconstruction accuracy was compared to the accuracy obtained from reconstructions in the baseline control condition. Reconstruction accuracy for the covert condition was significantly better than for the control condition (p < 0.005; paired two-sample t-test). The superior temporal gyrus, pre- and post-central gyrus provided the highest reconstruction information. The relationship between overt and covert speech reconstruction depended on anatomy. These results provide evidence that auditory representations of covert speech can be reconstructed from models that are built from an overt speech data set, supporting a partially shared neural substrate.	\N	\N
24908166	Aging is associated with declines in auditory processing including speech comprehension abilities. Here, we evaluated both brainstem and cortical speech-evoked brain responses to elucidate how aging impacts the neural transcription and transfer of speech information between functional levels of the auditory nervous system. Behaviorally, older adults showed slower, more variable speech classification performance than younger listeners, which coincided with reduced brainstem amplitude and increased, but delayed, cortical speech-evoked responses. Mild age-related hearing loss showed differential correspondence with neurophysiological responses showing negative (brainstem) and positive (cortical) correlations with brain activity. Spontaneous brain activity, that is, "neural noise," did not differ between older and younger adults. Yet, mutual information and correlations computed between brainstem and cortex revealed higher redundancy (i.e., lower interdependence) in speech information transferred along the auditory pathway implying less neural flexibility in older adults. Results are consistent with the notion that weakened speech encoding in brainstem is overcompensated by increased cortical dysinhibition in the aging brain. Findings suggest aging negatively impacts speech listening abilities by distorting the hierarchy of speech representations, reducing neural flexibility through increased neural redundancy, and ultimately impairing the acoustic-phonetic mapping necessary for robust speech understanding.	\N	\N
24931795	Alpha oscillations are a prominent electrophysiological signal measured across a wide range of species and cortical and subcortical sites. Alpha oscillations have been viewed for a long time as an "idling" rhythm, purely reflecting inactive sites. Despite earlier evidence from neurophysiology, awareness that alpha oscillations can substantially influence perception and behavior has grown only recently in cognitive neuroscience. Evidence for an active role of alpha for perception comes mainly from several visual, near-threshold experiments. In the current review, we extend this view by summarizing studies showing how alpha-defined brain states relate to illusory perception, i.e. cases of perceptual reports that are not "objectively" verifiable by distinct stimuli or stimulus features. These studies demonstrate that ongoing or prestimulus alpha oscillations substantially influence the perception of auditory, visual or multisensory illusions.	\N	\N
24935820	Action perception and recognition are core abilities fundamental for human social interaction. A parieto-frontal network (the mirror neuron system) matches visually presented biological motion information onto observers' motor representations. This process of matching the actions of others onto our own sensorimotor repertoire is thought to be important for action recognition, providing a non-mediated "motor perception" based on a bidirectional flow of information along the mirror parieto-frontal circuits. State-of-the-art machine learning strategies for hand action identification have shown better performances when sensorimotor data, as opposed to visual information only, are available during learning. As speech is a particular type of action (with acoustic targets), it is expected to activate a mirror neuron mechanism. Indeed, in speech perception, motor centers have been shown to be causally involved in the discrimination of speech sounds. In this paper, we review recent neurophysiological and machine learning-based studies showing (a) the specific contribution of the motor system to speech perception and (b) that automatic phone recognition is significantly improved when motor data are used during training of classifiers (as opposed to learning from purely auditory data).	\N	\N
24936610	All languages employ certain phonetic contrasts when distinguishing words. Infant speech perception is rapidly attuned to these contrasts before many words are learned, thus phonetic attunement is thought to proceed independently of lexical and referential knowledge. Here, evidence to the contrary is provided. Ninety-eight 9-month-old English-learning infants were trained to perceive a non-native Cantonese tone contrast.Two object–tone audiovisual pairings were consistently presented, which highlighted the target contrast (Object A with Tone X; Object B with Tone Y). Tone discrimination was then assessed. Results showed improved tone discrimination if object–tone pairings were perceived as being referential word labels, although this effect was modulated by vocabulary size. Results suggest how lexical and referential knowledge could play a role in phonetic attunement.	\N	\N
24945666	Naturalistic stimuli, such as normal speech and narratives, are opening up intriguing prospects in neuroscience, especially when merging neuroimaging with machine learning methodology. Here we propose a task-optimized spatial filtering strategy for uncovering individual magnetoencephalographic (MEG) responses to audiobook stories. Ten subjects listened to 1-h-long recording once, as well as to 48 repetitions of a 1-min-long speech passage. Employing response replicability as statistical validity and utilizing unsupervised learning methods, we trained spatial filters that were able to generalize over datasets of an individual. For this blind-signal-separation (BSS) task, we derived a version of multi-set similarity-constrained canonical correlation analysis (SimCCA) that theoretically provides maximal signal-to-noise ratio (SNR) in this setting. Irrespective of significant noise in unaveraged MEG traces, the method successfully uncovered feasible time courses up to ~120 Hz, with the most prominent signals below 20 Hz. Individual trial-to-trial correlations of such time courses reached the level of 0.55 (median 0.33 in the group) at ~0.5 Hz, with considerable variation between subjects. By this filtering, the SNR increased up to 20 times. In comparison, independent component analysis (ICA) or principal component analysis (PCA) did not improve SNR notably. The validity of the extracted brain signals was further assessed by inspecting their associations with the stimulus, as well as by mapping the contributing cortical signal sources. The results indicate that the proposed methodology effectively reduces noise in MEG recordings to that extent that brain responses can be seen to nonrecurring audiobook stories. The study paves the way for applications aiming at accurately modeling the stimulus-response-relationship by tackling the response variability, as well as for real-time monitoring of brain signals of individuals in naturalistic experimental conditions.	\N	\N
24946201	To examine active inhibition of irrelevant stimuli and evaluate its neural basis using functional near infrared spectroscopy in patients with attention deficits after traumatic brain injury (TBI). Case control study. Ten patients with TBI and 10 healthy control subjects participated in this study. The Paced Auditory Serial Addition Test (PASAT) was performed with (distracting PASAT) and without (PASAT) distracting Japanese kana phonetic characters presented between each number. A block design was used. Subjects alternately performed each task three times. Healthy controls performed better than patients with TBI on both the tasks. When performing the PASAT, healthy controls showed significant activity in every region of interest except the right lateral prefrontal cortex (PFC), but patients with TBI showed significant activity only in the left anterior PFC and left lateral PFC. When performing the distracting PASAT, the right lateral PFC was active in healthy controls, but not in patients with TBI. These results confirm that patients with moderate-to-severe TBI were affected by distractors that influenced order processing. It is suggested that the working memory of patients with TBI was affected by distracting stimuli, whereas that of healthy individuals was not.	\N	\N
24963624	Recent experimental evidence suggests that the perception of temporal intervals is influenced by the temporal context in which they are presented. A longstanding example is the time-order-error, wherein the perception of two intervals relative to one another is influenced by the order in which they are presented. Here, we test whether the perception of temporal intervals in an absolute judgment task is influenced by the preceding temporal context. Human subjects participated in a temporal bisection task with no anchor durations (partition method). Intervals were demarcated by a Gaussian blob (visual condition) or burst of white noise (auditory condition) that persisted for one of seven logarithmically spaced sub-second intervals. Crucially, the order in which stimuli were presented was first-order counterbalanced, allowing us to measure the carryover effect of every successive combination of intervals. The results demonstrated a number of distinct findings. First, the perception of each interval was biased by the prior response, such that each interval was judged similarly to the preceding trial. Second, the perception of each interval was also influenced by the prior interval, such that perceived duration shifted away from the preceding interval. Additionally, the effect of decision bias was larger for visual intervals, whereas auditory intervals engendered greater perceptual carryover. We quantified these effects by designing a biologically-inspired computational model that measures noisy representations of time against an adaptive memory prior while simultaneously accounting for uncertainty, consistent with a Bayesian heuristic. We found that our model could account for all of the effects observed in human data. Additionally, our model could only accommodate both carryover effects when uncertainty and memory were calculated separately, suggesting separate neural representations for each. These findings demonstrate that time is susceptible to similar carryover effects as other basic stimulus attributes, and that the brain rapidly adapts to temporal context.	\N	\N
24975235	Matrix sentence tests use words from a fixed word matrix to compose syntactically equivalent, but semantically unpredictable sentences. These tests are suitable for monitoring performance of cochlear implant (CI) users by repeated speech intelligibility testing. This study evaluates the Dutch matrix sentence test in CI users in quiet and in noise. It then investigates the possibility to improve the test-retest reliability for CI users by selecting subsets of sentences. Repeated speech intelligibility testing was performed in quiet and in noise. The effect of sentence selection on the test-retest reliability was predicted by computer simulations and experimentally evaluated using a cross-over design. Fifteen post-lingually deafened CI users, of which eleven participated in the cross-over study. The test-retest reliability equaled 2.3 dB in quiet and 1.3 dB in noise. The simulations predicted an improvement in test-retest reliability, especially in quiet. The cross-over study did not confirm the predictions. The results of the study suggest that the homogeneity of the sentences is not the prime component underlying the test-retest reliability. The Dutch matrix speech material and the selected subsets of sentences were equally suitable for speech intelligibility testing in CI users.	\N	\N
24993019	Conversation scenes are a typical example in which classical models of visual attention dramatically fail to predict eye positions. Indeed, these models rarely consider faces as particular gaze attractors and never take into account the important auditory information that always accompanies dynamic social scenes. We recorded the eye movements of participants viewing dynamic conversations taking place in various contexts. Conversations were seen either with their original soundtracks or with unrelated soundtracks (unrelated speech and abrupt or continuous natural sounds). First, we analyze how auditory conditions influence the eye movement parameters of participants. Then, we model the probability distribution of eye positions across each video frame with a statistical method (Expectation-Maximization), allowing the relative contribution of different visual features such as static low-level visual saliency (based on luminance contrast), dynamic low level visual saliency (based on motion amplitude), faces, and center bias to be quantified. Through experimental and modeling results, we show that regardless of the auditory condition, participants look more at faces, and especially at talking faces. Hearing the original soundtrack makes participants follow the speech turn-taking more closely. However, we do not find any difference between the different types of unrelated soundtracks. These eyetracking results are confirmed by our model that shows that faces, and particularly talking faces, are the features that best explain the gazes recorded, especially in the original soundtrack condition. Low-level saliency is not a relevant feature to explain eye positions made on social scenes, even dynamic ones. Finally, we propose groundwork for an audiovisual saliency model.	\N	\N
24993189	Multiple sound reflections from room materials and a listener's head induce slight spectral modifications of sounds. This coloration depends on the listener and source positions, and on the room itself. This study investigated whether coloration could help segregate competing sources. Obligatory streaming was evaluated for diotic speech-shaped noises using a rhythmic discrimination task. Thresholds for detecting anisochrony were always significantly higher when stimuli differed in spectrum. The tested differences corresponded to three spatial configurations involving different levels of head and room coloration. These results suggest that, despite the generally deleterious effects of reverberation on speech intelligibility, coloration could favor source segregation.	\N	\N
24993221	Prosodic rhythm in speech [the alternation of "Strong" (S) and "weak" (w) syllables] is cued, among others, by slow rates of amplitude modulation (AM) within the speech envelope. However, it is unclear exactly which envelope modulation rates and statistics are the most important for the rhythm percept. Here, the hypothesis that the phase relationship between "Stress" rate (∼2 Hz) and "Syllable" rate (∼4 Hz) AMs provides a perceptual cue for speech rhythm is tested. In a rhythm judgment task, adult listeners identified AM tone-vocoded nursery rhyme sentences that carried either trochaic (S-w) or iambic patterning (w-S). Manipulation of listeners' rhythm perception was attempted by parametrically phase-shifting the Stress AM and Syllable AM in the vocoder. It was expected that a 1π radian phase-shift (half a cycle) would reverse the perceived rhythm pattern (i.e., trochaic → iambic) whereas a 2π radian shift (full cycle) would retain the perceived rhythm pattern (i.e., trochaic → trochaic). The results confirmed these predictions. Listeners judgments of rhythm systematically followed Stress-Syllable AM phase-shifts, but were unaffected by phase-shifts between the Syllable AM and the Sub-beat AM (∼14 Hz) in a control condition. It is concluded that the Stress-Syllable AM phase relationship is an envelope-based modulation statistic that supports speech rhythm perception.	\N	\N
24993222	Perceptual compensation for coarticulation (PCCA) refers to listener responses consistent with perceptual reduction of the acoustic effects of the coarticulatory context on a target sound. The robustness of PCCA across individuals and across tasks have not been studied together previously. This study reports the results of two experiments designed to determine the robustness of perceptual compensation for vocalic influence on sibilant perception across tasks and the stability of such compensatory response within an individual. Identification and discrimination data, collected in the laboratory and on Amazon's Mechanical Turk, showed that individuals are moderately stable in their PCCA responses across tasks and the level of stability is consistent across both the lab-based and the internet-based cohorts, although some differences are observed.	\N	\N
24995901	Residual inhibition (RI) is the temporary inhibition of tinnitus by use of masking stimuli when the device is turned off. The main aim of this study was to evaluate the effects of RI induced by auditory electrical stimulation (AES) in the primary auditory pathways using early auditory-evoked potentials (AEPs) in subjective idiopathic tinnitus (SIT) subjects. A randomized placebo-controlled study was conducted on forty-four tinnitus subjects. All enrolled subjects based on the responses to AES, were divided into two groups of RI and Non-RI (NRI). The results of the electrocochleography (ECochG), auditory brain stem response (ABR) and brain stem transmission time (BTT) were determined and compared pre- and post-AES in the studied groups. The mean differences in the compound action potential (CAP) amplitudes and III/V and I/V amplitude ratios were significantly different between the RI, NRI and PES controls. BTT was significantly decreased associated with RI. The observed changes in AEP associated with RI suggested some peripheral and central auditory alterations. Synchronized discharges of the auditory nerve fibers and inhibition of the abnormal activity of the cochlear nerve by AES may play important roles associated with RI. Further comprehensive studies are required to determine the mechanisms of RI more precisely.	\N	\N
25000379	The purpose of this study was to determine the influence of dialect upon the perception of dysarthric speech. Speakers and listeners were self-identifying as either Caucasian American or African American. Three speakers were Caucasian American, three were African American. Four speakers had experienced a CVA and were dysarthric. Listeners were age matched and were equally divided for gender. Readers recorded 14 word sentences from the Assessment of Intelligibility of Dysarthric Speech. Listeners provided ratings of intelligibility, comprehensibility, and acceptability. Own-race biases were found for all measures; however, significant findings were found for intelligibility and comprehensibility in that the Caucasian Americans provided significantly higher scores for Caucasian American speakers. Clinical implications are discussed.	\N	\N
25003309	The idea that the human mind can be divided into distinct (but interacting) functional modules is an important presupposition in many theories of cognition. While previous research on modularity predominantly studied input domains (e.g., vision) or central processes, the present study focused on cognitive representations of output domains. Specifically, we asked to what extent output domain representations are encapsulated (i.e., immune to influence from other domains, representing a key feature of modularity) by studying determinants of interference between simultaneous action demands (oculomotor and vocal responses). To examine the degree of encapsulation, we compared single- vs. dual-response performance triggered by single stimuli. Experiment 1 addressed the role of stimulus modality under dimensionally overlapping response requirements (stimuli and responses were spatial and compatible throughout). In Experiment 2, we manipulated the presence of dimensional overlap across responses. Substantial performance costs associated with dual-response (vs. single-response) demands were observed across response modalities, conditions, and experiments. Dimensional overlap combined with shared spatial codes across responses enabled response-code priming (i.e., beneficial crosstalk between output domains). Overall, the results are at odds with the idea of strong encapsulation of output system representations and show how processing content determines the extent of interdependency between output domains in cognition.	\N	\N
25018691	In schizophrenia, evoked 40-Hz auditory steady-state responses (ASSRs) are impaired, which reflects the sensory deficits in this disorder, and baseline spontaneous oscillatory activity also appears to be abnormal. It has been debated whether the evoked ASSR impairments are due to the possible increase in baseline power. GABAergic interneuron-specific NMDA receptor (NMDAR) hypofunction mutant mice mimic some behavioral and pathophysiological aspects of schizophrenia. To determine the presence and extent of sensory deficits in these mutant mice, we recorded spontaneous local field potential (LFP) activity and its click-train evoked ASSRs from primary auditory cortex of awake, head-restrained mice. Baseline spontaneous LFP power in the pre-stimulus period before application of the first click trains was augmented at a wide range of frequencies. However, when repetitive ASSR stimuli were presented every 20 s, averaged spontaneous LFP power amplitudes during the inter-ASSR stimulus intervals in the mutant mice became indistinguishable from the levels of control mice. Nonetheless, the evoked 40-Hz ASSR power and their phase locking to click trains were robustly impaired in the mutants, although the evoked 20-Hz ASSRs were also somewhat diminished. These results suggested that NMDAR hypofunction in cortical GABAergic neurons confers two brain state-dependent LFP abnormalities in the auditory cortex; (1) a broadband increase in spontaneous LFP power in the absence of external inputs, and (2) a robust deficit in the evoked ASSR power and its phase-locking despite of normal baseline LFP power magnitude during the repetitive auditory stimuli. The "paradoxically" high spontaneous LFP activity of the primary auditory cortex in the absence of external stimuli may possibly contribute to the emergence of schizophrenia-related aberrant auditory perception.	\N	\N
25036146	The objective of this study was to examine how the level of current required for cochlear implant listeners to detect single-channel electrical pulse trains relates to loudness perception on the same channel. The working hypothesis was that channels with relatively high thresholds, when measured with a focused current pattern, interface poorly to the auditory nerve. For such channels, a smaller dynamic range between perceptual threshold and the most comfortable loudness would result, in part, from a greater sensitivity to changes in electrical field spread compared to low-threshold channels. The narrower range of comfortable listening levels may have important implications for speech perception. Data were collected from eight, adult cochlear implant listeners implanted with the HiRes90k cochlear implant (Advanced Bionics Corp.). The partial tripolar (pTP) electrode configuration, consisting of one intracochlear active electrode, two flanking electrodes carrying a fraction (σ) of the return current, and an extracochlear ground, was used for stimulation. Single-channel detection thresholds and most comfortable listening levels were acquired using the most focused pTP configuration possible (σ ≥ 0.8) to identify three channels for further testing-those with the highest, median, and lowest thresholds-for each subject. Threshold, equal-loudness contours (at 50% of the monopolar dynamic range), and loudness growth functions were measured for each of these three test channels using various pTP fractions. For all test channels, thresholds increased as the electrode configuration became more focused. The rate of increase with the focusing parameter σ was greatest for the high-threshold channel compared to the median- and low-threshold channels. The 50% equal-loudness contours exhibited similar rates of increase in level across test channels and subjects. Additionally, test channels with the highest thresholds had the narrowest dynamic ranges (for σ ≥ 0.5) and steepest growth of loudness functions for all electrode configurations. Together with previous studies using focused stimulation, the results suggest that auditory responses to electrical stimuli at both threshold and suprathreshold current levels are not uniform across the electrode array of individual cochlear implant listeners. Specifically, the steeper growth of loudness and thus smaller dynamic ranges observed for high-threshold channels are consistent with a degraded electrode-neuron interface, which could stem from lower numbers of functioning auditory neurons or a relatively large distance between the neurons and electrodes. These findings may have potential implications for how stimulation levels are set during the clinical mapping procedure, particularly for speech-processing strategies that use focused electrical fields.	\N	\N
25041936	In vision an extensive literature supports the existence of competitive dual-processing systems of category learning that are grounded in neuroscience and are partially-dissociable. The reflective system is prefrontally-mediated and uses working memory and executive attention to develop and test rules for classifying in an explicit fashion. The reflexive system is striatally-mediated and operates by implicitly associating perception with actions that lead to reinforcement. Although categorization is fundamental to auditory processing, little is known about the learning systems that mediate auditory categorization and even less is known about the effects of individual difference in the relative efficiency of the two learning systems. Previous studies have shown that individuals with elevated depressive symptoms show deficits in reflective processing. We exploit this finding to test critical predictions of the dual-learning systems model in audition. Specifically, we examine the extent to which the two systems are dissociable and competitive. We predicted that elevated depressive symptoms would lead to reflective-optimal learning deficits but reflexive-optimal learning advantages. Because natural speech category learning is reflexive in nature, we made the prediction that elevated depressive symptoms would lead to superior speech learning. In support of our predictions, individuals with elevated depressive symptoms showed a deficit in reflective-optimal auditory category learning, but an advantage in reflexive-optimal auditory category learning. In addition, individuals with elevated depressive symptoms showed an advantage in learning a non-native speech category structure. Computational modeling suggested that the elevated depressive symptom advantage was due to faster, more accurate, and more frequent use of reflexive category learning strategies in individuals with elevated depressive symptoms. The implications of this work for dual-process approach to auditory learning and depression are discussed.	\N	\N
25059267	Chronic tinnitus affects 5-15% of the general population; in 1% of individuals with tinnitus this condition severely affects their quality of life. Pharmacological treatment is one of the options for the management of tinnitus patients, but their efficacy remains controversial. AIM. To evaluate the level of evidence to support the use of different drugs in reducing the severity of tinnitus. The pharmacological groups that have been investigated for the treatment of tinnitus include anesthetics, anticonvulsants, antidepressants, antihistamines, benzodiazepines, diuretics, corticosteroids, and of other substances. Intravenous lidocaine seems to be effective, but the short duration of the effect and the adverse reactions prevent its use. Compared with placebo, carbamazepine and gabapentine have not demonstrated effectiveness although they may be effective in some patients with auditory nerve vascular compression or myoclonus. Tricyclic antidepressants are no more effective than placebo at reducing tinnitus severity although they may improve comorbid depression. There is insufficient evidence to evaluate the effectiveness of selective serotonin reuptake inhibitors and benzodiazepines. Acamprosate may decrease the severity of tinnitus, but the level of evidence is low. There are no consistent results in the studies with intratympanic gentamicin or steroids in tinnitus associated with Meniere's disease. The use of pharmacotherapy in reducing the severity of tinnitus is not well supported by prospective, randomized, placebo-controlled clinical trials. Various drugs have been shown to be effective in some studies, but the clinical evidence is limited. Large randomized clinical trials are needed.	\N	\N
25085738	We establish a new dissociation between the roles of working memory (WM) cognitive control and visual maintenance in selective attention as measured by the efficiency of distractor rejection. The extent to which focused selective attention can prevent distraction has been shown to critically depend on the level and type of load involved in the task. High perceptual load that consumes perceptual capacity leads to reduced distractor processing, whereas high WM load that reduces WM ability to exert priority-based executive cognitive control over the task results in increased distractor processing (e.g., Lavie, Trends in Cognitive Sciences, 9(2), 75-82, 2005). WM also serves to maintain task-relevant visual representations, and such visual maintenance is known to recruit the same sensory cortices as those involved in perception (e.g., Pasternak & Greenlee, Nature Reviews Neuroscience, 6(2), 97-107, 2005). These findings led us to hypothesize that loading WM with visual maintenance would reduce visual capacity involved in perception, thus resulting in reduced distractor processing-similar to perceptual load and opposite to WM cognitive control load. Distractor processing was assessed in a response competition task, presented during the memory interval (or during encoding; Experiment 1a) of a WM task. Loading visual maintenance or encoding by increased set size for a memory sample of shapes, colors, and locations led to reduced distractor response competition effects. In contrast, loading WM cognitive control with verbal rehearsal of a random letter set led to increased distractor effects. These findings confirm load theory predictions and provide a novel functional distinction between the roles of WM maintenance and cognitive control in selective attention.	\N	\N
25089573	One of the leading theories for dyslexia suggests that it is the result of a difficulty in auditory temporal processing (ATP). This theory, as well as others, is supported by studies showing group differences and correlation between phonological awareness and ATP. However, these studies do not provide causal relationship. In the current study the authors aimed to test causal relationship between ATP and phonological awareness by comparing the performance of dyslexic and normal reader students in phonological awareness tasks before and after a short-term (5-day) training in either temporal processing (dichotic temporal order judgment; TOJ), nontemporal processing (intensity discrimination), or no training. TOJ training resulted in significant reduction of TOJ threshold and increase in phonological awareness tasks' scores. Intensity discrimination training resulted in a decrease of intensity discrimination threshold, but with no change in phonological awareness tasks. Those who had no training, had no change in TOJ and intensity discrimination thresholds, as well as in the phonological awareness tasks. These results show that (a) a short-term training in temporal processing with no other perceptual cues for adult dyslexic and normal readers can be efficient in improving their phonological awareness; and (b) phonological awareness (dis) ability has causal relationship to ATP.	\N	\N
25096110	Three-month-olds discriminate resolved harmonic complexes on the basis of missing fundamental (MF) pitch. In view of reported difficulty in discriminating unresolved complexes at 7 months and striking changes in the organization of the auditory system during early infancy, infants' ability to discriminate unresolved complexes is of some interest. This study investigated the ability of 3-month-olds, 7-month-olds, and adults to discriminate the pitch of unresolved harmonic complexes using an observer-based method. Stimuli were MF complexes bandpass filtered with a -12 dB/octave slope, combined in random phase, presented at 70 dB sound pressure level (SPL) for 650 ms with a 50 ms rise/fall with a pink noise at 65 dB SPL. The conditions were (1) "LOW" unresolved harmonics (2500-4500 Hz) based on MFs of 160 and 200 Hz and (2) "HIGH" unresolved harmonics (4000-6000 Hz) based on MFs of 190 and 200 Hz. To demonstrate MF discrimination, participants had to ignore spectral changes in complexes with the same fundamental and respond only when the fundamental changed. Nearly all infants tested categorized complexes by MF pitch suggesting discrimination of pitch extracted from unresolved harmonics by 3 months. Adults also categorized the complexes by MF pitch, although musically trained adults were more successful than musically untrained adults.	\N	\N
25096125	This paper investigated how auditory and vibrotactile feedback information is integrated within the context of violin quality evaluation. Fifteen violinists evaluated three violins on four criteria-"Rich Sound," "Loud and Powerful," "Alive and Responsive," and "Pleasure"-during a perceptual experiment. Violinists first evaluated the violins one at a time under three experimental conditions: (1) playing, (2) listening to it (played by a professional player) in an active way by fingering the score on an isolated neck, (3) same as (2) with vibrotactile feedback provided at the isolated neck. Violinists were then asked to evaluate the violins through pairwise comparisons under condition (3): Each violin was paired with itself while the level of vibrations of the isolated neck was either the original one or divided by two. The first part of the experiment demonstrated that Loud and Powerful judgments were affected by the presence of vibrations given that violins were rated louder in condition (3) than in (2). In the second part, violins were rated more positively with original vibration level at the isolated neck than with half the level, for all criteria but Alive and Responsive. Consistently with sensory interaction, the magnitude of the enhancement remained relatively constant across violins.	\N	\N
25111522	Assess surgical complications, postoperative residual hearing, and speech perception outcomes of placement of a middle ear implant on the round window in conductive and mixed hearing loss cases. Single-subject, repeated-measures design where each subject served as his or her own control. Tertiary referral medical systems. Eighteen subjects with either conductive or mixed hearing loss who could not benefit from conventional amplification were enrolled in a clinical trial investigating vibratory stimulation of the round window. The floating mass transducer (FMT) was positioned in the round window niche. Unaided residual hearing, and aided sound field thresholds and speech perception abilities were evaluated preoperatively, and at 1, 3, 6, and 10 months post-activation of the external speech processor. Six subjects experienced complications that either required further medical management or resolved on their own. There was no difference in residual bone conduction thresholds or unaided word discrimination over time. All subjects experienced a significant improvement in aided speech perception abilities as compared to preoperative performance. Subjects with conductive and mixed hearing loss with placement of the FMT in the round window niche experienced improved sound field thresholds and speech perception, without compromising residual hearing thresholds. Vibratory stimulation of the round window via a middle ear implant may be an appropriate treatment option for patients with conductive and mixed hearing loss. Additional research is needed on the preferred placement of the FMT, improvement of functional gain, and methods to limit postoperative complications and need for revision surgery.	\N	\N
25118919	To correlate the findings of an open-field audiometry with the thresholds of steady-state auditory-evoked potentials (SSAEPs) found in infants of up to 6 months of age with sensorineural hearing loss. This study included 19 infants with sensorineural hearing loss (8 males and 11 females), with minimum age of 2 months and maximum age of 6 months. The SSAEPs were assessed at 500 and 2000 Hz, and the audiometry was performed in open field through observation of behavioral responses to sound stimuli, at the same frequencies. We observed a significant correlation between the findings of both tests conducted at 500 and 2000 Hz, with p-values of 0.002 and 0.013, respectively. There was no statistical difference between ears (p=0.532) and genders (p=0.615). We conclude that there was a significant correlation between the SSAEP thresholds and the findings of the open-field audiometry. Therefore, we can affirm that the SSAEPs are a viable examination, able to predict the degree and configuration of hearing loss in infants of up to 6 months of age, and that they can be included in the clinical routine of hearing assessments conducted in children.	\N	\N
25133472	Hearing preservation (HP) surgery was initiated more than 10 years ago for combined electric and acoustic stimulation (EAS). Preserved residual low-frequency hearing has been demonstrated to improve speech perception in noise as well as music appreciation in EAS users up to 2 years. Multiple study groups aimed to evaluate initial loss of residual hearing (RH) as a consequence of HP surgery. However, after 1 year and 2 years of follow-up, further decline was reported. This study aimed to determine RH, speech perception, and the subjective benefits of EAS 10 years after HP surgery. Nine postlingual EAS partially deaf patients who underwent HP surgery at Antwerp University Hospital were included in this study (11 implanted ears). Hearing preservation (0% = loss of hearing; >0%-25% = minimal HP; >25%-75% = partial HP; >75% = complete HP), speech perception and subjective benefits were evaluated preoperatively; at 3, 6, 12, 18, and 24 months postoperatively; and annually thereafter. Complete HP was obtained in three of 11 ears; partial HP in five of 11 ears; and minimal HP in two of 11 ears, measured during their most recent follow-up. One subject lost his RH completely across time. The mean rate of HP was 48% (ranging from 6 months up to 10 years postoperatively). Speech perception analysis up to 10 years showed a continuous statistically significant improvement. The maximum subjective benefit was reached 3 months after implantation and subsequently remained statistically significant unchanged for the next 10 years. Long-term HP in EAS users after HP surgery is feasible, although a small continuous decline of HP rate of 3% per year was observed (measured from first fitting up to 6 years postoperative). Nevertheless, a continuous improvement was found in the speech perception results of the EAS users across 10 years. Moreover, the positive subjective benefit, assessed 3 months postoperative, remained stable up to 10 years.	\N	\N
25143548	When a high harmonic is removed from a cosine-phase harmonic complex, we hear a sine tone pop out of the perception; the sine tone has the pitch of the high harmonic, while the tone complex has the pitch of its fundamental frequency, f0. This phenomenon is commonly referred to as Duifhuis Pitch (DP). This paper describes, for the first time, the cortical representation of DP observed with magnetoencephalography. In experiment 1, conditions that produce the perception of a DP were observed to elicit a classic onset response in auditory cortex (P1m, N1m, P2m), and an increment in the sustained field (SF) established in response to the tone complex. Experiment 2 examined the effect of the phase spectrum of the complex tone on the DP activity: Schroeder-phase negative waves elicited a transient DP complex with a similar shape to that observed with cosine-phase waves but with much longer latencies. Following the transient DP activity, the responses of the negative and positive Schroeder-phase waves converged, and the increment in the SF slowly died away. In the absence of DP, the two Schroeder-phase conditions with low peak factors both produced larger SFs than cosine-phase waves with large peak factors. A model of the auditory periphery that includes coupling between adjacent frequency channels is used to explain the early neuromagnetic activity observed in auditory cortex.	\N	\N
25153664	This study was designed to evaluate the binaural effects from bimodal hearing according to the aided hearing threshold in the nonimplanted ear. Subjects included 17 individuals who continued to use a hearing aid (HA) in the nonimplanted ear for more than 6 months postoperatively. Speech perception and sound localization were tested with unilateral cochlear implantation (CI) and bimodal hearing with and without background noise. Materials were presented at an average of 70 dB sound pressure level from a front loudspeaker in a quiet condition and then with background noise at a signal-to-noise ratio of +10 dB HL. Speech perception scores were based on percent-correct performance of repeating a spoken word under each condition. Sound localization scores were obtained by averaging the sum of angle differences between the active loudspeaker and the loudspeaker indicated by the subject. Speech perception scores (mean ± SD) of unilateral CI and bimodal hearing were 63.3% ± 17.7% and 73.1% ± 18.5% under the quiet condition (p = 0.029) and 65.5% ± 21.9% and 70.9% ± 23.6% under the noisy condition (p = 0.01), respectively. Angle differences (mean ± SD) of unilateral CI and bimodal hearing were 72.8 ± 27.4 degrees and 84.1 ± 29.9 degrees under the quiet condition (p = 0.052) and 79.3 ± 26.9 degrees and 77.3 ± 22.0 degrees under the noisy condition (p = 0.906), respectively. Patients were divided into two groups according to their aided hearing thresholds: Group 1 (aided hearing threshold ≤50 dB HL; n = 8) and Group 2 (aided hearing threshold >50 dB HL; n = 9). The speech perception scores of bimodal hearing in each group were 85.3% ± 13.3% and 60.8% ± 17.5% (p = 0.023) under the quiet condition and 82.7% ± 9.0% and 59.4% ± 26.8% under the noisy condition (p = 0.052), respectively. For sound localization, the angle differences of bimodal hearing in each group were 54 ± 28.6 degrees and 83.9 ± 11.9 degrees under the quiet condition (p = 0.042) and 63.0 ± 23.5 degrees and 89 ± 22.6 degrees under the noisy condition (p = 0.049), respectively. Based on the relationship between the aided hearing level and bimodal hearing performance, this current study suggests that bimodal benefits for sound localization and speech perception in noise are significant but only when sound detection is adequate for the hearing aids. Therefore, bimodal hearing could be applied to selective patients with favorable aided hearing levels.	\N	\N
25153739	Unconscious priming is sensitive to contextual factors. The present study examined this adaptive process using masked arrow primes (< or >). Some targets required specific "fixed" left/right responses (< or >) and others required "free" left/right responses (<>). Different groups (n = 30 each) received response-congruent primes (SOA = 75 msec.) on 0.2, 0.5, or 0.8 of the fixed-response trials. Fixed responses were facilitated by congruent primes and free responses were faster when congruent with the prime. Critically, these masked priming effects emerged only in the 0.8 group. The pattern of extant prime-proportion effects in this paradigm best supports an adaptive associative-strength account rather than memory-recruitment or response-bias-suppression accounts.	\N	\N
25155249	Computational modeling and eye-tracking were used to investigate how phonological and semantic information interact to influence the time course of spoken word recognition. We extended our recent models (Chen & Mirman, 2012; Mirman, Britt, & Chen, 2013) to account for new evidence that competition among phonological neighbors influences activation of semantically related concepts during spoken word recognition (Apfelbaum, Blumstein, & McMurray, 2011). The model made a novel prediction: Semantic input modulates the effect of phonological neighbors on target word processing, producing an approximately inverted-U-shaped pattern with a high phonological density advantage at an intermediate level of semantic input-in contrast to the typical disadvantage for high phonological density words in spoken word recognition. This prediction was confirmed with a new analysis of the Apfelbaum et al. data and in a visual world paradigm experiment with preview duration serving as a manipulation of strength of semantic input. These results are consistent with our previous claim that strongly active neighbors produce net inhibitory effects and weakly active neighbors produce net facilitative effects.	\N	\N
25156097	The primary objective of the study was to investigate the feasibility, reliability, and validity of the Dutch digits in noise (DIN) test for measuring speech recognition in hearing aid and cochlear implant users and compare results to the standard sentences-in-noise (SIN) test. The relation between speech reception thresholds for DIN test and SIN test was analysed to determine the validity of the DIN test. As linguistic skills were expected to make different contributions in these tests, their influence was analysed. Participants were 12 normal-hearing listeners, 24 hearing aid users, and 24 cochlear implant users. The DIN test was feasible for more participants than the SIN test. Intraclass correlation coefficients showed high reliability. The standard error of measurement was smaller for the DIN test than for the SIN test. DIN test and SIN test were highly correlated (r = 0.95 and r = 0.56 for NH+ HA and CI users respectively). In the regression analysis no significant contribution of basic linguistic skills or personal factors was found. In the assessment of speech recognition in noise of aided hearing-impaired listeners with hearing aids or cochlear implants, the DIN test is a feasible, reliable and valid test.	\N	\N
25156757	In four experiments in which participants searched for multiple target digits we hypothesized that search should be fastest when the targets are arranged closely together on the number line without any intervening distractor digits, i.e., the targets form a contiguous and coherent group. In Experiment 1 search performance was better for targets defined by numerical magnitude than parity (i.e., evenness); this result supports our hypothesis but could also be due to the linear separability of targets from distractors or the numerical distance between them. Experiment 2 controlled for target-distractor linear separability and numerical distance, yielding faster search when targets were surrounded by distractors on the number line than when they surrounded distractors. This result is consistent with target contiguity and coherence but also with grouping by similarity of target shapes. Experiment 3 controlled for all three alternative explanations (linear separability, numerical distance, and shape similarity) and search performance was better for contiguous targets than separated targets. In Experiment 4 search performance was better for a coherent target group than one with intervening distractors. Of the possibilities we considered, only the hypothesis based on the contiguity and coherence of the target group on the number line can account for the results from all four experiments.	\N	\N
25158373	To evaluate cochlear functioning in patients (18-45 years old) with varying stages of chronic kidney disease (CKD). Using purposive sampling, 50 participants, 10 in each of the 5 stages of CKD, were selected and underwent pure tone audiometric testing and distortion product otoacoustic emissions (DPOAEs). Significant differences (p < 0.05) were found between pure tone audiometry and DPOAEs in detecting early cochlear dysfunction in the high-frequency range in stages 3 (6,000/5,000 Hz; p = 0.00), 4 (6,000/5,000 Hz; p < 0.03) and 5 (4,000/3,333 Hz; p < 0.01, 8,000/6,667 Hz: p < 0.05) with DPOAEs being more sensitive in identifying early cochlear dysfunction. Patients in stages 1 and 2 presented with normal puretone thresholds and DPOAEs, suggesting that cochlear functioning in these patients was normal. Early cochlear dysfunction, thereby indicating a subclinical hearing loss, was identified in stages 3, 4 and 5 by DPOAE testing. In addition, blood test results, drug intake and concomitant conditions were recorded and analysed which suggested a relationship between reduced cochlear functioning and increased electrolyte levels, treatment regimens and concomitant conditions. Participants in the later stages of CKD presented with early cochlear dysfunction, presenting with subclinical hearing loss. It was postulated that this subclinical hearing loss resulted from a combination of electrolytic, urea and creatinine imbalances, together with concomitant medical conditions and ototoxic drug intake. It was concluded that audiological monitoring be included in the management of patients with CKD and that DPOAEs be introduced as part of the test battery to monitor cochlear function in patients with varying degrees of CKD.	\N	\N
25170790	Absolute pitch (AP) is the rare ability to identify or produce different pitches without using reference tones. At least two sequential processing stages are assumed to contribute to this phenomenon. The first recruits a pitch memory mechanism at an early stage of auditory processing, whereas the second is driven by a later cognitive mechanism (pitch labeling). Several investigations have used active tasks, but it is unclear how these two mechanisms contribute to AP during passive listening. The present work investigated the temporal dynamics of tone processing in AP and non-AP (NAP) participants by using EEG. We applied a passive oddball paradigm with between- and within-tone category manipulations and analyzed the MMN reflecting the early stage of auditory processing and the P3a response reflecting the later cognitive mechanism during the second processing stage. Results did not reveal between-group differences in MMN waveforms. By contrast, the P3a response was specifically associated with AP and sensitive to the processing of different pitch types. Specifically, AP participants exhibited smaller P3a amplitudes, especially in between-tone category conditions, and P3a responses correlated significantly with the age of commencement of musical training, suggesting an influence of early musical exposure on AP. Our results reinforce the current opinion that the representation of pitches at the processing level of the auditory-related cortex is comparable among AP and NAP participants, whereas the later processing stage is critical for AP. Results are interpreted as reflecting cognitive facilitation in AP participants, possibly driven by the availability of multiple codes for tones.	\N	\N
25173195	Speaker's voice occupies a central role as the cornerstone of auditory social interaction. Here, we review the evidence suggesting that speaker's voice constitutes an integral context cue in auditory memory. Investigation into the nature of voice representation as a memory cue is essential to understanding auditory memory and the neural correlates which underlie it. Evidence from behavioral and electrophysiological studies suggest that while specific voice reinstatement (i.e., same speaker) often appears to facilitate word memory even without attention to voice at study, the presence of a partial benefit of similar voices between study and test is less clear. In terms of explicit memory experiments utilizing unfamiliar voices, encoding methods appear to play a pivotal role. Voice congruency effects have been found when voice is specifically attended at study (i.e., when relatively shallow, perceptual encoding takes place). These behavioral findings coincide with neural indices of memory performance such as the parietal old/new recollection effect and the late right frontal effect. The former distinguishes between correctly identified old words and correctly identified new words, and reflects voice congruency only when voice is attended at study. Characterization of the latter likely depends upon voice memory, rather than word memory. There is also evidence to suggest that voice effects can be found in implicit memory paradigms. However, the presence of voice effects appears to depend greatly on the task employed. Using a word identification task, perceptual similarity between study and test conditions is, like for explicit memory tests, crucial. In addition, the type of noise employed appears to have a differential effect. While voice effects have been observed when white noise is used at both study and test, using multi-talker babble does not confer the same results. In terms of neuroimaging research modulations, characterization of an implicit memory effect reflective of voice congruency is currently lacking.	\N	\N
25175541	Development of a sense of self is a fundamental process needed for human social interaction. Although functional neuroimaging studies have revealed the importance of medial prefrontal cortex (mPFC) in self-referencing, how this function develops in infancy remains poorly understood. To determine the cerebral basis underlying processing of self-related stimuli, we used behavioral measures and functional multi-channel near-infrared spectroscopy (fNIRS) to measure prefrontal cortical responses in 6-month-old infants hearing their own names. We also investigated the influence of a mother's voice on name perception in infants - an ability that plays a crucial role in the recognition of social signals. Experiment 1 measured the behavioral preferences of infants for their own names and for other names, spoken either by their mothers or by strangers. Results showed that infants significantly preferred their own name to other names, regardless of speaker type. Experiment 2 examined hemodynamic responses to the same four conditions in the prefrontal cortex. Compared with other names, hearing their own names, especially when spoken by their mother, elicited greater activity in the infant's dorsal mPFC. Furthermore, the magnitude of the cerebral response correlated with the degree of behavioral preference only when involving their mother's voice. These findings suggest that, particularly in the context of their mothers' voice, the dorsal mPFC of infants is already sensitive to social signals related to self at 6 months. At the same time, familiarity and affection related processing are also discussed as possible factors modulating dorsal mPFC activation at this age.	\N	\N
25178986	Working memory (WM) is a latent cognitive structure that serves to store and manipulate a limited amount of information over a short time period. How information is maintained in WM remains a debated issue: it is unclear whether stimuli from different sensory domains are maintained under distinct mechanisms or maintained under the same mechanism. Previous neuroimaging research on this issue to date has focused on individual brain regions and has not provided a comprehensive view of the functional networks underlying multi-domain WM. To study the functional networks involved in visual and auditory WM, we applied constrained principal component analysis (CPCA) to a functional magnetic resonance imaging (fMRI) dataset acquired when participants performed a change-detection task requiring them to remember only visual, only auditory, or both visual and auditory stimuli. Analysis revealed evidence of both [1] domain-specific networks responsive to either visual or auditory WM (but not both), and [2] domain-general networks responsive to both visual and auditory WM. The domain-specific networks showed load-dependent activations during only encoding, whereas a domain-general network was sensitive to WM load across encoding, maintenance, and retrieval. The latter domain-general network likely reflected attentional processes involved in WM encoding, retrieval, and possibly maintenance as well. These results do not support the domain-specific account of WM maintenance but instead favor the domain-general theory that items from different sensory domains are maintained under the same mechanism.	\N	\N
25178987	Current views suggest that autism spectrum disorders (ASDs) are characterised by enhanced low-level auditory discrimination abilities. Little is known, however, about whether enhanced abilities are universal in ASD and how they relate to symptomatology. We tested auditory discrimination for intensity, frequency and duration in 21 adults with ASD and 21 IQ and age-matched controls. Contrary to predictions, there were significant deficits in ASD on all acoustic parameters. The findings suggest that low-level auditory discrimination ability varies widely within ASD and this variability relates to IQ level, and influences the severity of restricted and repetitive behaviours (RRBs). We suggest that it is essential to further our understanding of the potential contributing role of sensory perception ability on the emergence of RRBs.	\N	\N
25186122	Sensory over-responsivity (SOR) refers to an exaggerated, intense, or prolonged behavioral response to ordinary sensory stimuli. The relationship of SOR to psychiatric disorders remains poorly understood. The current study examined the SOR construct within typically developing children with clinically significant anxiety, including the prevalence and course of SOR symptoms and relationship between SOR symptoms, demographic factors, and psychopathology. Children presenting at an anxiety specialty clinic (n = 88) completed a psychiatric diagnostic assessment, which included parent-report measures of SOR, anxiety, obsessive-compulsive disorder (OCD), and global behavior and child-report measures of anxiety, depression, and OCD. Sensory over-responsivity symptoms were very common: 93.2% were bothered by at least 1 tactile or auditory sensation, and the mean number of bothersome sensations was 9.2 (SD = 7.4). SOR symptoms were reported to be "moderately bothersome" on average and to onset at an early age. Sensory Over-Responsivity Inventory (SensOR) scores did not differ by psychiatric disorder diagnosis, but SensOR scores significantly correlated with measures of OCD and depression. Higher SensOR scores were associated with greater global impairment. A high rate of SOR symptom occurrence was observed in this sample of children seeking anxiety treatment, suggesting that SOR may not be entirely independent of anxiety and may be closely associated with OCD. Future research on the validity and nosology of SOR using psychiatric samples is warranted.	\N	\N
25190408	This study examines how visual speech information affects native judgments of the intelligibility of speech sounds produced by non-native (L2) speakers. Native Canadian English perceivers as judges perceived three English phonemic contrasts (/b-v, θ-s, l-ɹ/) produced by native Japanese speakers as well as native Canadian English speakers as controls. These stimuli were presented under audio-visual (AV, with speaker voice and face), audio-only (AO), and visual-only (VO) conditions. The results showed that, across conditions, the overall intelligibility of Japanese productions of the native (Japanese)-like phonemes (/b, s, l/) was significantly higher than the non-Japanese phonemes (/v, θ, ɹ/). In terms of visual effects, the more visually salient non-Japanese phonemes /v, θ/ were perceived as significantly more intelligible when presented in the AV compared to the AO condition, indicating enhanced intelligibility when visual speech information is available. However, the non-Japanese phoneme /ɹ/ was perceived as less intelligible in the AV compared to the AO condition. Further analysis revealed that, unlike the native English productions, the Japanese speakers produced /ɹ/ without visible lip-rounding, indicating that non-native speakers' incorrect articulatory configurations may decrease the degree of intelligibility. These results suggest that visual speech information may either positively or negatively affect L2 speech intelligibility.	\N	\N
25190410	Hearing-aid noise reduction should reduce background noise, but not disturb the target speech. This objective is difficult because noise reduction suffers from a trade-off between the amount of noise removed and signal distortion. It is unknown if this important trade-off differs between normal-hearing (NH) and hearing-impaired (HI) listeners. This study separated the negative effect of noise reduction (distortion) from the positive effect (reduction of noise) to allow the measurement of the detection threshold for noise-reduction (NR) distortion. Twelve NH subjects and 12 subjects with mild to moderate sensorineural hearing loss participated in this study. The detection thresholds for distortion were determined using an adaptive procedure with a three-interval, two-alternative forced-choice paradigm. Different levels of distortion were obtained by changing the maximum amount of noise reduction. Participants were also asked to indicate their preferred NR strength. The detection threshold for overall distortion was higher for HI subjects than for NH subjects, suggesting that stronger noise reduction can be applied for HI listeners without affecting the perceived sound quality. However, the preferred NR strength of HI listeners was closer to their individual detection threshold for distortion than in NH listeners. This implies that HI listeners tolerate fewer audible distortions than NH listeners.	\N	\N
25190427	The purpose of this study was to evaluate the feasibility and efficiency of an observer-based, two-interval forced-choice infant psychophysical testing procedure. Ten of 11 infants (7-9 months of age) achieved a criterion of 80%-correct detection of a 50-dB sound pressure level noise band in a single testing session. Fewer trials were needed to reach criterion using the two-interval procedure than previously reported for the single-interval observer-based psychophysical procedure [Olsho, Koch, Halpin, and Carter (1987). Devel. Psychol. 23, 627-640]. These results provide preliminary evidence that the two-interval procedure is feasible and efficient while controlling for observer and listener response bias.	\N	\N
25191774	This study aims to establish whether mothers of children with specific language impairments (SLI) have reduced emotional competence and whether individual dimensions of maternal emotional competence are related to emotional and behavioral problems in children. The clinical sample comprised 97 preschool children (23 girls) with SLI from, while the peer sample comprised 60 (34 girls) developmentally normal preschool children. The emotional competence of mothers was evaluated using the Emotional Competence Questionnaire (ESCQ-45). Emotional and behavioral difficulties in children were assessed by mothers, speech therapists, and teachers, using Achenbach's CBCL and CTRF scales. A lower emotional competence was found in mothers of children with specific language impairments. Mothers in clinical and peer samples differed in their ability to express emotions, while there was no statistically significant difference in their ability to recognize and manage emotions. Poor emotional regulation in mothers was linked to increased emotional reactivity, anxiety, and depressive manifestations in children with SLI, as well as to their speech comprehension. Emotional expression in mothers seems to be important for psychopathology in children with SLI, and their expressive and receptive speech. Our findings suggest that, in addition to the rehabilitation of children with SLI, clinical practice should implement preventative work with parents to enhance their emotional competence.	\N	\N
25196948	Research on how lexical tone is neuroanatomically represented in the human brain is central to our understanding of cortical regions subserving language. Past studies have exclusively focused on tone perception of the spoken language, and little is known as to the lexical tone processing in reading visual words and its associated brain mechanisms. In this study, we performed two experiments to identify neural substrates in Chinese tone reading. First, we used a tone judgment paradigm to investigate tone processing of visually presented Chinese characters. We found that, relative to baseline, tone perception of printed Chinese characters were mediated by strong brain activation in bilateral frontal regions, left inferior parietal lobule, left posterior middle/medial temporal gyrus, left inferior temporal region, bilateral visual systems, and cerebellum. Surprisingly, no activation was found in superior temporal regions, brain sites well known for speech tone processing. In activation likelihood estimation (ALE) meta-analysis to combine results of relevant published studies, we attempted to elucidate whether the left temporal cortex activities identified in Experiment one is consistent with those found in previous studies of auditory lexical tone perception. ALE results showed that only the left superior temporal gyrus and putamen were critical in auditory lexical tone processing. These findings suggest that activation in the superior temporal cortex associated with lexical tone perception is modality-dependent.	\N	\N
25198514	A growing body of evidence suggests that conscious visual awareness is not a prerequisite for human fear learning. For instance, humans can learn to be fearful of subliminal fear relevant images--images depicting stimuli thought to have been fear relevant in our evolutionary context, such as snakes, spiders, and angry human faces. Such stimuli could have a privileged status in relation to manipulations used to suppress usually salient images from awareness, possibly due to the existence of a designated sub-cortical 'fear module'. Here we assess this proposition, and find it wanting. We use binocular masking to suppress awareness of images of snakes and wallabies (particularly cute, non-threatening marsupials). We find that subliminal presentations of both classes of image can induce differential fear conditioning. These data show that learning, as indexed by fear conditioning, is neither contingent on conscious visual awareness nor on subliminal conditional stimuli being fear relevant.	\N	\N
25200176	Following prolonged exposure to asynchronous multisensory signals, the brain adapts to reduce the perceived asynchrony. Here, in three separate experiments, participants performed a synchrony judgment task on audiovisual, audiotactile or visuotactile stimuli and we used inter-trial analyses to examine whether temporal recalibration occurs rapidly on the basis of a single asynchronous trial. Even though all combinations used the same subjects, task and design, temporal recalibration occurred for audiovisual stimuli (i.e., the point of subjective simultaneity depended on the preceding trial's modality order), but none occurred when the same auditory or visual event was combined with a tactile event. Contrary to findings from prolonged adaptation studies showing recalibration for all three combinations, we show that rapid, inter-trial recalibration is unique to audiovisual stimuli. We conclude that recalibration occurs at two different timescales for audiovisual stimuli (fast and slow), but only on a slow timescale for audiotactile and visuotactile stimuli.	\N	\N
25211190	Children with a history of amblyopia, even if resolved, exhibit impaired visual-auditory integration and perceive speech differently. To determine whether a history of amblyopia is associated with abnormal visual-auditory speech integration. Retrospective observational study at an academic pediatric ophthalmologic clinic with an average of 4 years of follow-up. Participants were at least 3 years of age and without any history of neurologic or hearing disorders. Of 39 children originally in our study, 6 refused to participate. The remaining 33 participants completed the study. Twenty-four participants (mean [SD] age, 7.0 [1.5] years) had a history of amblyopia in 1 eye, with a visual acuity of at least 20/20 in the nonamblyopic eye. Nine controls (mean [SD] age, 8.0 [3.4] years) were recruited from referrals for visually insignificant etiologies or through preschool-screening eye examinations; all had 20/20 in both eyes. Participants were presented with a video demonstrating the McGurk effect (ie, a stimulus presenting an audio track playing the sound /pa/ and a separate video track of a person articulating /ka/). Normal visual-auditory integration produces the perception of hearing a fusion sound /ta/. Participants were asked to report which sound was perceived, /ka/, /pa/, or /ta/. Prevalence of perception of the fusion /ta/ sound. Prior to the study, amblyopic children were hypothesized to less frequently perceive /ta/. The McGurk effect was perceived by 11 of the 24 participants with amblyopia (45.8%) and all 9 controls (100%) (adjusted odds ratio, 22.3 [95% CI, 1.2-426.0]; P = .005). The McGurk effect was perceived by 100% of participants with amblyopia that was resolved by 5 years of age and by 100% of participants whose onset at amblyopia developed at or after 5 years of age. However, only 18.8% of participants with amblyopia that was unresolved by 5 years of age (n = 16) perceived the McGurk effect (adjusted odds ratio, 27.0 [95% CI, 1.1-654.0]; P = .02). This pilot study suggests that children with a history of amblyopia have impaired visual-auditory speech perception. Early childhood appears to serve as an approximate time point for the development of successful visual-auditory fusion, by which time amblyopia must have either resolved or begun. Interventions to resolve amblyopia may not only influence visual acuity but may also influence the perception of sound.	\N	\N
25217343	Attentional control theory suggests that heightened anxiety, whether due to trait or state factors, causes an increased vulnerability to distraction even when the distracters are emotionally neutral. Recent passive oddball studies appear to support this theory in relation to the distraction caused by emotionally neutral sounds. However such studies have manipulated emotional state via the content of task stimuli, thus potentially confounding changes in emotion with differences in task demands. To identify the effect of anxiety on the distraction caused by emotionally neutral sounds, 50 participants completed a passive oddball task requiring emotionally neutral sounds to be ignored. Crucially, state anxiety was manipulated independent of the task stimuli (via unrelated audiovisual stimuli) thus removing confounds relating to task demands. Neither state or trait anxiety was found to influence the susceptibility to distraction by emotionally neutral sounds. These findings contribute to the ongoing debate concerning the impact of emotion on attention.	\N	\N
25219227	To enhance speech recognition, as well as Mandarin tone recognition in noice, we proposed a speech coding strategy called zero-crossing of fine structure in low frequency (LFFS) for cochlear implant based on low frequency non-uniform sampling (LFFS for short). In the range of frequency perceived boundary of human ear, we used zero-crossing time of the fine structure to generate the stimulus pulse sequences based on the frequency selection rule. Acoustic simulation results showed that although on quiet background the performance of LFFS was similar to continuous interleaved sampling (CIS), on the noise background the performance of LFFS in Chinese tones, words and sentences were significantly better than CIS. In addition to this, we also got better Mandarin recognition factors distribution by using the improved index distribution model. LFFS contains more tonal information which was able to effectively improve Mandarin recognition of the cochlear implant.	\N	\N
25231617	Whenever the visual stream is abruptly disturbed by eye movements, blinks, masks, or flashes of light, the visual system needs to retrieve the new locations of current targets and to reconstruct the timing of events to straddle the interruption. This process may introduce position and timing errors. We here report that very similar errors are seen in human subjects across three different paradigms when disturbances are caused by either eye movements, as is well known, or, as we now show, masking. We suggest that the characteristic effects of eye movements on position and time, spatial and temporal compression and saccadic suppression of displacement, are consequences of the interruption and the subsequent reconnection and are seen also when visual input is masked without any eye movements. Our data show that compression and suppression effects are not solely a product of ocular motor activity but instead can be properties of a correspondence process that links the targets of interest across interruptions in visual input, no matter what their source.	\N	\N
25234404	In this study, we investigated the role of interactive auditory feedback in modulating the inadvertent forward drift experienced while attempting to walk in place with closed eyes following a few minutes of treadmill walking. Simulations of footstep sounds upon surface materials such as concrete and snow were provided by means of a system composed of headphones and shoes augmented with sensors. In a control condition, participants could hear their actual footstep sounds. Results showed an overall enhancement of the forward drift after treadmill walking independent of the sound perceived, while the strength of the aftereffect, measured as the proportional increase (posttest/pretest) in forward drift, was higher under the influence of snow compared to both concrete and actual sound. In addition, a higher knee angle flexion was found during the snow sound condition both before and after treadmill walking. Behavioral results confirmed those of a perceptual questionnaire, which showed that the snow sound was effective in producing strong pseudo-haptic illusions. Our results provide evidence that the walking in place aftereffect results from a recalibration of haptic, visuo-motor but also sound-motor control systems. Self-motion perception is multimodal.	\N	\N
25234884	The medial olivocochlear reflex (MOCR) modulates cochlear amplifier gain and is thought to facilitate the detection of signals in noise. High-resolution distortion product otoacoustic emissions (DPOAEs) were recorded in teens, young, middle-aged, and elderly adults at moderate levels using primary tones swept from 0.5 to 4 kHz with and without a contralateral acoustic stimulus (CAS) to elicit medial efferent activation. Aging effects on magnitude and phase of the 2f1-f2 DPOAE and on its components were examined, as was the link between speech-in-noise performance and MOCR strength. Results revealed a mild aging effect on the MOCR through middle age for frequencies below 1.5 kHz. Additionally, positive correlations were observed between strength of the MOCR and performance on select measures of speech perception parsed into features. The elderly group showed unexpected results including relatively large effects of CAS on DPOAE, and CAS-induced increases in DPOAE fine structure as well as increases in the amplitude and phase accumulation of DPOAE reflection components. Contamination of MOCR estimates by middle ear muscle contractions cannot be ruled out in the oldest subjects. The findings reiterate that DPOAE components should be unmixed when measuring medial efferent effects to better consider and understand these potential confounds.	\N	\N
25234912	With a cochlear implant, when stimulation from multiple channels is interleaved, the perceived loudness is greater than the loudness associated with any of the individual channels presented in isolation. This phenomenon is known as loudness summation. This study examined if loudness summation with monopolar and tripolar stimulation were equivalent at two loudnesses and two spacing configurations. Results suggest that loudness summation is similar for monopolar and tripolar modes. However, larger summation differences were observed for softer sounds and louder sounds with a larger spatial separation. The results are consistent with the idea that loudness summation is dependent on channel interaction and have implications for implementing current-focused processing strategies.	\N	\N
25238461	Language comprehension is more than a process of decoding the literal meaning of a speaker's utterance. Instead, by making the assumption that speakers choose their words to be informative in context, listeners routinely make pragmatic inferences that go beyond the linguistic data. If language learners make these same assumptions, they should be able to infer word meanings in otherwise ambiguous situations. We use probabilistic tools to formalize these kinds of informativeness inferences-extending a model of pragmatic language comprehension to the acquisition setting-and present four experiments whose data suggest that preschool children can use informativeness to infer word meanings and that adult judgments track quantitatively with informativeness.	\N	\N
25243992	Less proficient basic auditory processing has been previously connected to dyslexia. However, it is unclear whether a low proficiency level is a correlate of having a familial risk for reading problems, or whether it causes dyslexia. In this study, children's processing of amplitude rise time (ART), intensity and frequency differences was measured with event-related potentials (ERPs). ERP components of interest are components reflective of auditory change detection; the mismatch negativity (MMN) and late discriminative negativity (LDN). All groups had an MMN to changes in ART and frequency, but not to intensity. Our results indicate that fluent readers at risk for dyslexia, poor readers at risk for dyslexia and fluent reading controls have an LDN to changes in ART and frequency, though the scalp activation of frequency processing was different for familial risk children. On intensity, only controls showed an LDN. Contrary to previous findings, our results suggest that neither ART nor frequency processing is related to reading fluency. Furthermore, our results imply that diminished sensitivity to changes in intensity and differential lateralization of frequency processing should be regarded as correlates of being at familial risk for dyslexia, that do not directly relate to reading fluency.	\N	\N
25246562	Temporal cues are important for discerning word boundaries and syllable segments in speech; their perception facilitates language acquisition and development. Beat synchronization and neural encoding of speech reflect precision in processing temporal cues and have been linked to reading skills. In poor readers, diminished neural precision may contribute to rhythmic and phonological deficits. Here we establish links between beat synchronization and speech processing in children who have not yet begun to read: preschoolers who can entrain to an external beat have more faithful neural encoding of temporal modulations in speech and score higher on tests of early language skills. In summary, we propose precise neural encoding of temporal modulations as a key mechanism underlying reading acquisition. Because beat synchronization abilities emerge at an early age, these findings may inform strategies for early detection of and intervention for language-based learning disabilities.	\N	\N
25248621	We used a haptic enumeration task to investigate whether enumeration can be facilitated by perceptual grouping in the haptic modality. Eight participants were asked to count tangible dots as quickly and accurately as possible, while moving their finger pad over a tactile display. In Experiment 1, we manipulated the number and organization of the dots, while keeping the total exploration area constant. The dots were either evenly distributed on a horizontal line (baseline condition) or organized into groups based on either proximity (dots placed in closer proximity to each other) or configural cues (dots placed in a geometric configuration). In Experiment 2, we varied the distance between the subsets of dots. We hypothesized that when subsets of dots can be grouped together, the enumeration time will be shorter and accuracy will be higher than in the baseline condition. The results of both experiments showed faster enumeration for the configural condition than for the baseline condition, indicating that configural grouping also facilitates haptic enumeration. In Experiment 2, faster enumeration was also observed for the proximity condition than for the baseline condition. Thus, perceptual grouping speeds up haptic enumeration by both configural and proximity cues, suggesting that similar mechanisms underlie perceptual grouping in both visual and haptic enumeration.	\N	\N
25251488	A continuing debate in language acquisition research is whether there are critical periods (CPs) in development during which the system is most responsive to environmental input. Recent advances in neurobiology provide a mechanistic explanation of CPs, with the balance between excitatory and inhibitory processes establishing the onset and molecular brakes establishing the offset of windows of plasticity. In this article, we review the literature on human speech perception development within the context of this CP model, highlighting research that reveals the interplay of maturational and experiential influences at key junctures in development and presenting paradigmatic examples testing CP models in human subjects. We conclude with a discussion of how a mechanistic understanding of CP processes changes the nature of the debate: The question no longer is, "Are there CPs?" but rather what processes open them, keep them open, close them, and allow them to be reopened.	\N	\N
25255646	The aim of this study was to investigate distinctive change in the hearing impaired elderly listeners, especially about speech recognition. Subjects were 525 patients (235 males, 290 females), from 60 to 98 years of age who had visited the Hearing Aid Clinic of Otorhinolaryngology, National Center for Geriatrics and Gerontology Hospital, between June 2001 and December 2012. Pure-tone air conduction threshold determination was administered to each subject. The speech audiometry materials used to define speech discrimination ability were Japanese monosyllabic word lists, 67S word lists. Sex- and age-specific trends in maximum discrimination score (MDS) and rollover index (RI) were shown in this study. RI was computed by the formula (PBmax-PBmin)/PBmax. PBmax has almost the same meaning as MDS in Japan. PBmin represented the lowest PB score above the test intensity level of PBmax. Mean MDSs were 80.8% in their sixties, 75.3% in their seventies, 60.7% in their eighties, and 45.5% in their nineties. The rate of decrease in mean MDS per decade accelerated in the older generation. Mean RIs were 0.18 in patients in their sixties, 0.24 in their seventies, 0.30 in their eighties, and 0.30 in their nineties. It increased until the age of eighties. In the model 1, multiple logistic analyses were performed to examine the effect of age (in 10-year increments), sex and mean hearing levels in pure tone average of values at 500, 1000, 2000, 4000 Hz (in 10 dB increments) on the MDS < 60%. Significant associations were observed between MDS < 60% and age (odds ratio, 3.03; 95% confidence interval, 2.38 to 3.85), and mean hearing levels in pure tone average of values at 500, 1000, 2000, 4000 Hz (2.33; 2.03 to 2.68). Sex was not associated with MDS < 60%. In the model 2, multiple logistic analyses adjusted for age and sex were performed to examine the effect of hearing level at test frequencies of 125, 250, 500, 1000, 2000, 4000, and 8000 Hz (in 10 dB increments)on the MDS < 60%. Significant associations were observed between MDS < 60% and hearing level at 250 Hz (2.04; 1.44 to 2.89), and 2000 Hz (1.46; 1.16 to 1.83), and 4000 Hz(1.24; 1.02 to 1.50). These outcomes suggest that the important point in qualifying the fitting of hearing aid is to present the list words at an adequate sound pressure level for evaluation of speech understanding especially in the hearing impaired elderly listeners.	\N	\N
25276437	The present study investigated 24 individuals suffering from chronic tinnitus (TI) and 24 nonaffected controls (CO). We recorded resting-state EEG and collected psychometric data to obtain information about how chronic tinnitus experience affects the cognitive and emotional state of TI. The study was meant to disentangle TI with high distress from those who suffer less from persistent tinnitus based on both neurophysiological and behavioral data. A principal component analysis of psychometric data uncovers two distinct independent dimensions characterizing the individual tinnitus experience. These independent states are distress and presence, the latter is described as the perceived intensity of sound experience that increases with tinnitus duration devoid of any considerable emotional burden. Neuroplastic changes correlate with the two independent components. TI with high distress display increased EEG activity in the oscillatory range around 25 Hz (upper β-band) that agglomerates over frontal recording sites. TI with high presence show enhanced EEG signal strength in the δ-, α-, and lower γ-bands (30-40 Hz) over bilateral temporal and left perisylvian electrodes. Based on these differential patterns we suggest that the two dimensions, namely, distress and presence, should be considered as independent dimensions of chronic subjective tinnitus.	\N	\N
25299833	The present study aimed to determine the extent of hearing preservation retrospectively after atraumatic cochlear implant (CI) surgery using a specialized surgical technique and specially designed flexible electrode to minimize cochlear trauma. Retrospective study. Academic tertiary care center. A consecutive series of 34 patients who had some preoperative residual hearing were included in this study. Patients underwent CI surgery with a flexible 28-mm electrode using a round window insertion technique. All patients had at least 6 months of postoperative follow-up including audiometric testing and speech perception determined using the Freiburg monosyllable word test and the Oldenburger Sentence Test in noise. Audiometric testing served as a proxy for the evaluation of cochlear trauma and hearing preservation. Hearing was preserved to within 20 dB of preoperative low-frequency pure-tone audiometry (PTA) in 40.7% of patients. Hearing was preserved to within 20 dB of preoperative high-frequency PTA in 35.7% of patients. Overall, a deterioration in hearing thresholds was observed between preoperative assessment and first fitting. Speech perception improved significantly over time after surgery. Using appropriate surgical techniques, and electrodes specially designed to minimize cochlear trauma, hearing preservation can be achieved.	\N	\N
25301014	To isolate the neural mechanisms associated with recognizing objects from those processing basic visual properties, control stimuli are required that contain the same perceptual properties as the objects but are unrecognizable. We demonstrate that conventional methods for generating control stimuli (phase scrambling, box scrambling, texture scrambling) yield poor controls because they dramatically distort the basic visual properties (e.g., spatial frequency, perceptual organization) to which even the earliest stages of visual processing are sensitive. We developed a new scrambling method, using a diffeomorphic transformation that preserves the basic perceptual properties of the image while removing meaning. We acquired perceptual ratings to determine the least amount of scrambling necessary to remove recognition. We hypothesized that our "diffeomorphic" images would produce neural activity at the earliest stages of the visual system that more closely matched activity in response to intact images relative to the other scrambling methods. To test this hypothesis, we used the HMAX computational model of object recognition and compared the simulated neural activity at the earliest stages of the visual system (layers S1, C1, and S2) between a set of 149 images scrambled using each distortion method to their intact version. We found that scrambled "diffeomorphed" images were indistinguishable to intact images in each layer of the model, but all of the other distortion methods yielded quite different patterns. Our results indicate that "diffeomorphed" images serve as more appropriate control stimuli in neuroimaging studies that aim to disentangle the representations of perceptual and semantic object properties.	\N	\N
25315376	Under normal conditions, human speech is remarkably robust to degradation by noise and other distortions. However, people with hearing loss, including those with cochlear implants, often experience great difficulty in understanding speech in noisy environments. Recent work with normal-hearing listeners has shown that the amplitude fluctuations inherent in noise contribute strongly to the masking of speech. In contrast, this study shows that speech perception via a cochlear implant is unaffected by the inherent temporal fluctuations of noise. This qualitative difference between acoustic and electric auditory perception does not seem to be due to differences in underlying temporal acuity but can instead be explained by the poorer spectral resolution of cochlear implants, relative to the normally functioning ear, which leads to an effective smoothing of the inherent temporal-envelope fluctuations of noise. The outcome suggests an unexpected trade-off between the detrimental effects of poorer spectral resolution and the beneficial effects of a smoother noise temporal envelope. This trade-off provides an explanation for the long-standing puzzle of why strong correlations between speech understanding and spectral resolution have remained elusive. The results also provide a potential explanation for why cochlear-implant users and hearing-impaired listeners exhibit reduced or absent masking release when large and relatively slow temporal fluctuations are introduced in noise maskers. The multitone maskers used here may provide an effective new diagnostic tool for assessing functional hearing loss and reduced spectral resolution.	\N	\N
25322936	Social learning in infancy is known to be facilitated by multimodal (e.g., visual, tactile, and verbal) cues provided by caregivers. In parallel with infants' development, recent research has revealed that maternal neural activity is altered through interaction with infants, for instance, to be sensitive to infant-directed speech (IDS). The present study investigated the effect of mother- infant multimodal interaction on maternal neural activity. Event-related potentials (ERPs) of mothers were compared to non-mothers during perception of tactile-related words primed by tactile cues. Only mothers showed ERP modulation when tactile cues were incongruent with the subsequent words, and only when the words were delivered with IDS prosody. Furthermore, the frequency of mothers' use of those words was correlated with the magnitude of ERP differentiation between congruent and incongruent stimuli presentations. These results suggest that mother-infant daily interactions enhance multimodal integration of the maternal brain in parenting contexts.	\N	\N
25324090	Brief exposure to time-compressed speech yields both learning and generalization. Whether such learning continues over the course of multi-session training and if so whether it is more or less specific than exposure-induced learning is not clear, because the outcomes of intensive practice with time-compressed speech have rarely been reported. The goal here was to determine whether prolonged training on time-compressed speech yields additional learning and generalization beyond that induced by brief exposure. Listeners practiced the semantic verification of time-compressed sentences for one or three training sessions. Identification of trained and untrained tokens was subsequently compared between listeners who trained for one or three sessions, listeners who were briefly exposed to 20 time-compressed sentences and naive listeners. Trained listeners outperformed the other groups of listeners on the trained condition, but only the group that was trained for three sessions outperformed the other groups when tested with untrained tokens. These findings suggest that although learning of distorted speech can occur rapidly, more stable learning and generalization might be achieved with longer, multi-session practice. It is suggested that the findings are consistent with the framework proposed by the Reverse Hierarchy Theory of perceptual learning.	\N	\N
25324114	This paper presents an efficient method to compute the numerical solutions of transmission-line (TL) cochlear models, and its application on the model of Verhulst et al. The stability region of the model is extended by adopting a variable step numerical method to solve the system of ordinary differential equations that describes it, and by adopting an adaptive scheme to take in account variations in the system status within each numerical step. The presented method leads to improve simulations numerical accuracy and large computational savings, leading to employ TL models for more extensive simulations than currently possible.	\N	\N
25325841	To determine factors related to high levels of speech recognition in patients with the auditory brainstem implant (ABI). Retrospective case review. International multicenter data from hospitals and tertiary referral facilities. Patients with neurofibromatosis type 2 (NF2) and bilateral vestibular schwannomas. ABIs were placed after the removal of vestibular schwannomas. Demographic and surgical data were collected from 26 patients with ABIs who achieved scores of better than 30% correct identification of sentences presented in quiet listening conditions and without lipreading cues. Scores better than 30% speech recognition of standard sentence test materials (HINT or equivalent) in quiet listening conditions were obtained in 26 of the 84 NF2 patients (31%). ABI speech recognition was correlated with surgical position, length of deafness, the number of distinct pitch electrodes, perceptual levels, and ABI stimulation rate, but not correlated with tumor size, tumor stage, the number of electrodes used, or electrophysiological recordings. This paper presents the consensus opinion from a meeting of surgeons to compare outcomes across ABI surgical centers. The consensus opinion was that brainstem trauma is a primary factor in the variability of outcomes in NF2 patients. The significant co-factors in outcomes implied that ABI surgery should be accomplished with great care to minimize physical and venous trauma to the brainstem. It is clear that high levels of speech recognition, including high levels of open-set speech recognition, are possible with the ABI even in patients with NF2 and large tumors.	\N	\N
25329080	How is semantic memory influenced by individual differences under conditions of distraction? This question was addressed by observing how participants recalled visual target words--drawn from a single category--while ignoring spoken distractor words that were members of either the same or a different (single) category. Working memory capacity (WMC) was related to disruption only with synchronous, not asynchronous, presentation, and distraction was greater when the words were presented synchronously. Subsequent experiments found greater negative priming of distractors among individuals with higher WMC, but this may be dependent on targets and distractors being comparable category exemplars. With less dominant category members as distractors, target recall was impaired--relative to control--only among individuals with low WMC. The results highlight the role of cognitive control resources in target-distractor selection and the individual-specific cost implications of such cognitive control.	\N	\N
25333740	Words are made up of speech sounds. Almost all accounts of child speech development assume that children learn the pronunciation of first language (L1) speech sounds by imitation, most claiming that the child performs some kind of auditory matching to the elements of ambient speech. However, there is evidence to support an alternative account and we investigate the non-imitative child behavior and well-attested caregiver behavior that this account posits using Elija, a computational model of an infant. Through unsupervised active learning, Elija began by discovering motor patterns, which produced sounds. In separate interaction experiments, native speakers of English, French and German then played the role of his caregiver. In their first interactions with Elija, they were allowed to respond to his sounds if they felt this was natural. We analyzed the interactions through phonemic transcriptions of the caregivers' utterances and found that they interpreted his output within the framework of their native languages. Their form of response was almost always a reformulation of Elija's utterance into well-formed sounds of L1. Elija retained those motor patterns to which a caregiver responded and formed associations between his motor pattern and the response it provoked. Thus in a second phase of interaction, he was able to parse input utterances in terms of the caregiver responses he had heard previously, and respond using his associated motor patterns. This capacity enabled the caregivers to teach Elija to pronounce some simple words in their native languages, by his serial imitation of the words' component speech sounds. Overall, our results demonstrate that the natural responses and behaviors of human subjects to infant-like vocalizations can take a computational model from a biologically plausible initial state through to word pronunciation. This provides support for an alternative to current auditory matching hypotheses for how children learn to pronounce.	\N	\N
25345762	Sudden sensorineural hearing loss (SSNHL) is strictly related to inner ear vascular injuries and recently to some atherosclerotic risk factors. The pathogenic role of inflammatory molecules in atherosclerosis is well established. However, there is little knowledge about the potential role of inflammatory cytokines and adhesion molecules on SSNHL etiology. The aim of this study was to evaluate the role of proinflammatory genetic polymorphisms of the MCP-1 (CCL2), E-selectin, and interleukin (IL)-6 gene in SSNHL patients. We evaluated the frequency and distribution of selected single nucleotide polymorphisms of the MCP-1 (CCL2), E-selectin, and IL-6 gene in 87 SSNHL patients and 107 healthy controls. Our results did not show significant difference between the compared groups for MCP-1 and E-selectin genes, whereas a significant difference was reported for the IL-6 gene (P < .0001). The main finding of our study is that the 174G/G polymorphism (with a wider distribution of wt/wt genotype in SSNHL patients than in the healthy controls) of the IL-6 gene is significantly associated with the risk of SSNHL, which is consistent with a previous finding on serum levels of IL-6 in SSNHL. It is possible that the variant acts as a triggering agent of different lipidemia-related phenotypes. Both the -174G/G polymorphism and elevated IL-6 levels in SSNHL patients could suggest that IL-6 plays a role in the inner ear involvement by atherosclerotic inflammatory events.	\N	\N
25349105	To assess spoken language comprehension in non-speaking children with severe cerebral palsy (CP) and to explore possible associations with motor type and disability. Eighty-seven non-speaking children (44 males, 43 females, mean age 6y 8mo, SD 2y 1mo) with spastic (54%) or dyskinetic (46%) CP (Gross Motor Function Classification System [GMFCS] levels IV [39%] and V [61%]) underwent spoken language comprehension assessment with the computer-based instrument for low motor language testing (C-BiLLT), a new and validated diagnostic instrument. A multiple linear regression model was used to investigate which variables explained the variation in C-BiLLT scores. Associations between spoken language comprehension abilities (expressed in z-score or age-equivalent score) and motor type of CP, GMFCS and Manual Ability Classification System (MACS) levels, gestational age, and epilepsy were analysed with Fisher's exact test. A p-value <0.05 was considered statistically significant. Chronological age, motor type, and GMFCS classification explained 33% (R=0.577, R(2) =0.33) of the variance in spoken language comprehension. Of the children aged younger than 6 years 6 months, 52.4% of the children with dyskinetic CP attained comprehension scores within the average range (z-score ≥-1.6) as opposed to none of the children with spastic CP. Of the children aged older than 6 years 6 months, 32% of the children with dyskinetic CP reached the highest achievable age-equivalent score compared to 4% of the children with spastic CP. No significant difference in disability was found between CP-related variables (MACS levels, gestational age, epilepsy), with the exception of GMFCS which showed a significant difference in children aged younger than 6 years 6 months (p=0.043). Despite communication disabilities in children with severe CP, particularly in dyskinetic CP, spoken language comprehension may show no or only moderate delay. These findings emphasize the importance of introducing alternative and/or augmentative communication devices from early childhood.	\N	\N
25350759	We examined neural indices of pre-attentive phonological and attentional auditory discrimination in children with developmental language disorder (DLD, n = 23) and typically developing (n = 16) peers from a geographically isolated Russian-speaking population with an elevated prevalence of DLD. Pre-attentive phonological MMN components were robust and did not differ in two groups. Children with DLD showed attenuated P3 and atypically distributed P2 components in the attentional auditory discrimination task; P2 and P3 amplitudes were linked to working memory capacity, development of complex syntax, and vocabulary. The results corroborate findings of reduced processing capacity in DLD and support a multifactorial view of the disorder.	\N	\N
25372405	A major cue to the location of a sound source is the interaural time difference (ITD)-the difference in sound arrival time at the two ears. The neural representation of this auditory cue is unresolved. The classic model of ITD coding, dominant for a half-century, posits that the distribution of best ITDs (the ITD evoking a neuron's maximal response) is unimodal and largely within the range of ITDs permitted by head-size. This is often interpreted as a place code for source location. An alternative model, based on neurophysiology in small mammals, posits a bimodal distribution of best ITDs with exquisite sensitivity to ITDs generated by means of relative firing rates between the distributions. Recently, an optimal-coding model was proposed, unifying the disparate features of these two models under the framework of efficient coding by neural populations. The optimal-coding model predicts that distributions of best ITDs depend on head size and sound frequency: for high frequencies and large heads it resembles the classic model, for low frequencies and small head sizes it resembles the bimodal model. The optimal-coding model makes key, yet unobserved, predictions: for many species, including humans, both forms of neural representation are employed, depending on sound frequency. Furthermore, novel representations are predicted for intermediate frequencies. Here, we examine these predictions in neurophysiological data from five mammalian species: macaque, guinea pig, cat, gerbil and kangaroo rat. We present the first evidence supporting these untested predictions, and demonstrate that different representations appear to be employed at different sound frequencies in the same species.	\N	\N
25375171	Gender dysphoria (also known as "transsexualism") is characterized as a discrepancy between anatomical sex and gender identity. Research points towards neurobiological influences. Due to the sexually dimorphic characteristics of the human voice, voice gender perception provides a biologically relevant function, e.g. in the context of mating selection. There is evidence for a better recognition of voices of the opposite sex and a differentiation of the sexes in its underlying functional cerebral correlates, namely the prefrontal and middle temporal areas. This fMRI study investigated the neural correlates of voice gender perception in 32 male-to-female gender dysphoric individuals (MtFs) compared to 20 non-gender dysphoric men and 19 non-gender dysphoric women. Participants indicated the sex of 240 voice stimuli modified in semitone steps in the direction to the other gender. Compared to men and women, MtFs showed differences in a neural network including the medial prefrontal gyrus, the insula, and the precuneus when responding to male vs. female voices. With increased voice morphing men recruited more prefrontal areas compared to women and MtFs, while MtFs revealed a pattern more similar to women. On a behavioral and neuronal level, our results support the feeling of MtFs reporting they cannot identify with their assigned sex.	\N	\N
25379450	Autism Spectrum Disorder (ASD) is characterized by impairments in language and social-emotional cognition. Yet, findings of emotion recognition from affective prosody in individuals with ASD are inconsistent. This study investigated emotion recognition and neural processing of affective prosody in high-functioning adults with ASD relative to neurotypical (NT) adults. Individuals with ASD showed mostly typical brain activation of the fronto-temporal and subcortical brain regions in response to affective prosody. Yet, the ASD group showed a trend towards increased activation of the right caudate during processing of affective prosody and rated the emotional intensity lower than NT individuals. This is likely associated with increased attentional task demands in this group, which might contribute to social-emotional impairments.	\N	\N
25382428	To verify the receiver in the ear and receiver in the aid adaptations by measuring in situ the speech perception and users' level of satisfaction. The study was approved by the research ethics committee (Process: 027/2011). Twenty subjects older than 18 years with audiological diagnosis of mild and moderate bilateral descending sensorineural hearing loss were evaluated. The subjects were divided into two groups, where G1 (group 1) was fitted with open-fit hearing aids with the built-in receiver unit (receiver in the ear) and G2 (group 2) was fitted with open-fit hearing aids with RITE. A probe microphone measurement was performed to check the gain and output provided by the amplification and for assessment of speech perception with Hearing in Noise Test with and without hearing aids. After a period of six weeks of use without interruption, the subjects returned for follow-up and answered the Satisfaction with Amplification in Daily Life questionnaire, and were again subjected to Hearing in Noise Test. Both groups presented better test results for speech recognition in the presence of noise. Groups 1 and 2 were satisfied with the use of hearing aids and improved speech recognition in silent and noisy situations with hearing aids.	\N	\N
25382429	There is still no consensus in the literature as to the best acoustic stimulus for capturing vestibular evoked myogenic potential (VEMP). Low-frequency tone bursts are generally more effective than high-frequency, but recent studies still use clicks. Reproducibility is an important analytical parameter to observe the reliability of responses. To determine the reproducibility of p13 and n23 latency and amplitude of the VEMP for stimuli with different tone-burst frequencies, and to define the best test frequency. Cross-sectional cohort study. VEMP was captured in 156 ears, on the sternocleidomastoid muscle, using 100 tone-burst stimuli at frequencies of 250, 500, 1000, and 2000Hz, and sound intensity of 95dB nHL. Responses were replicated, that is, recorded three times on each side. No significant difference was observed for p13 and n23 latencies of the VEMP, captured at three moments with tone-burst stimuli at 250, 500, and 1000Hz. Only the frequency of 2000Hz showed a difference between captures of this potential (p<0.001). p13 and n23 amplitude analysis was also similar in the test-retest for all frequencies analyzed. p13 and n23 latencies and amplitudes of VEMP for tone-burst stimuli at frequencies of 250, 500, and 1000Hz are reproducible.	\N	\N
25424987	The closure positive shift (CPS) event related potential (ERP) is commonly used as a neural measure of phrase boundary perception in speech. The present study investigated whether the CPS was elicited by acoustic cues at phrase boundaries in English. ERPs were recorded when participants listened passively to sentences with either early or late phrase boundaries. The closure positive shift (CPS) ERP was elicited at both early and late phrase boundaries. However, the latency, amplitude, and scalp distribution of these passive CPS ERPs in English sentences differed to active CPS ERPs measured in non-English sentences in previous studies. These results show that acoustic cues at the phrase boundaries in English are sufficient to elicit the CPS, and suggest that different processes might be involved in the generation of the CPS in active and passive conditions.	\N	\N
25438583	The present study assessed brain activity changes related to perception of consonant and dissonant chords by musicians and non-musicians. Perception of dissonant chords in non-musicians was accompanied by increase of lower theta activity over right anterior regions, while consonant chords induced greater theta activity over left anterior regions; this pattern of asymmetrical activation was not observed in musicians. ERP analysis revealed that musicians had greater amplitude of early components (P100, N200) than non-musicians irrespective of chord type. The obtained results reflect more efficient musical harmony processing and, possibly, less emotional perception of chords in musicians.	\N	\N
25445998	The localization of neuronal generators during an ERP study, using a high-density electroencephalogram (HD-EEG) equipment was made on three Evoked Related Potential (ERP) components, i.e., the Mismatch Negativity (MMN), the P300 and the N400. Furthermore, the ERP characteristics, their field distribution and the area of their maximum field intensity were extracted and compared between young and elderly, as well as between females and males. A two tone oddball experiment was conducted, involving 27 young adults and 18 elderly, healthy and right handed, and HD-EEG data were acquired. These data were then subjected to auditory ERPs extraction and thorough statistical analysis. The derived experimental results revealed significant age-related differences to both the latencies and the amplitudes of the MMN and the P300 and the topographic distribution of the HD-EEG amplitudes. Additionally, a shift in the maximum intensities from frontal to temporal lobe with aging appeared in the case of the P300, whereas no effect was observed for the MMN component. No statistical significant differences (p>0.05) due to age was found in N400 characteristics. Finally, gender-related differences were significant in the response time of the subjects, finding males response faster. The level and the location of the maximum intensity of sources also differed between genders, especially in young subjects. These findings justify the enhanced potential of HD-EEG data to accurately reflect the age and gender dependencies at the three components of simple auditory ERPs and pave the way for the investigation of neurodegenerative pathologies, such as the Alzheimer's disease.	\N	\N
25446245	Perceptual grouping is the process of organizing sounds into perceptually meaningful elements. Psychological studies have found that tones presented as a regular frequency or temporal pattern are grouped according to gestalt principles, such as similarity, proximity, and good continuity. Predictive coding theory suggests that this process helps create an internal model for the prediction of sounds in a tone sequence and that an omission-related brain response reflects the violation of this prediction. However, it remains unclear which brain areas are related to this process, especially in paying attention to the stimuli. To clarify this uncertainty, the present study investigated the neural correlates of perceptual grouping effects. Using magnetoencephalography (MEG), we recorded the evoked response fields (ERFs) of amateur musicians and nonmusicians to sound omissions in tone sequences with a regular or random pattern of three different frequencies during an omission detection task. Omissions in the regular sequences were detected faster and evoked greater activity in the left Heschl's gyrus (HG), right postcentral gyrus, and bilateral superior temporal gyrus (STG) than did omissions in the irregular sequences. Additionally, an interaction between musical experience and regularity was found in the left HG/STG. Tone-evoked responses did not show this difference, indicating that the expertise effect did not reflect the superior tone processing acquired by amateur musicians due to musical training. These results suggest that perceptual grouping based on repetition of a pattern of frequencies affects the processing of omissions in tone sequences and induces more activation of the bilateral auditory cortex by violating internal models. The interaction in the left HG/STG may suggest different styles of processing for musicians and nonmusicians, although this difference was not reflected at the behavioral level.	\N	\N
25447067	The effects of ear of presentation and competing speech on N400s to spoken words in context were examined in a dichotic sentence priming paradigm. Auditory sentence contexts with a strong or weak semantic bias were presented in isolation to the right or left ear, or with a competing signal presented in the other ear at a SNR of -12 dB. Target words were congruent or incongruent with the sentence meaning. Competing speech attenuated N400s to both congruent and incongruent targets, suggesting that the demand imposed by a competing signal disrupts the engagement of semantic comprehension processes. Bias strength affected N400 amplitudes differentially depending upon ear of presentation: weak contexts presented to the le/RH produced a more negative N400 response to targets than strong contexts, whereas no significant effect of bias strength was observed for sentences presented to the re/LH. The results are consistent with a model of semantic processing in which the RH relies on integrative processing strategies in the interpretation of sentence-level meaning.	\N	\N
25448166	In this article, we review the PET neuroimaging literature, which indicates peculiarities of brain networks involved in speech restoration after cochlear implantation. We consider data on implanted patients during stimulation as well as during resting state, which indicates basic long-term reorganisation of brain functional architecture. On the basis of our analysis of neuroimaging literature and considering our own studies, we indicate that auditory recovery in deaf patients after cochlear implantation partly relies on visual cues. The brain develops mechanisms of audio-visual integration as a strategy to achieve high levels of speech recognition. It turns out that this neuroimaging evidence is in line with behavioural findings of better audiovisual integration in these patients. Thus, strong visually and audio-visually based rehabilitation during the first months after cochlear implantation would significantly improve and fasten the functional recovery of speech intelligibility and other auditory functions in these patients. We provide perspectives for further neuroimaging studies in cochlear implanted patients, which would help understand brain organisation to restore auditory cognitive processing in the implanted patients and would potentially suggest novel approaches for their rehabilitation. This article is part of a Special Issue entitled <Lasker Award>.	\N	\N
25459663	In his pioneering research on the neural mechanisms of filial imprinting, Gabriel Horn has gone a long way to fulfilling Karl Lashley's dream of finding the 'engram' or memory trace in the brain. Here we review recent research into the engram(s) of song learning in songbirds, particularly zebra finches. When juvenile songbirds learn their songs from a tutor, they form and alter a central representation of the tutor song, known as the 'template'. Secondary auditory regions in the caudal medial pallium are likely to contain the neural substrate for the representation of tutor song, but the roles of the different regions remain to be elucidated. Female zebra finches do not sing, but nevertheless form an auditory memory of their father's song, for which the neural substrate is located in the caudomedial pallium. In males that are learning their songs, there is continual interaction between the secondary auditory regions and sensorimotor regions, similar to the interaction between Broca's and Wernicke's areas in human infants acquiring speech and language.	\N	\N
25460240	Visual attention and perceptual grouping both help us from being overloaded by the vast amount of information, and attentional search is delayed when a target overlaps with a snake-like collinear distractor (Jingling & Tseng, 2013). We assessed whether awareness of the collinear distractor is required for this modulation. We first identified that visible long (=9 elements), but not short (=3 elements) collinear distractor slowed observers' detection of an overlapping target. Then we masked part of a long distractor (=9 elements) with continuous flashing color patches (=6 elements) so that the combined dichoptic percept to observers' awareness was a short collinear distractor (=3 elements). We found that the invisible collinear parts, like visible ones, can form a continuous contour to impair search, suggesting that conscious awareness is not a pre-requisite for contour integration and its interaction with selective attention.	\N	\N
25461917	Recent studies have demonstrated the positive effects of musical training on the perception of vocally expressed emotion. This study investigated the effects of musical training on event-related potential (ERP) correlates of emotional prosody processing. Fourteen musicians and fourteen control subjects listened to 228 sentences with neutral semantic content, differing in prosody (one third with neutral, one third with happy and one third with angry intonation), with intelligible semantic content (semantic content condition--SCC) and unintelligible semantic content (pure prosody condition--PPC). Reduced P50 amplitude was found in musicians. A difference between SCC and PPC conditions was found in P50 and N100 amplitude in non-musicians only, and in P200 amplitude in musicians only. Furthermore, musicians were more accurate in recognizing angry prosody in PPC sentences. These findings suggest that auditory expertise characterizing extensive musical training may impact different stages of vocal emotional processing.	\N	\N
25463460	Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the central auditory system. Altered GABAergic neurotransmission has been found in both the inferior colliculus and the auditory cortex in animal models of presbycusis. Edited magnetic resonance spectroscopy (MRS), using the MEGA-PRESS sequence, is the most widely used technique for detecting GABA in the human brain. However, to date there has been a paucity of studies exploring changes to the GABA concentrations in the auditory region of patients with presbycusis. In this study, sixteen patients with presbycusis (5 males/11 females, mean age 63.1 ± 2.6 years) and twenty healthy controls (6 males/14 females, mean age 62.5 ± 2.3 years) underwent audiological and MRS examinations. Pure tone audiometry from 0.125 to 8 kHz and tympanometry were used to assess the hearing abilities of all subjects. The pure tone average (PTA; the average of hearing thresholds at 0.5, 1, 2 and 4 kHz) was calculated. The MEGA-PRESS sequence was used to measure GABA+ concentrations in 4 × 3 × 3 cm(3) volumes centered on the left and right Heschl's gyri. GABA+ concentrations were significantly lower in the presbycusis group compared to the control group (left auditory regions: p = 0.002, right auditory regions: p = 0.008). Significant negative correlations were observed between PTA and GABA+ concentrations in the presbycusis group (r = -0.57, p = 0.02), while a similar trend was found in the control group (r = -0.40, p = 0.08). These results are consistent with a hypothesis of dysfunctional GABAergic neurotransmission in the central auditory system in presbycusis and suggest a potential treatment target for presbycusis.	\N	\N
25463556	Previous research has revealed that the inhibition of return (IOR) effect emerges when individuals respond to a target at the same location as their own previous response or the previous response of a co-actor. The latter social IOR effect is thought to occur because the observation of co-actor's response evokes a representation of that action in the observer and that the observation-evoked response code subsequently activates the inhibitory mechanisms underlying IOR. The present study was conducted to determine if knowledge of the co-actor's response alone is sufficient to evoke social IOR. Pairs of participants completed responses to targets that appeared at different button locations. Button contact generated location-contingent auditory stimuli (high and low tones in Experiment 1 and colour words in Experiment 2). In the Full condition, the observer saw the response and heard the auditory stimuli. In the Auditory Only condition, the observer did not see the co-actor's response, but heard the auditory stimuli generated via button contact to indicate response endpoint. It was found that, although significant individual and social IOR effects emerged in the Full conditions, there were no social IOR effects in the Auditory Only conditions. These findings suggest that knowledge of the co-actor's response alone via auditory information is not sufficient to activate the inhibitory processes leading to IOR. The activation of the mechanisms that lead to social IOR seems to be dependent on processing channels that code the spatial characteristics of action.	\N	\N
25468188	Schizophrenia and bipolar disorder share common etiological factors and pathophysiological pathways and have overlapping clinical features. Only few studies have directly compared early auditory information processing in the two disorders. The objective of this study was to investigate the M100 and M200 auditory responses in patients with schizophrenia and bipolar disorder and compare them with healthy controls using magnetoencephalography (MEG). Whole-head MEG data were acquired during an auditory oddball paradigm in 24 schizophrenia patients, 26 bipolar I disorder patients, and 31 healthy controls. The strengths and latencies of M100 and M200 in both hemispheres and the dipole source localizations were investigated from the standard stimuli. The M100 and M200 dipolar sources were localized to the left and right posterior portion of the superior temporal gyrus (STG) in all the subjects. An asymmetric pattern of M100 and M200 auditory response with more anterior sources in the right STG was observed in the healthy controls. However, both the schizophrenia and bipolar disorder patients showed a symmetric M100 and M200 source pattern. When compared with the healthy control group, both patient groups showed significantly reduced M100 and M200 source strength in both hemispheres. Our study suggests that early auditory information processing deficits may be similar in schizophrenia and bipolar disorder and may be related to abnormalities of the STG.	\N	\N
25470620	The aim was to investigate whether frequency compression (FC) hearing aids provide additional benefit to that conferred by conventional amplification. Participants wore the same hearing aid with FC enabled and disabled for six weeks (ABA design) in each condition. Speech recognition tests (in both quiet and in noise) were administered alongside two questionnaires. Performance was compared across the two signal processing conditions and at different time points. Twelve experienced hearing-aid users (aged 65-84 years old) with moderate-to-severe high-frequency hearing loss participated in the study. FC resulted in statistically significantly higher mean scores in all of the administered speech tests. Improvements over time were limited to high frequency phoneme perception. No effect of FC on self-report outcomes was observed. FC may lead to significant improvements in speech perception outcomes in both quiet and noise for many individuals. No participant was significantly disadvantaged by the use of FC.	\N	\N
25480080	Although there is an emerging consensus that both musical and linguistic pitch processing can be problematic for individuals with a developmental disorder termed congenital amusia, the nature of such a pitch-processing deficit, especially that demonstrated in a speech setting, remains unclear. Therefore, this study tested the performance of native Mandarin speakers, both with and without amusia, on discrimination and imitation tasks for Cantonese level tones, aiming to shed light on this issue. Results suggest that the impact of the phonological deficit, coupled with that of the domain-general pitch deficit, could provide a more comprehensive interpretation of Mandarin amusics' speech impairment. Specifically, when there was a high demand for pitch sensitivity, as in fine-grained pitch discriminations, the operation of the pitch-processing deficit played the more predominant role in modulating amusics' speech performance. But when the demand was low, as in discriminating naturally produced Cantonese level tones, the impact of the phonological deficit was more pronounced compared to that of the pitch-processing deficit. However, despite their perceptual deficits, Mandarin amusics' imitation abilities were comparable to controls'. Such selective impairment in tonal perception suggests that the phonological deficit more severely implicates amusics' input pathways.	\N	\N
25481793	Auditory categorization is a vital skill for perceiving the acoustic environment. Categorization depends on the discriminability of the sensory input as well as on the ability of the listener to adaptively make use of the relevant features of the sound. Previous studies on categorization have focused either on speech sounds when studying discriminability or on visual stimuli when assessing optimal cue utilization. Here, by contrast, we examined neural sensitivity to stimulus discriminability and optimal cue utilization when categorizing novel, non-speech auditory stimuli not affected by long-term familiarity. In a functional magnetic resonance imaging (fMRI) experiment, listeners categorized sounds from two category distributions, differing along two acoustic dimensions: spectral shape and duration. By introducing spectral degradation after the first half of the experiment, we manipulated both stimulus discriminability and the relative informativeness of acoustic cues. Degradation caused an overall decrease in discriminability based on spectral shape, and therefore enhanced the informativeness of duration. A relative increase in duration-cue utilization was accompanied by increased activity in left parietal cortex. Further, discriminability modulated right planum temporale activity to a higher degree when stimuli were spectrally degraded than when they were not. These findings provide support for separable contributions of parietal and posterior temporal areas to perceptual categorization. The parietal cortex seems to support the selective utilization of informative stimulus cues, while the posterior superior temporal cortex as a primarily auditory brain area supports discriminability particularly under acoustic degradation.	\N	\N
25485662	In recent years, a number of models of orthographic coding have been proposed in which the orthographic code consists of a set of units representing bigrams (open-bigram models). Three masked priming experiments were undertaken in an attempt to evaluate this idea: a conventional masked priming experiment, a sandwich priming experiment (Lupker & Davis, 2009) and an experiment involving a masked prime same-different task (Norris & Kinoshita, 2008). Three prime types were used, first-letter superset primes (e.g., wjudge-JUDGE), last-letter superset primes (e.g., judgew-JUDGE) and standard substitution-letter primes (e.g., juwge-JUDGE). In none of the experiments was there any evidence that the superset primes were more effective primes, the prediction made by open-bigram models. In fact, in the second and third experiments, first-letter superset primes were significantly worse primes than the other two prime types. These results provide no evidence for the existence of open-bigram units. They also suggest that prime-target mismatches at the first position produce orthographic codes that are less similar than mismatches at other positions. Implications for models of orthographic coding are discussed.	\N	\N
25486807	The spatial specificity of auditory aftereffect was studied after a short-time adaptation (5 s) to the broadband noise (20-20000 Hz). Adapting stimuli were sequences of noise impulses with the constant amplitude, test stimuli--with the constant and changing amplitude: an increase of amplitude of impulses in sequence was perceived by listeners as approach of the sound source, while a decrease of amplitude--as its withdrawal. The experiments were performed in an anechoic chamber. The auditory aftereffect was estimated under the following conditions: the adapting and test stimuli were presented from the loudspeaker located at a distance of 1.1 m from the listeners (the subjectively near spatial domain) or 4.5 m from the listeners (the subjectively near spatial domain) or 4.5 m from the listeners (the subjectively far spatial domain); the adapting and test stimuli were presented from different distances. The obtained data showed that perception of the imitated movement of the sound source in both spatial domains had the common characteristic peculiarities that manifested themselves both under control conditions without adaptation and after adaptation to noise. In the absence of adaptation for both distances, an asymmetry of psychophysical curves was observed: the listeners estimated the test stimuli more often as approaching. The overestimation by listeners of test stimuli as the approaching ones was more pronounced at their presentation from the distance of 1.1 m, i. e., from the subjectively near spatial domain. After adaptation to noise the aftereffects showed spatial specificity in both spatial domains: they were observed only at the spatial coincidence of adapting and test stimuli and were absent at their separation. The aftereffects observed in two spatial domains were similar in direction and value: the listeners estimated the test stimuli more often as withdrawing as compared to control. The result of such aftereffect was restoration of the symmetry of psychometric curves and of the equiprobable estimation of direction of movement of test signals.	\N	\N
25487588	A pilot study found the masking level difference (MLD) normal value of Chinese aged from 10 to 40, served to clinical practice. Seventy-three normal persons with hearing threshold < 20 dB and no disorder of otology were divided into three groups: classified 10-20 age as A group, 21-30 age as B group, 31-40 age as C group. MLD of age, gender and race were determined by the audiometer with dual channel by playing audio test disc. Same tests were compared with English language. The mean value of MLD in Chinese was (11.1 ± 3.4) dB and the 95% normal reference values were between 4.4 to 17.8 dB . There was no difference in term of gender. The value of MLD increased with age. In the term of language, foreign showed high value of MLD than that of Chinese. The measuring of MLD depends on age and language but not depends on gender. The normal threshold of MLD depends on age and language should be measured when normal values were applied to assess MLD in clinical practice.	\N	\N
25495831	Individuals with autism spectrum disorders (ASD) show enhanced perceptual and memory abilities in the domain of pitch, but also perceptual deficits in other auditory domains. The present study investigated their skills with respect to "echoic memory," a form of short-term sensory memory intimately tied to auditory perception, using a developmental perspective. We tested 23 high-functioning participants with ASD and 26 typically developing (TD) participants, distributed in two age groups (children vs. young adults; mean ages: ∼11 and ∼21 years). By means of an adaptive psychophysical procedure, we measured the longest period for which periodic (i.e., repeated) noise could be reliably discriminated from nonperiodic (i.e., plain random) noise. On each experimental trial, a single noise sample was presented to the participant, who had to classify this sound as periodic or nonperiodic. The TD adults performed, on average, much better than the other three groups, who performed similarly overall. As a function of practice, the measured thresholds improved for the TD participants, but did not change for the ASD participants. Thresholds were not correlated to performance in a test assessing verbal memory. The variance of the participants' response biases was larger among the ASD participants than among the TD participants. The results mainly suggest that echoic memory takes a long time to fully develop in TD humans, and that this development stops prematurely in persons with ASD.	\N	\N
25497692	Listeners vary substantially in their ability to recognize speech in noisy environments. Here we examined the role of genetic variation on individual differences in speech recognition in various noise backgrounds. Background noise typically varies in the levels of energetic masking (EM) and informational masking (IM) imposed on target speech. Relative to EM, release from IM is hypothesized to place greater demand on executive function to selectively attend to target speech while ignoring competing noises. Recent evidence suggests that the long allele variant in exon III of the DRD4 gene, primarily expressed in the prefrontal cortex, may be associated with enhanced selective attention to goal-relevant high-priority information even in the face of interference. We investigated the extent to which this polymorphism is associated with speech recognition in IM and EM conditions. In an unscreened adult sample (Experiment 1) and a larger screened replication sample (Experiment 2), we demonstrate that individuals with the DRD4 long variant show better recognition performance in noise conditions involving significant IM, but not in EM conditions. In Experiment 2, we also obtained neuropsychological measures to assess the underlying mechanisms. Mediation analysis revealed that this listening condition-specific advantage was mediated by enhanced executive attention/working memory capacity in individuals with the long allele variant. These findings suggest that DRD4 may contribute specifically to individual differences in speech recognition ability in noise conditions that place demands on executive function.	\N	\N
25500178	The challenge in getting a decent signal to the brain for users of cochlear implants (CIs) is described. A breakthrough occurred in 1989 that later enabled most users to understand conversational speech with their restored hearing alone. Subsequent developments included stimulation in addition to that provided with a unilateral CI, either with electrical stimulation on both sides or with acoustic stimulation in combination with a unilateral CI, the latter for persons with residual hearing at low frequencies in either or both ears. Both types of adjunctive stimulation produced further improvements in performance for substantial fractions of patients. Today, the CI and related hearing prostheses are the standard of care for profoundly deaf persons and ever-increasing indications are now allowing persons with less severe losses to benefit from these marvelous technologies. The steps in achieving the present levels of performance are traced, and some possibilities for further improvements are mentioned. This article is part of a Special Issue entitled <Lasker Award>.	\N	\N
25502451	A systematic review of the literature to evaluate the clinical outcome of cochlear implantation for patients with single-sided deafness (SSD) or asymmetrical hearing loss (AHL). We searched the PubMed, Embase, Cochrane Library, and CINAHL databases from their inception up to December 10, 2013 for SSD or AHL and cochlear implantation or their synonyms. In total, 781 articles were retrieved, of which 15 satisfied the eligibility criteria. Our outcomes of interest were speech perception in noise, sound localization, quality of life (QoL), and tinnitus. Critical appraisal showed that six studies reported on less than five patients or that they carried a low directness of evidence or a high risk of bias. Therefore, we extracted the data of nine studies (n = 112). Patient numbers, age, duration of deafness, classification of deafness, pure tone audiometry, follow-up duration, and outcome measurements were extracted from all nine articles. Because of large heterogeneity between studies, we were not able to pool data in a meta-analysis. We therefore summarized the results of the studies specified per outcome. There are no high-level-of-evidence studies concerning cochlear implantation in patients with SSD or AHL. Current literature suggests important benefits of cochlear implantation regarding sound localization, QoL, and tinnitus. Varying results were reported for speech perception in noise, possibly caused by the large clinical heterogeneity between studies. Larger and high-quality studies are certainly warranted.	\N	\N
25512041	The issue of whether human perception of speech and song recruits integrated or dissociated neural systems is contentious. This issue is difficult to address directly since these stimulus classes differ in their physical attributes. We therefore used a compelling illusion (Deutsch et al. 2011) in which acoustically identical auditory stimuli are perceived as either speech or song. Deutsch's illusion was used in a functional MRI experiment to provide a direct, within-subject investigation of the brain regions involved in the perceptual transformation from speech into song, independent of the physical characteristics of the presented stimuli. An overall differential effect resulting from the perception of song compared with that of speech was revealed in right midposterior superior temporal sulcus/right middle temporal gyrus. A left frontotemporal network, previously implicated in higher-level cognitive analyses of music and speech, was found to co-vary with a behavioural measure of the subjective vividness of the illusion, and this effect was driven by the illusory transformation. These findings provide evidence that illusory song perception is instantiated by a network of brain regions that are predominantly shared with the speech perception network.	\N	\N
25536235	A large number of neuroimaging studies have investigated imagined sensory processing and motor behaviours. These studies have reported neural activation patterns for imagined processes that resemble those of real sensory and motor events. The widespread use of such methods has raised questions about the extent to which imagined sensorimotor events mimic their overt counterparts, including their ability to elicit sensorimotor interactions. Direct behavioural evidence of imagery-induced multisensory interactions has been found recently in tasks involving auditory and visual processing. An influence of sensory imagery on the control of motor action, however, has not been investigated previously. Here, we show that both real and imagined moving sounds induce involuntary ocular movement in a nonvisual tracking task. The present data build on the results of previous studies of sensory imagery by showing that such conditions activate sensory neural areas. Moreover, we show an engagement of functional sensorimotor networks for imagined stimuli in a manner similar to the processing of real auditory stimuli.	\N	\N
25536844	A central problem in recent research on speech production concerns the question to what extent speakers adapt their linguistic expressions to the needs of their addressees. It is claimed that speakers sometimes leak information about objects that are only visible for them and not for their listeners. Previous research only takes the occurrence of adjectives as evidence for the leakage of privileged information. The present study hypothesizes that leaked information is also encoded in the prosody of those adjectives. A production experiment elicited adjectives that leak information and adjectives that do not leak information. An acoustic analysis and prominence rating task showed that adjectives that leak information were uttered with a higher pitch and perceived as more prominent compared to adjectives that do not leak information. Furthermore, a guessing task suggested that the adjectives' prosody relates to how listeners infer possible privileged information.	\N	\N
25545633	Past experience of everyday life activities, which forms the basis of our knowledge about the world, greatly affects how we understand stories. Yet, little is known about how this influence is instantiated in the human brain. Here, we used functional magnetic resonance imaging to investigate how past experience facilitates functional connectivity during the comprehension of stories rich in perceptual and motor details. We found that comprehenders' past experience with the scenes and actions described in the narratives selectively modulated functional connectivity between lower- and higher-level areas within the neural systems for visual and motor processing, respectively. These intramodal interactions may play an important role in integrating personal knowledge about a narrated situation with an evolving discourse representation. This study provides empirical evidence consistent with the idea that regions related to visual and motor processing are involved in the reenactment of experience as proposed by theories of embodied cognition.	\N	\N
25549509	The motor system is engaged when we perceive movement in the environment, even when we have no sensorimotor experience of that movement. It has been suggested that this ability relies on internal models that comprise specific exteroceptive representations, such as audition and vision. It has been shown that, for human movements, the quality of perception depends on the closeness between the perceived movement and the perceiver's own capability of reproducing it. Thus, if we are able to reproduce a movement, we also have the interoceptive motor memories that enable us to run internal models and perceive the same movements more accurately when merely observed. In a behavioral study we investigated if participants would be able to distinguish between self-produced and other-produced movement sounds from a previously recorded hurdling performance. We also analyzed if participants' discriminative ability would vary as a function of specific sound features, examining rhythmic step structure and amplitude range. The results reveal that participants were able to distinguish between their own and others' movement sounds. However, changing either rhythmic step structure or amplitude range of the sounds did not influence this self-other discrimination. We suggest that identification of one's own movement sounds is holistically achieved as an auditory gestalt.	\N	\N
25567437	To investigate the functional evaluation of auditory cortex by functional magnetic resonance imaging (fMRI) before cochlear implantation (CI). Twenty-one children with severe to profound sensorineural hearing loss (SNHL) (7 cases with normal inner ear structure, 3 cases with large vestibular aqueduct syndrome, 1 case with cochlear nerve hypoplasia) and 7 children with normal hearing were examined by fMRI under sedation. The subjects received acoustic stimuli at four random frequencies (500, 1 000, 2 000, 4 000 Hz) during fMRI examination. Tones were interleaved with silence in a block-periodic fMRI design with 16-second on-off intervals.Each stimulus repeated twice and the total acquisition time was 4 minutes and 28 seconds. Activation was identified in the auditory cortex of the 28 subjects in response to monaural and binaural acoustic stimulation, which was shown in the transverse temporal gyrus (Heschl gyrus), the thalamus and both.Of the 21 patients with SNHL, contralateral dominance was shown in six cases, ipsilateral dominance in five cases and bilateral equilibrium in 10 cases when one ear was exposed to the stimuli. Of the seven children with normal hearing, contralateral dominance was shown in three cases, ipsilateral dominance in two cases and bilateral equilibrium in two cases.No significant difference of the activation intensity in auditory cortex was shown between children with SNHL and normal hearing (P > 0.05). Good hearing recovery was obtained in the 21 patients after CI. No significant difference in the level of hearing and speech rehabilitation was shown between children with LVAS and with normal inner ear structure.Listening behavior response threshold was 55 dBHL in the case with cochlear nerve hypoplasia 10 months after CI. fMRI would be a feasible means of evaluating the function of the auditory cortex, which can be used for assessing the function of the entire auditory system prior to CI combined with ABR and imaging.	\N	\N
25575604	Cochlear implant users show a profile of residual, yet poorly understood, musical abilities. An ability that has received little to no attention in this population is entrainment to a musical beat. We show for the first time that a heterogeneous group of cochlear implant users is able to find the beat and move their bodies in time to Latin Merengue music, especially when the music is presented in unpitched drum tones. These findings not only reveal a hidden capacity for feeling musical rhythm through the body in the deaf and hearing impaired population, but illuminate promising avenues for designing early childhood musical training that can engage implanted children in social musical activities with benefits potentially extending to non-musical domains.	\N	\N
25596462	Emotional verbal messages are typically encountered in meaningful contexts, for instance, during face-to-face communication in social situations. Yet, they are often investigated by confronting single participants with isolated words on a computer screen, thus potentially lacking ecological validity. In the present study we recorded event-related brain potentials (ERPs) during emotional word processing in communicative situations provided by videos of a speaker, assuming that emotion effects should be augmented by the presence of a speaker addressing the listener. Indeed, compared to non-communicative situations or isolated word processing, emotion effects were more pronounced, started earlier and lasted longer in communicative situations. Furthermore, while the brain responded most strongly to negative words when presented in isolation, a positivity bias with more pronounced emotion effects for positive words was observed in communicative situations. These findings demonstrate that communicative situations--in which verbal emotions are typically encountered--strongly enhance emotion effects, underlining the importance of social and meaningful contexts in processing emotional and verbal messages.	\N	\N
25603582	Learning and transfer were investigated for a categorical structure that could be mapped without loss of information from 1 sensory modality to another. The category space was composed of 3 nonoverlapping, linearly separable categories whose members were structured, temporal events. Each stimulus was composed of a sequence of on-off events that varied in duration and number of subevents (complexity). Categories were learned visually, haptically, or auditorily and transferred to the same or another modality. Despite the.isomorphism across modalities, significant differences appeared in both learning and transfer. The visual modality showed an early learning advantage, with information on the transfer test preserved best when encoded visually during learning, worst when encoded haptically, with auditory encoding intermediate. False recognition rates were elevated when categories were learned haptically and transferred to another modality. In general, classification accuracy was highest for the category prototype, with false recognition of the category prototype higher in the cross-modality conditions. The results are discussed in terms of current theories in modality transfer including the difficulties inherent when calculation of similarity must be considered in a cross-modal situation.	\N	\N
25611595	Most general theories on serial order working memory (WM) assume the existence of position markers that are bound to the to-be-remembered items to keep track of the serial order. So far, the exact cognitive/neural characteristics of these markers have remained largely underspecified, while direct empirical evidence for their existence is mostly lacking. In the current study we demonstrate that retrieval from verbal serial order WM can be facilitated or hindered by spatial cuing: begin elements of a verbal WM sequence are retrieved faster after cuing the left side of space, while end elements are retrieved faster after cuing the right side of space. In direct complement to our previous work--where we showed the reversed impact of WM retrieval on spatial processing--we argue that the current findings provide us with a crucial piece of evidence suggesting a direct and functional involvement of space in verbal serial order WM. We outline the idea that serial order in verbal WM is coded within a spatial coordinate system with spatial attention being involved when searching through WM, and we discuss how this account can explain several hallmark observations related to serial order WM.	\N	\N
25620313	Despite a robust hearing conservation program, military personnel continue to be at high risk for noise induced hearing loss (NIHL). For more than a decade, a number of laboratories have investigated the use of antioxidants as a safe and effective adjunct to hearing conservation programs. Of the antioxidants that have been investigated, N-acetylcysteine (NAC) has consistently reduced permanent NIHL in the laboratory, but its clinical efficacy is still controversial. This study provides a prospective, randomized, double-blinded, placebo-controlled clinical trial investigating the safety profile and the efficacy of NAC to prevent hearing loss in a military population after weapons training. Of the 566 total study subjects, 277 received NAC while 289 were given placebo. The null hypothesis for the rate of STS was not rejected based on the measured results. While no significant differences were found for the primary outcome, rate of threshold shifts, the right ear threshold shift rate difference did approach significance (p = 0.0562). No significant difference was found in the second primary outcome, percentage of subjects experiencing an adverse event between placebo and NAC groups (26.7% and 27.4%, respectively, p = 0.4465). Results for the secondary outcome, STS rate in the trigger hand ear, did show a significant difference (34.98% for placebo-treated, 27.14% for NAC-treated, p-value = 0.0288). Additionally, post-hoc analysis showed significant differences in threshold shift rates when handedness was taken into account. While the secondary outcomes and post-hoc analysis suggest that NAC treatment is superior to the placebo, the present study design failed to confirm this. The lack of significant differences in overall hearing loss between the treatment and placebo groups may be due to a number of factors, including suboptimal dosing, premature post-exposure audiograms, or differences in risk between ears or subjects. Based on secondary outcomes and post hoc analyses however, further studies seem warranted and are needed to clarify dose response and the factors that may have played a role in the observed results.	\N	\N
25620314	This study explored the role of formant transitions and F0-contour continuity in binding together speech sounds into a coherent stream. Listening to a repeating recorded word produces verbal transformations to different forms; stream segregation contributes to this effect and so it can be used to measure changes in perceptual coherence. In experiment 1, monosyllables with strong formant transitions between the initial consonant and following vowel were monotonized; each monosyllable was paired with a weak-transitions counterpart. Further stimuli were derived by replacing the consonant-vowel transitions with samples from adjacent steady portions. Each stimulus was concatenated into a 3-min-long sequence. Listeners only reported more forms in the transitions-removed condition for strong-transitions words, for which formant-frequency discontinuities were substantial. In experiment 2, the F0 contour of all-voiced monosyllables was shaped to follow a rising or falling pattern, spanning one octave. Consecutive tokens either had the same contour, giving an abrupt F0 change between each token, or alternated, giving a continuous contour. Discontinuous sequences caused more transformations and forms, and shorter times to the first transformation. Overall, these findings support the notion that continuity cues provided by formant transitions and the F0 contour play an important role in maintaining the perceptual coherence of speech.	\N	\N
25631452	Schizophrenia patients with auditory verbal hallucinations (AVH) have reduced structural integrity in the left arcuate fasciculus (AFL) compared to healthy controls. However, it is neither known whether these changes are specific to AVH, as opposed to hallucinations or schizophrenia per se, nor how radial and/or axial diffusivity are altered. This study aimed to test the hypothesis that reductions to the structural integrity of the AFL are specifically associated with AVH in schizophrenia. Diffusion tensor imaging scans and clinical data were obtained from the Australian Schizophrenia Research Bank for 39 schizophrenia patients with lifetime AVH (18 current, 21 remitted), 74 schizophrenia patients with no lifetime AVH (40 with lifetime hallucinations in other modalities, 34 no lifetime hallucinations) and 40 healthy controls. Fractional anisotropy was significantly reduced in the AFL of patients with lifetime AVH compared to both healthy controls (Cohen's d=1.24) and patients without lifetime AVH (d=.72), including compared to the specific subsets of patients without AVH who either had hallucinations in other modalities (d=.69) or no history of any hallucinations (d=.73). Radial, but not axial, diffusivity was significantly increased in patients with lifetime AVH compared to both healthy controls (d=.89) and patients without lifetime AVH (d=.39). Evidence was found for a non-linear relation between fractional anisotropy in the AFL and state AVH. Reduced integrity of the AFL is specifically associated with AVH, as opposed to schizophrenia in general or hallucinations in other modalities. Increased radial diffusivity suggests dysmyelination or demyelination of the AFL may play a role in AVH.	\N	\N
25632078	Despite recent progress in our understanding of sensorimotor integration in speech learning, a comprehensive framework to investigate its neural basis is lacking at behaviorally relevant timescales. Structural and functional imaging studies in humans have helped us identify brain networks that support speech but fail to capture the precise spatiotemporal coordination within the networks that takes place during speech learning. Here we use neuronal oscillations to investigate interactions within speech motor networks in a paradigm of speech motor adaptation under altered feedback with continuous recording of EEG in which subjects adapted to the real-time auditory perturbation of a target vowel sound. As subjects adapted to the task, concurrent changes were observed in the theta-gamma phase coherence during speech planning at several distinct scalp regions that is consistent with the establishment of a feedforward map. In particular, there was an increase in coherence over the central region and a decrease over the fronto-temporal regions, revealing a redistribution of coherence over an interacting network of brain regions that could be a general feature of error-based motor learning in general. Our findings have implications for understanding the neural basis of speech motor learning and could elucidate how transient breakdown of neuronal communication within speech networks relates to speech disorders.	\N	\N
25644083	French-learning infants have language-specific difficulties in processing lexical stress due to the lack of lexical stress in French. These difficulties in discriminating between words with stress-initial (trochaic) and stress-final (iambic) patterns emerge by 10months of age in the easier context of low variability (using a single item pronounced with a trochaic pattern vs. an iambic pattern) as well as in the more challenging context of high segmental variability (using lists of segmentally different trochaic and iambic items). These findings raise the question of stress pattern perception in simultaneous bilinguals learning French and a second language using stress at the lexical level. Bijeljac-Babic, Serres, Höhle, and Nazzi (2012) established that at 10 months of age, in the simpler context of low variability, such bilinguals have better stress discrimination abilities than French-learning monolinguals. The current study explored whether this advantage extends to the more challenging context of high segmental variability. Results first establish stress pattern discrimination in a group of bilingual 10-month-olds learning French and one language with (variable) lexical stress, but not in French-learning 10-month-old monolinguals. Second, discrimination in bilinguals appeared not to be affected by the language balance of the infants, suggesting that sensitivity to stress patterns might be maintained in these bilingual infants provided that they hear at least 30% of a language with lexical stress.	\N	\N
25653380	In the diverse mechanosensory systems that animals evolved, the waveform of stimuli can be encoded by phase locking in spike trains of primary afferents. Coding of the fine structure of sounds via phase locking is thought to be critical for hearing. The upper frequency limit of phase locking varies across species and is unknown in humans. We applied a method developed previously, which is based on neural adaptation evoked by forward masking, to analyze mass potentials recorded on the cochlea and auditory nerve in the cat. The method allows us to separate neural phase locking from receptor potentials. We find that the frequency limit of neural phase locking obtained from mass potentials was very similar to that reported for individual auditory nerve fibers. The results suggest that this is a promising approach to examine neural phase locking in humans with normal or impaired hearing or in other species for which direct recordings from primary afferents are not feasible.	\N	\N
25656319	Models of speech production explain event-related suppression of the auditory cortical response as reflecting a comparison between auditory predictions and feedback. The present MEG study was designed to test two predictions from this framework: (1) whether the reduced auditory response varies as a function of the mismatch between prediction and feedback; (2) whether individual variation in this response is predictive of speech-motor adaptation. Participants alternated between online imitation and listening tasks. In the imitation task, participants began each trial producing the same vowel (/e/) and subsequently listened to and imitated auditorily-presented vowels varying in acoustic distance from /e/. Results replicated suppression, with a smaller M100 during speaking than listening. Although we did not find unequivocal support for the first prediction, participants with less M100 suppression were better at the imitation task. These results are consistent with the enhancement of M100 serving as an error signal to drive subsequent speech-motor adaptation.	\N	\N
25660196	Under certain conditions, sighted and blind humans can use echoes to discern characteristics of otherwise silent objects. Previous research concluded that robust horizontal-plane object localisation ability, without using head movement, depends on information above 2 kHz. While a strong interaural level difference (ILD) cue is available, it was not clear if listeners were using that or the monaural level cue that necessarily accompanies ILD. In this experiment, 13 sighted and normal-hearing listeners were asked to identify the right-vs.-left position of an object in virtual auditory space. Sounds were manipulated to remove binaural cues (binaural vs. diotic presentation) and prevent the use of monaural level cues (using level roving). With low- (<2 kHz) and high- (>2 kHz) frequency bands of noise, performance with binaural presentation and level rove exceeded that expected from use of monaural level cues and that with diotic presentation. It is argued that a high-frequency binaural cue (most likely ILD), and not a monaural level cue, is crucial for robust object localisation without head movement.	\N	\N
25660759	Impairments in neural function are common when oxygen supply to the brain is reduced. This study examined neurocognitive processes that are vulnerable to oxygen deprivation. We induced moderate-to-severe hypoxia in healthy adults, thereby inducing impairments caused by low brain oxygen availability. 22 healthy adults participated in this matched-pairs study with a single-blind, randomised design. Baseline neurocognitive function was examined during a familiarisation trial and participants were assigned to hypoxia (10% O2) or sham (21% O2) groups. Neurocognitive performance was assessed via computerised test battery after 50 min of breathing a gas mixture that reduced arterial oxygen saturation by 20% (p<0.01). Hypoxia severely reduced performance across all neurocognitive domain scores; with significant drops in neurocognitive index (-20%), composite memory (-30%), verbal memory (-34%), visual memory (-23%), processing speed (-36%), executive function (-20%), psychomotor speed (-24%), reaction time (-10%), complex attention (-19%) and cognitive flexibility (-18%; all p<0.05). Practice effects were blocked by hypoxia but occurred in sham for information processing speed (+30%), executive function (+14%), psychomotor speed (+18%), reaction time (+5%), cognitive flexibility (+14%), and overall cognitive functioning (+9%; all p<0.05). Neuropsychological performance decrements caused by acute experimental hypoxia are comparable to cognitive domains impaired with high altitude exposure and mild traumatic brain injury.	\N	\N
25676810	Neurologically healthy individuals use sensory feedback to alter future movements by updating internal models of the effector system and environment. For example, when visual feedback about limb movements or auditory feedback about speech movements is experimentally perturbed, the planning of subsequent movements is adjusted - i.e., sensorimotor adaptation occurs. A separate line of studies has demonstrated that experimentally delaying the sensory consequences of limb movements causes the sensory input to be attributed to external sources rather than to one's own actions. Yet similar feedback delays have remarkably little effect on visuo-motor adaptation (although the rate of learning varies, the amount of adaptation is only moderately affected with delays of 100-200ms, and adaptation still occurs even with a delay as long as 5000ms). Thus, limb motor learning remains largely intact even in conditions where error assignment favors external factors. Here, we show a fundamentally different result for sensorimotor control of speech articulation: auditory-motor adaptation to formant-shifted feedback is completely eliminated with delays of 100ms or more. Thus, for speech motor learning, real-time auditory feedback is critical. This novel finding informs theoretical models of human motor control in general and speech motor control in particular, and it has direct implications for the application of motor learning principles in the habilitation and rehabilitation of individuals with various sensorimotor speech disorders.	\N	\N
25678274	While there is growing understanding of visual selective attention in children, some aspects such as selection in the presence of distractors are not well understood. Adult studies suggest that when presented with a visual search task, an enhanced negativity is seen beginning around 200 ms (the N2pc) that reflects selection of a target item among distractors. However, it is not known if similar selective attention-related activity is seen in children during visual search. This study was designed to investigate the presence of the N2pc in children. Nineteen children (ages 9-12 years) and 21 adults (ages 18-22 years) completed a visual search task in which they were asked to attend to a fixation surrounded by both a target and a distractor stimulus. Three types of displays were analyzed at parietal electrodes P7 and P8; lateral target/lateral distractor, lateral target/midline distractor, and midline target/lateral distractor. Both adults and children showed a significant increased negativity contralateral compared to ipsilateral to the target (reflected in the N2pc) in both displays with a lateral target while no such effect was seen in displays with a midline target. This suggests that children also utilized additional resources to select a target item when distractors are present. These findings demonstrate that the N2pc can be used as a marker of attentional object selection in children.	\N	\N
25681737	Aging usually decreases the ability to understand language under difficult listening conditions. However, aging is also associated with increased between-subject variability. Here, we studied potential sources of inter-individual differences and investigated spoken language understanding of younger and older adults (age ranges 21-35 and 57-74 years, respectively) in a simulated "cocktail-party" scenario. A naturalistic "stock-price monitoring" task was employed in which prices of listed companies were simultaneously recited by four speakers at different locations in space. The participants responded when prices of a target company exceeded specific values, while ignoring all other companies. According to their individual performance levels three subgroups of participants were composed, consisting of 12 high-performing and 12 low-performing older adults, and 12 young adults matching the high-performing older group. The analysis of the event-related brain potentials indicated that all older adults showed delayed attentional control (indicated by a later P2) and reduced speech processing (indicated by a reduced N400), relative to the younger adults. High-performing older adults differed in increased allocation of attention and inhibitory control (indicated by a stronger P2-N2 complex) from their low-performing counterparts. The results are consistent with the idea of an adjustment of mental resources that could help compensating potential deficiencies in peripheral and central auditory processing.	\N	\N
25704552	Grapheme-color synesthetes perceive achromatic graphemes to be inherently colored. In this study grapheme-color synesthetes and non-synesthetes discriminated (1) the color of visual targets presented along with aurally presented digit primes, and (2) the identity of aurally presented digit targets presented with visual color primes. Reaction times to visual color targets were longer when the color of the target was incongruent with the synesthetic percept reported for the prime. Likewise, discriminating aurally presented digit targets took longer when the color of the prime was incongruent with the synesthetic percept for the target. These priming effects were absent in non-synesthetes. We conclude that binding between digits and colors in grapheme-color synesthetes can occur bidirectionally across senses. The results are in line with the idea that synesthesia is the result of linking inducing stimuli (e.g. digits) to synesthetic percepts (colors) at an abstract - supra-modal - conceptual level of processing.	\N	\N
25705651	Noise is a major cause of health disorders in workers and has unique importance in the auditory analysis of people exposed to it. The purpose of this study is to evaluate the arithmetic mean of the auditory thresholds at frequencies of 3, 4, and 6 kHz of workers from five professional categories exposed to occupational noise. We propose a retrospective cross-sectional cohort study to analyze 2.140 audiograms from seven companies having five sectors of activity: one footwear company, one beverage company, two ceramics companies, two metallurgical companies, and two transport companies. When we compared two categories, we noticed a significant difference only for cargo carriers in comparison to the remaining categories. In all activity sectors, the left ear presented the worst values, except for the footwear professionals (P > 0.05). We observed an association between the noise exposure time and the reduction of audiometric values for both ears. Significant differences existed for cargo carriers in relation to other groups. This evidence may be attributed to different forms of exposure. A slow and progressive deterioration appeared as the exposure time increased.	\N	\N
25705995	To investigate audiological and quality of life outcomes for a new active transcutaneous device, called the bone conduction implant (BCI), where the transducer is implanted under intact skin. A clinical study with sound field audiometry and questionnaires at six-month follow-up was conducted with a bone-anchored hearing aid on a softband as reference device. Six patients (age 18-67 years) with mild-to-moderate conductive or mixed hearing loss. The surgical procedure was found uneventful with no adverse events. The first hypothesis that BCI had a statistically significant improvement over the unaided condition was proven by a pure-tone-average improvement of 31.0 dB, a speech recognition threshold improvement in quiet (27.0 dB), and a speech recognition score improvement in noise (51.2 %). At speech levels, the signal-to-noise ratio threshold for BCI was - 5.5 dB. All BCI results were better than, or similar to the reference device results, and the APHAB and GBI questionnaires scores showed statistically significant improvements versus the unaided situation, supporting the second and third hypotheses. The BCI provides significant hearing rehabilitation for patients with mild-to-moderate conductive or mixed hearing impairments, and can be easily and safely implanted under intact skin.	\N	\N
25707867	The magnitude of spatial distance between sound stimuli is critically important for their preattentive discrimination, yet the effect of stimulus context on auditory motion processing is not clear. This study investigated the effects of acoustical change and stimulus context on preattentive spatial change detection. Auditory event-related potentials (ERPs) were recorded for stationary midline noises and two patterns of sound motion produced by linear or abrupt changes of interaural time differences. Each of the three types of stimuli was used as standard or deviant in different blocks. Context effects on mismatch negativity (MMN) elicited by stationary and moving sound stimuli were investigated by reversing the role of standard and deviant stimuli, while the acoustical stimulus parameters were kept the same. That is, MMN amplitudes were calculated by subtracting ERPs to identical stimuli presented as standard in one block and deviant in another block. In contrast, effects of acoustical change on MMN amplitudes were calculated by subtracting ERPs of standards and deviants presented within the same block. Preattentive discrimination of moving and stationary sounds indexed by MMN was strongly dependent on the stimulus context. Higher MMNs were produced in oddball configurations where deviance represented increments of the sound velocity, as compared to configurations with velocity decrements. The effect of standard-deviant reversal was more pronounced with the abrupt sound displacement than with gradual sound motion.	\N	\N
25722025	Most high-level auditory functions require one to detect the onset and offset of sound sequences as well as registering the rate at which sounds are presented within the sound trains. By recording event-related brain potentials to onsets and offsets of tone trains as well as to changes in the presentation rate, we tested whether these fundamental auditory capabilities are functional at birth. Each of these events elicited significant event-related potential components in sleeping healthy neonates. The data thus demonstrate that the newborn brain is sensitive to these acoustic features suggesting that infants are geared towards the temporal aspects of segregating sound sources, speech and music perception already at birth.	\N	\N
25726273	Auditory processing is remarkably fast and sensitive to the precise temporal structure of acoustic signals over a range of scales, from submillisecond phenomena such as localization to the construction of elementary auditory attributes at tens of milliseconds to basic properties of speech and music at hundreds of milliseconds. In light of the rapid (and often transitory) nature of auditory phenomena, in order to investigate the neurocomputational basis of auditory perception and cognition, a technique with high temporal resolution is appropriate. Here we briefly outline the utility of magnetoencephalography (MEG) for the study of the neural basis of audition. The basics of MEG are outlined in brief, and some of the most-used neural responses are described. We discuss the classic transient evoked fields (e.g., M100), responses elicited by change in a stimulus (e.g., pitch-onset response), the auditory steady-state response, and neural oscillations (e.g., theta-phase tracking). Because of the high temporal resolution and the good spatial resolution of MEG, paired with the convenient location of human auditory cortex for MEG-based recording, electromagnetic recording of this type is well suited to investigate various aspects from audition, from crafted laboratory experiments on pitch perception or scene analysis to naturalistic speech and music tasks.	\N	\N
25730639	In serial recall tasks, presenting items in alternating female and male voices impairs performance relative to the single-voice presentation. This phenomenon, termed the talker-variability effect (TVE), was recently reexamined by Hughes, Marsh, and Jones (2009, 2011), who used the effect as confirmatory evidence for their perceptual-gestural account of serial recall performance. Despite the authors' claim of generalisability, the serial recall paradigm employed did not reflect the standard parameters more generally adopted in verbal short-term memory research. Specifically, the presentation rate of the stimuli was almost 3 times that typically used. We sought to determine if the TVE, as observed by Hughes et al., was generalisable to the standard serial recall task by directly comparing recall performance in talker-variable conditions at fast and slow stimulus presentation rates. Experiment 1 employed a systematic replication of the foundational study undertaken by Hughes et al. (2009). Utilising a novel stimulus set, Experiment 2 provided a subsequent test of the generalisability of the TVE, examining the influence of item properties. Both experiments showed a robust TVE at the atypical fast presentation rate; however, for the slower item presentation, the TVE was unreliable. Furthermore, error analysis suggests that item recall also contributes to the TVE, contrary to the current explanation proposed by Hughes et al. (2009, 2011). The challenge of the present data to the perceptual-gestural account of the TVE is explored. Alternative accounts that focus on the resource cost of categorical speech perception in the context of talker variability are posited.	\N	\N
25732931	Pacific bluefin tuna (Thunnus orientalis) is a highly migratory, commercially valuable species potentially vulnerable to acoustic noise generated from human activities which could impact behavior and fitness. Although significant efforts have been made to understand hearing abilities of fishes, the large size and need to continuously swim for respiration have hindered investigations with tuna and other large pelagic species. In this study, Pacific bluefin tuna were trained to respond to a pure tone sound stimulus ranging 325-800 Hz and their hearing abilities quantified using a staircase psychophysical technique. Hearing was most sensitive from 400 to 500 Hz in terms of particle motion (radial acceleration -88 dB re 1 m s(-2); vertical acceleration -86 dB re 1 m s(-2)) and sound pressure (83 dB re 1 μPa). Compared to yellowfin tuna (Thunnus albacares) and kawakawa (Euthynnus affinis), Pacific bluefin tuna has a similar bandwidth of hearing and best frequency, but greater sensitivity overall. Careful calibration of the sound stimulus and experimental tank environment, as well as the adoption of behavioral methodology, demonstrates an experimental approach highly effective for the study of large fish species in the laboratory.	\N	\N
25740512	In normal listeners, the tonal rules of music guide musical expectancy. In a minority of individuals, known as amusics, the processing of tonality is disordered, which results in severe musical deficits. It has been shown that the tonal rules of music are neurally encoded, but not consciously available in amusics. Previous neurophysiological studies have not explicitly controlled the level of attention in tasks where participants ignored the tonal structure of the stimuli. Here, we test whether access to tonal knowledge can be demonstrated in congenital amusia when attention is controlled. Electric brain responses were recorded while asking participants to detect an individually adjusted near-threshold click in a melody. In half the melodies, a note was inserted that violated the tonal rules of music. In a second task, participants were presented with the same melodies but were required to detect the tonal deviation. Both tasks required sustained attention, thus conscious access to the rules of tonality was manipulated. In the click-detection task, the pitch deviants evoked an early right anterior negativity (ERAN) in both groups. In the pitch-detection task, the pitch deviants evoked an ERAN and P600 in controls but not in amusics. These results indicate that pitch regularities are represented in the cortex of amusics, but are not consciously available. Moreover, performing a pitch-judgment task eliminated the ERAN in amusics, suggesting that attending to pitch information interferes with perception of pitch. We propose that an impaired top-down frontotemporal projection is responsible for this disorder.	\N	\N
25740534	When two musical notes with simple frequency ratios are played simultaneously, the resulting musical chord is pleasing and evokes a sense of resolution or "consonance". Complex frequency ratios, on the other hand, evoke feelings of tension or "dissonance". Consonance and dissonance form the basis of harmony, a central component of Western music. In earlier work, we provided evidence that consonance perception is based on neural temporal coding in the brainstem (Bones et al., 2014). Here, we show that for listeners with clinically normal hearing, aging is associated with a decline in both the perceptual distinction and the distinctiveness of the neural representations of different categories of two-note chords. Compared with younger listeners, older listeners rated consonant chords as less pleasant and dissonant chords as more pleasant. Older listeners also had less distinct neural representations of consonant and dissonant chords as measured using a Neural Consonance Index derived from the electrophysiological "frequency-following response." The results withstood a control for the effect of age on general affect, suggesting that different mechanisms are responsible for the perceived pleasantness of musical chords and affective voices and that, for listeners with clinically normal hearing, age-related differences in consonance perception are likely to be related to differences in neural temporal coding.	\N	\N
25744662	Hearing loss is one of the most common symptoms of mitochondrial disorders. However, audiological phenotypes associated with different molecular defects in mtDNA are not yet well characterized. A large cohort of 1499 nonconsanguineous patients aged 5-40 years with hearing loss of unknown etiology was screened for mutations in mtDNA. For further analysis, patients harboring m.1555A>G and m.3243A>G were selected. Hearing status of the patients was assessed by pure tone audiometry. Patterns of audiograms (hearing threshold levels at each examined frequency) were statistically compared among the carriers of the m.1555A>G and the m.3243A>G mutations. We identified 20 patients positive for m.1555A>G mutation and 16 patients positive for m.3243A>G change. The frequency of the above transitions was calculated in our cohort as 1.33% and 1.06%, respectively. Seventeen affected family members carrying the mutations were included into the study. Typical shape of the audiograms in patients with m.1555A>G mutation presented a ski-slope pattern, whereas the audiometric curves among the m.3243A>G individuals had a pantonal shape (a flat curve) with slight downward sloping at the higher frequencies. The differences were statistically significant. The onset of hearing loss was noted earlier among m.1555A>G than m.3243A>G patients (12.5 and 26 years, respectively). Aminoglycoside administration was declared in both groups in 11 and 4 cases respectively, and caused abrupt hearing deterioration in all cases. A pattern of audiogram in patients with mitochondrial deafness may suggest a localization of mtDNA mutation. The pathogenesis of the audiometric differences needs further study.	\N	\N
25768088	Cartilage conduction (CC) is a new form of sound transmission which is induced by a transducer being placed on the aural cartilage. Although the conventional forms of sound transmission to the cochlea are classified into air or bone conduction (AC or BC), previous study demonstrates that CC is not classified into AC or BC (Laryngoscope 124: 1214-1219). Next interesting issue is whether CC is a hybrid of AC and BC. Seven volunteers with normal hearing participated in this experiment. The threshold-shifts by water injection in the ear canal were measured. AC, BC, and CC thresholds at 0.5-4 kHz were measured in the 0%-, 40%-, and 80%-water injection conditions. In addition, CC thresholds were also measured for the 20%-, 60%-, 100%-, and overflowing-water injection conditions. The contributions of the vibrations of the cartilaginous portion were evaluated by the threshold-shifts. For AC and BC, the threshold-shifts by the water injection were 22.6-53.3 dB and within 14.9 dB at the frequency of 0.5-4 kHz, respectively. For CC, when the water was filled within the bony portion, the thresholds were elevated to the same degree as AC. When the water was additionally injected to reach the cartilaginous portion, the thresholds at 0.5 and 1 kHz dramatically decreased by 27.4 and 27.5 dB, respectively. In addition, despite blocking AC by the injected water, the CC thresholds in force level were remarkably lower than those for BC. The vibration of the cartilaginous portion contributes to the sound transmission, particularly in the low frequency range. Although the airborne sound is radiated into the ear canal in both BC and CC, the mechanism underlying its generation is different between them. CC generates airborne sound in the canal more efficiently than BC. The current findings suggest that CC is not a hybrid of AC and BC.	\N	\N
25784489	Electrical stimulation of upper limb nerves evokes a train of high-frequency wavelets (high-frequency oscillations, HFOs) on the human scalp. These HFOs are related to the influence of arousal-promoting structures on somatosensory input processing, and are generated in the primary somatosensory cortex (post-synaptic HFOs) and the terminal tracts of thalamocortical radiations (pre-synaptic HFOs). We previously reported that HFOs do not undergo habituation to repeated stimulations; here, we verified whether HFOs could be modulated by external sensitizing stimuli. We recorded somatosensory evoked potentials (SSEPs) in 15 healthy volunteers before and after sensitization training with an auditory stimulus. Pre-synaptic HFO amplitudes, reflecting somatosensory thalamic/thalamocortical activity, significantly increased after the sensitizing acoustic stimulation, whereas both the low-frequency N20 SSEP component and post-synaptic HFOs were unaffected. Cross-talk between subcortical arousal-related structures is a probable mechanism for the pre-synaptic HFO effect observed in this study. We propose that part of the ascending somatosensory input encoded in HFOs is specifically able to convey sensitized inputs. This preferential involvement in sensitization mechanisms suggests that HFOs play a critical role in the detection of potentially relevant stimuli, and act at very early stages of somatosensory input processing.	\N	\N
25813739	Perception of simultaneity and temporal order is studied with simultaneity judgment (SJ) and temporal-order judgment (TOJ) tasks. In the former, observers report whether presentation of two stimuli was subjectively simultaneous; in the latter, they report which stimulus was subjectively presented first. SJ and TOJ tasks typically give discrepant results, which has prompted the view that performance is mediated by different processes in each task. We looked at these discrepancies from a model that yields psychometric functions whose parameters characterize the timing, decisional, and response processes involved in SJ and TOJ tasks. We analyzed 12 data sets from published studies in which both tasks had been used in within-subjects designs, all of which had reported differences in performance across tasks. Fitting the model jointly to data from both tasks, we tested the hypothesis that common timing processes sustain simultaneity and temporal-order judgments, with differences in performance arising from task-dependent decisional and response processes. The results supported this hypothesis, also showing that model psychometric functions account for aspects of SJ and TOJ data that classical analyses overlook. Implications for research on perception of simultaneity and temporal order are discussed.	\N	\N
25813742	Previous studies have shown that humans are sensitive to statistical patterns indicating the likely locations, identities, and timings of visual targets. Here we tested whether participants can also use this kind of information to ameliorate the attentional blink (AB)—a reduction in accuracy for the second of two targets (T1, T2) presented at brief intertarget intervals (lags). In particular, we asked whether participants can use patterns arising from differential distributions of intertarget lags across trials to predict the arrival of T2. We tested this by comparing the ABs in an aging versus a nonaging distribution of trials, where aging refers to the increased likelihood of T2, given that it has not yet occurred, when lags occur with equal frequencies. Experiments 1 and 2 showed that the aging condition yielded greater T2 accuracy at longer lags than did the nonaging condition. In Experiment 3, we used a more sensitive response time measure to show faster T2 discrimination at shorter lags in the nonaging condition. These results demonstrate that participants can predict the likely onset of T2 by using statistical patterns present in the AB task, and that they can use this ability to more effectively direct limited processing resources.	\N	\N
25827259	Infants' attention is captured by the redundancy of amodal stimulation in multimodal objects and events. Evidence from this study demonstrates that intersensory redundancy can facilitate discrimination of rhythm changes presented in the visual modality alone in visually impaired infants, suggesting that multisensory rehabilitation strategies could prove helpful in this population.	\N	\N
25862624	Animal models of tinnitus complement human findings and potentially deepen our insight into the neural substrates of tinnitus. The fact that animal data are largely based on recordings from the auditory system, in particular from subcortical structures, makes comparison with human electrophysiological data from predominantly cortical areas difficult. Electro/magnetoencephalography and imaging data extend beyond the auditory cortex. The most challenging link to be made is the one between the macroscopic data in humans and the microscopic (single neuron action potentials) and mesoscopic (local field potentials) results obtained in animal models. Since invasive recordings in humans are rare, a bridge needs to be built on the basis of changes in brain rhythms in animals with putative tinnitus.	\N	\N
25878278	There is substantial evidence that sensory deprivation leads to important cross-modal brain reorganization that is paralleled by enhanced perceptual abilities. However, it remains unclear how widespread these enhancements are, and whether they are intercorrelated or arise at the expense of other perceptual abilities. One specific area where such a trade-off might arise is that of spatial hearing, where blind individuals have been shown to possess superior monaural localization abilities in the horizontal plane, but inferior localization abilities in the vertical plane. While both of these tasks likely involve the use of monaural cues due to the absence of any relevant binaural signal, there is currently no proper explanation for this discrepancy, nor has any study investigated both sets of abilities in the same sample of blind individuals. Here, we assess whether the enhancements observed in the horizontal plane are related to the deficits observed in the vertical plane by testing sound localization in both planes in groups of blind and sighted persons. Our results show that the blind individuals who displayed the highest accuracy at localizing sounds monaurally in the horizontal plane are also the ones who exhibited the greater deficit when localizing in the vertical plane. These findings appear to argue against the idea of generalized perceptual enhancements in the early blind, and instead suggest the possibility of a trade-off in the localization proficiency between the two auditory spatial planes, such that learning to use monaural cues for the horizontal plane comes at the expense of using those cues to localize in the vertical plane.	\N	\N
25880903	Stuttering is a neurodevelopmental disorder that affects the timing and rhythmic flow of speech production. When speech is synchronized with an external rhythmic pacing signal (e.g., a metronome), even severe stuttering can be markedly alleviated, suggesting that people who stutter may have difficulty generating an internal rhythm to pace their speech. To investigate this possibility, children who stutter and typically-developing children (n=17 per group, aged 6-11 years) were compared in terms of their auditory rhythm discrimination abilities of simple and complex rhythms. Children who stutter showed worse rhythm discrimination than typically-developing children. These findings provide the first evidence of impaired rhythm perception in children who stutter, supporting the conclusion that developmental stuttering may be associated with a deficit in rhythm processing.	\N	\N
25896774	In this report, we used filtered noise bands to constrain listeners' access to interaural level differences (ILDs) and interaural time differences (ITDs) in a sound source localization task. The samples of interest were listeners with single-sided deafness (SSD) who had been fit with a cochlear implant in the deafened ear (SSD-CI). The comparison samples included listeners with normal hearing and bimodal hearing, i.e., with a cochlear implant in 1 ear and low-frequency acoustic hearing in the other ear. The results indicated that (i) sound source localization was better in the SSD-CI condition than in the SSD condition, (ii) SSD-CI patients rely on ILD cues for sound source localization, (iii) SSD-CI patients show functional localization abilities within 1-3 months after device activation and (iv) SSD-CI patients show better sound source localization than bimodal CI patients but, on average, poorer localization than normal-hearing listeners. One SSD-CI patient showed a level of localization within normal limits. We provide an account for the relative localization abilities of the groups by reference to the differences in access to ILD cues.	\N	\N
25912703	In this review we analyse cochlear implantation in terms of the fundamental aspects of the functioning of the auditory system. Concepts concerning neuronal plasticity applied to electrical stimulation in perinatal and adult deep hypoacusis are reviewed, and the latest scientific bases that justify early implantation following screening for congenital deafness are discussed. Finally, this review aims to serve as an example of the importance of fostering the sub-specialty of neurotology in our milieu, with the aim of bridging some of the gaps between specialties and thus improving both the knowledge in the field of research on auditory pathologies and in the screening of patients. The objectives of this review, targeted above all towards specialists in the field of otorhinolaryngology, are to analyse some significant neurological foundations in order to reach a better understanding of the clinical events that condition the indications and the rehabilitation of patients with cochlear implants, as well as to use this means to foster the growth of the sub-specialty of neurotology.	\N	\N
25914938	The study examined the effect of structural composition, position of occlusion, and education background on response time and accuracy rate of adult participants in recognition of occluded Chinese characters used in graphic design. Based on 18 Chinese characters selected from the top 4,000 most commonly used characters, a recognition experiment was conducted. Results indicated that, for the characters with two different composition structures, the right position was the best position of occlusion because the recognition of the radical or feature of a character would be least affected, leading to a shorter response time and more accurate reading comprehension. Educational background did not have a significant influence on response time and recognition accuracy.	\N	\N
25914939	This study examined the effects of audio-visual aids on anxiety, comprehension test scores, and retention in reading and listening to short stories in English as a Foreign Language (EFL) classrooms. Reading and listening tests, general and test anxiety, and retention were measured in English-major college students in an experimental group with audio-visual aids (n=83) and a control group without audio-visual aids (n=94) with similar general English proficiency. Lower reading test anxiety, unchanged reading comprehension scores, and better reading short-term and long-term retention after four weeks were evident in the audiovisual group relative to the control group. In addition, lower listening test anxiety, higher listening comprehension scores, and unchanged short-term and long-term retention were found in the audiovisual group relative to the control group after the intervention. Audio-visual aids may help to reduce EFL learners' listening test anxiety and enhance their listening comprehension scores without facilitating retention of such materials. Although audio-visual aids did not increase reading comprehension scores, they helped reduce EFL learners' reading test anxiety and facilitated retention of reading materials.	\N	\N
25948273	The human brain has evolved to operate effectively in highly complex acoustic environments, segregating multiple sound sources into perceptually distinct auditory objects. A recent theory seeks to explain this ability by arguing that stream segregation occurs primarily due to the temporal coherence of the neural populations that encode the various features of an individual acoustic source. This theory has received support from both psychoacoustic and functional magnetic resonance imaging (fMRI) studies that use stimuli which model complex acoustic environments. Termed stochastic figure-ground (SFG) stimuli, they are composed of a "figure" and background that overlap in spectrotemporal space, such that the only way to segregate the figure is by computing the coherence of its frequency components over time. Here, we extend these psychoacoustic and fMRI findings by using the greater temporal resolution of electroencephalography to investigate the neural computation of temporal coherence. We present subjects with modified SFG stimuli wherein the temporal coherence of the figure is modulated stochastically over time, which allows us to use linear regression methods to extract a signature of the neural processing of this temporal coherence. We do this under both active and passive listening conditions. Our findings show an early effect of coherence during passive listening, lasting from ∼115 to 185 ms post-stimulus. When subjects are actively listening to the stimuli, these responses are larger and last longer, up to ∼265 ms. These findings provide evidence for early and preattentive neural computations of temporal coherence that are enhanced by active analysis of an auditory scene.	\N	\N
25951749	The debate about the causal role of the motor system in speech perception has been reignited by demonstrations that motor processes are engaged during the processing of speech sounds. Here, we evaluate which aspects of auditory speech processing are affected, and which are not, in a stroke patient with dysfunction of the speech motor system. We found that the patient showed a normal phonemic categorical boundary when discriminating two non-words that differ by a minimal pair (e.g., ADA-AGA). However, using the same stimuli, the patient was unable to identify or label the non-word stimuli (using a button-press response). A control task showed that he could identify speech sounds by speaker gender, ruling out a general labelling impairment. These data suggest that while the motor system is not causally involved in perception of the speech signal, it may be used when other cues (e.g., meaning, context) are not available.	\N	\N
25970594	Previous studies investigating speech perception in noise have typically been conducted with static masker positions. The aim of this study was to investigate the effect of spatial separation of source and masker (spatial release from masking, SRM) in a moving masker setup and to evaluate the impact of adaptive beamforming in comparison with fixed directional microphones in cochlear implant (CI) users. Speech reception thresholds (SRT) were measured in S0N0 and in a moving masker setup (S0Nmove) in 12 normal hearing participants and 14 CI users (7 subjects bilateral, 7 bimodal with a hearing aid in the contralateral ear). Speech processor settings were a moderately directional microphone, a fixed beamformer, or an adaptive beamformer. The moving noise source was generated by means of wave field synthesis and was smoothly moved in a shape of a half-circle from one ear to the contralateral ear. Noise was presented in either of two conditions: continuous or modulated. SRTs in the S0Nmove setup were significantly improved compared to the S0N0 setup for both the normal hearing control group and the bilateral group in continuous noise, and for the control group in modulated noise. There was no effect of subject group. A significant effect of directional sensitivity was found in the S0Nmove setup. In the bilateral group, the adaptive beamformer achieved lower SRTs than the fixed beamformer setting. Adaptive beamforming improved SRT in both CI user groups substantially by about 3 dB (bimodal group) and 8 dB (bilateral group) depending on masker type. CI users showed SRM that was comparable to normal hearing subjects. In listening situations of everyday life with spatial separation of source and masker, directional microphones significantly improved speech perception with individual improvements of up to 15 dB SNR. Users of bilateral speech processors with both directional microphones obtained the highest benefit.	\N	\N
26027328	The parallel psychophysical and MMN study focused at the sensitivity of human hearing system to variations in velocity of sound image movement. The motion of sound stimuli with various velocities in the 450 deg/s to 732 deg/s range in increments of 6 deg/s to the left or to the right from the head midline was simulated by introducing linear changes of interaural delay into dichotic stimuli. The psychophysical experiments were designed according to the 2-alternative forced choice paradigm. The subjects were presented by pairs of moving stimuli and were asked to decide which moved faster. The stimuli created for the present study ensured that the subjects performed the discrimination task without relying on associated cues of sound displacement or duration. The psychophysical measures were compared with electrophysiological indexes of sound processing (auditory evoked responses (ERPs) and mismatch negativity (MMN)). Significant MMN was elicited by the difference of 170 deg/s between the reference and test velocity, which corresponded to the relative velocity increase of 38%. At the same time, the difference thresholds for velocity were much higher and exceeded 50%. The results suggest that MMN magnitude depended on the velocity difference between standard and deviant stimuli and was more sensitive to velocity difference than psychophysical measure.	\N	\N
26067532	In peripheral vision, objects that are easily discriminated on their own become less discriminable in the presence of surrounding clutter. This phenomenon is known as crowding.The neural mechanisms underlying crowding are not well understood. Better insight might come from single-neuron recording in nonhuman primates, provided they exhibit crowding; however, previous demonstrations of crowding have been confined to humans. In the present study, we set out to determine whether crowding occurs in rhesus macaque monkeys. We found that animals trained to identify a target letter among flankers displayed three hallmarks of crowding as established in humans. First, at a given eccentricity, increasing the spacing between the target and the flankers improved recognition accuracy. Second, the critical spacing, defined as the minimal spacing at which target discrimination was reliable, was proportional to eccentricity. Third, the critical spacing was largely unaffected by object size. We conclude that monkeys, like humans, experience crowding. These findings open the door to studies of crowding at the neuronal level in the monkey visual system.	\N	\N
26075675	Vibroplasty has offered a new modality of hearing rehabilitation in patients with mixed, conductive, and sensorineural hearing loss who cannot wear hearing aids. Potentially, the positioning of the floating mass transducer (FMT) in vibroplasty surgery has a critical effect on hearing outputs. In this study, the impact on hearing outputs and coupling efficiency are evaluated by comparing various vibroplasty applications in the middle ear. No other study to date has examined the coupling efficiency of round window (RW) versus an ossicular vibroplasty application. Prospective cohort study of patients with underlying ear pathologies who were not able to wear hearing aids. This is an ongoing prospective study of 16 patients. All patients had a standard audiological test battery. Direct drive transfer function analysis results were correlated with bone conduction thresholds to assess the efficiency of the FMT coupling. Speech perception in quiet and quality of life measure questionnaires were used to assess outcomes. Nine patients had round window vibroplasty, six patients had stapes vibroplasty, and one patient had traditional incus vibroplasty. Patients with a soft tissue coupler between the FMT and the RW had significantly reduced coupling efficiency. Patients who had direct RW contact had significantly improved coupling efficiency. Patients who underwent stapes or incus vibroplasty had the greatest coupling efficiency. This study demonstrates that attachment to the stapes or incus provides the best coupling when compared to round window vibroplasty. When applicable, stapes or incus coupling should be the first choice when implementing vibroplasty.	\N	\N
26184883	Communication by sounds requires that the communication channels (i.e. speech/speakers and other sound sources) had been established. This allows to separate concurrently active sound sources, to track their identity, to assess the type of message arriving from them, and to decide whether and when to react (e.g., reply to the message). We propose that these functions rely on a common generative model of the auditory environment. This model predicts upcoming sounds on the basis of representations describing temporal/sequential regularities. Predictions help to identify the continuation of the previously discovered sound sources to detect the emergence of new sources as well as changes in the behavior of the known ones. It produces auditory event representations which provide a full sensory description of the sounds, including their relation to the auditory context and the current goals of the organism. Event representations can be consciously perceived and serve as objects in various cognitive operations.	\N	\N
26222939	To compare children with typical language development (TLD) and evolutional phonological disorder (EPD) regarding the phonemic discrimination and the linguistic performance of language levels (morphological, syntactic, semantic, and perceptual and productive vocabulary). The sample comprised 36 children, aged between 5 years and 7 years and 11 months, with TLD and EPD. Children with EPD were awaiting care in the speech units of two higher education institutions and children with TLD were screened in public schools. For inclusion in the study, the criteria were the following: being authorized by the informed consent and being within the required age group. After the inclusion of children, all subjects underwent the phonemic discrimination test with figures, to the average phrase value test, which assesses the morphosyntactic and semantic/lexical aspects, and the expressive vocabulary test. For statistical evaluation of the influence of variables, Spearman's nonparametric correlation coefficient was used, and for comparison between the groups regarding evaluation performance, Mann-Whitney test was used. Only children with EPD showed influence of phonemic discrimination in other linguistic levels. In addition, a significant difference was observed between the performances of both groups in relation to the phonemic discrimination, vocabulary, and all levels assessed in the questions and description modality. The comparison between both groups showed a statistically significant difference in phonemic discrimination and morphosyntactic and lexical/semantic development, with better performance in the TLD group.	\N	\N
26222946	To analyze the intra- and inter-rater agreement for visual analog scale and numerical scale in task of sustained vowel and to determine numerical cutoff points to visual analog scale corresponding to the degrees of the numeric scale. We selected 205 samples of the usual task of the sustained vowel /a/. Six voice specialists rated the overall degree of vocal deviation, first by visual analog scale and, after two days, by the numeric scale. The results obtained by both scales were compared and the intra- and inter-rater agreement, the correlation between the scales, and the estimated cutoff points using the intraclass correlation and concordance Kappa coefficients, the Spearman coefficient, and analysis of variance, and the values of sensitivity and specificity were analyzed. A strong correlation was observed between the scales. The following numerical cutoff values were found for visual analog scale corresponding to the numerical scale: neutral (degree zero) - 0 to 34 mm; mild (degree one) - 34.1 to 51 mm; moderate (degree two) - 51.1 to 63.5 mm; intense (degree three) - 63.6 to 77.5 mm; and extreme (degree four) - above 77.5 mm. The visual analog scale and numerical scale showed a strong correlation, being observed the greater intra- and inter-rater agreement in visual analog scale. Numerical cutoff values for visual analog scale were found. This correlation enables the comparison between the results found in the evaluation of the overall degree of vocal deviation by both scales, which are widely used in research and in the clinical speech therapy routine.	\N	\N
26356376	During dental treatments, patients may experience negative emotions associated with the procedure. This study was conducted with the aim of using functional magnetic resonance imaging (fMRI) to visualize cerebral cortical stimulation among dental patients in response to auditory stimuli produced by ultrasonic scaling and power suction equipment. Subjects (n = 7) aged 23-35 years were recruited for this study. All were right-handed and underwent clinical pure-tone audiometry testing to reveal a normal hearing threshold below 20 dB hearing level (HL). As part of the study, subjects initially underwent a dental calculus removal treatment. During the treatment, subjects were exposed to ultrasonic auditory stimuli originating from the scaling handpiece and salivary suction instruments. After dental treatment, subjects were imaged with fMRI while being exposed to recordings of the noise from the same dental instrument so that cerebral cortical stimulation in response to aversive auditory stimulation could be observed. The independent sample confirmatory t-test was used. Subjects also showed stimulation in the amygdala and prefrontal cortex, indicating that the ultrasonic auditory stimuli elicited an unpleasant response in the subjects. Patients experienced unpleasant sensations caused by contact stimuli in the treatment procedure. In addition, this study has demonstrated that aversive auditory stimuli such as sounds from the ultrasonic scaling handpiece also cause aversive emotions. This study was indicated by observed stimulation of the auditory cortex as well as the amygdala, indicating that noise from the ultrasonic scaling handpiece was perceived as an aversive auditory stimulus by the subjects. Subjects can experience unpleasant sensations caused by the sounds from the ultrasonic scaling handpiece based on their auditory stimuli.	\N	\N
26380996	The purpose was to evaluate brain plasticity that contributes to speech performance after cochlear implantation (CI) in postlingual elderly (>60 years) patients. Fifteen elderly postlingual deaf patients who underwent preoperative brain fluorodeoxyglucose positron emission tomography (FDG-PET) and were followed-up for more than 1 year after CI were included. The mean age of these patients was 64.6 years (range, 60-80 years). Based on their sentence score at 1 year after CI surgery, the patients were classified into two groups: poor performers (CID score of <80) and good performers (CID score of ≥80). The duration of deafness, age at operation, preoperative residual hearing, and preoperative brain metabolism were analyzed. SPM5 software was used for FDG-PET image preprocessing and statistical analysis. Neither deafness duration nor preoperative residual hearing was associated with speech performance. The age at operation had little association with speech performance. Deaf patients whose brain metabolism was higher in frontotemporal regions became good CI users but those with higher metabolism in visual association areas became poor CI users. No significant cortical area of higher metabolism was associated with the duration of deafness. Overactivation in the visual processing pathway correlated with a poor CI outcome at 1 year. Deaf patients who are going to be poorer performers with CI devices maintain visual information processing during preoperative silent resting periods.	\N	\N
26381009	The occurrence of oval window atresia is a rare anomaly with conductive hearing loss. Traditional atresia surgeries involve challenging surgical techniques with risks of irreversible inner ear damage. Recent reports on Bonebridge (Medel, Innsbruck, Austria), a novel implantable bone conduction hearing aid system, assert that the device is safe and effective for conductive hearing loss. We present a case of Bonebridge implantation in an eight-year-old girl with bilateral oval window atresia.	\N	\N
26382004	Previewing distracters enhances the efficiency of visual search. Watson and Humphreys (1997) proposed that the preview benefit rests on visual marking, a mechanism which actively encodes distracter locations at preview and inhibits them afterwards at search. As Watson and Humphreys did, we used a letter-color search task to study constraints of visual marking in conjunction search and near-efficient single-feature search with single-colored and homogeneous distracter letters. Search performance was measured for fixed target and distracter features (block design) and for randomly changed features across trials (random design). In single-feature search there was a full preview benefit for both block and random designs. In conjunction search a full preview benefit was obtained only for the block design; randomly changing target and distracter features disrupted the preview benefit. However, the preview benefit was restored when the distracters were organized in spatially coherent blocks. These findings imply that the temporal segregation of old and new items is sufficient for visual marking in near-efficient single-feature search, while in conjunction search it is not. We propose a supplanting grouping principle for the preview benefit: When the new items add a new color, conjunction search is initialized and attentional resources are withdrawn from the marking mechanism. Visual marking can be restored by a second grouping principle that joins with temporal asynchrony. This principle can be either spatial or feature based. In the case of the latter, repetition priming is necessary to establish joint grouping by color and temporal asynchrony.	\N	\N
26463676	The effects of inner ear abnormality on audibility have been explored since the early 20th century when sound detection measures were first used to define and quantify 'hearing loss'. The development in the 1970s of objective measures of cochlear hair cell function (cochlear microphonics, otoacoustic emissions, summating potentials) and auditory nerve/brainstem activity (auditory brainstem responses) have made it possible to distinguish both synaptic and auditory nerve disorders from sensory receptor loss. This distinction is critically important when considering aetiology and management. In this review we address the clinical and pathophysiological features of auditory neuropathy that distinguish site(s) of dysfunction. We describe the diagnostic criteria for: (i) presynaptic disorders affecting inner hair cells and ribbon synapses; (ii) postsynaptic disorders affecting unmyelinated auditory nerve dendrites; (iii) postsynaptic disorders affecting auditory ganglion cells and their myelinated axons and dendrites; and (iv) central neural pathway disorders affecting the auditory brainstem. We review data and principles to identify treatment options for affected patients and explore their benefits as a function of site of lesion.	\N	\N
22284837	Best practices concerning the audiological management of the child diagnosed with auditory neuropathy spectrum disorder (ANSD) have not been definitively defined nor fully understood. One reason is that previous studies have demonstrated conflicting findings regarding the outcomes of cochlear implantation for children with ANSD. Thus, the question remains whether children with ANSD are able to achieve similar outcomes following cochlear implantation as those children with sensorineural hearing loss (SNHL). To assess speech perception outcomes for children with cochlear implants who have a diagnosis of ANSD as well as their age-matched peers who have sensorineural hearing loss. Retrospective study Thirty-five subject pairs (n = 70) ranging in age at implant activation from to 10 to 121 mo (mean 39.2 mo) were included in this retrospective study. Subjects were matched on variables including age at initial implant activation and months of implant use at postoperative test point. Speech recognition scores for monosyllabic and multisyllabic stimuli were compared across the subject groups. For those not developmentally and/or linguistically ready for completion of open-set speech recognition testing with recorded stimuli, GASP (Glendonald Auditory Screening Procedure) word recognition and/or questionnaire data using either the LittlEARS or Meaningful Auditory Integration Scale were compared across the groups. Statistical analysis using a repeated-measures analysis of variance (ANOVA) evaluated the effects of etiology (ANSD or SNHL) on postoperative outcomes. The results of this study demonstrate that children with ANSD can clearly benefit from cochlear implantation and that their long-term outcomes are similar to matched peers with SNHL on measures of speech recognition. There were no significant differences across the ANSD and SNHL groups on any of the tested measures. Cochlear implantation is a viable treatment option for children with a diagnosis of ANSD who are not making auditory progress with hearing aids that have been fit using the Desired Sensation Level method (DSL v5.0). Expected outcomes of cochlear implantation for children with ANSD, excluding children with cochlear nerve deficiency, are no different than for children with non-ANSD SNHL. These results are important for counseling families on the expected outcomes and realistic expectations following cochlear implantation for children with ANSD who demonstrate no evidence of cochlear nerve deficiency.	\N	\N
23935931	Auditory sensory modulation difficulties and problems with automatic re-orienting to sound are well documented in autism spectrum disorders (ASD). Abnormal preattentive arousal processes may contribute to these deficits. In this study, we investigated components of the cortical auditory evoked potential (CAEP) reflecting preattentive arousal in children with ASD and typically developing (TD) children aged 3-8 years. Pairs of clicks ('S1' and 'S2') separated by a 1 sec S1-S2 interstimulus interval (ISI) and much longer (8-10 sec) S1-S1 ISIs were presented monaurally to either the left or right ear. In TD children, the P50, P100 and N1c CAEP components were strongly influenced by temporal novelty of clicks and were much greater in response to the S1 than the S2 click. Irrespective of the stimulation side, the 'tangential' P100 component was rightward lateralized in TD children, whereas the 'radial' N1c component had higher amplitude contralaterally to the stimulated ear. Compared to the TD children, children with ASD demonstrated 1) reduced amplitude of the P100 component under the condition of temporal novelty (S1) and 2) an attenuated P100 repetition suppression effect. The abnormalities were lateralized and depended on the presentation side. They were evident in the case of the left but not the right ear stimulation. The P100 abnormalities in ASD correlated with the degree of developmental delay and with the severity of auditory sensory modulation difficulties observed in early life. The results suggest that some rightward-lateralized brain networks that are crucially important for arousal and attention re-orienting are compromised in children with ASD and that this deficit contributes to sensory modulation difficulties and possibly even other behavioral deficits in ASD.	\N	\N
21823798	In older adults, difficulties processing complex auditory scenes, such as speech comprehension in noisy environments, might be due to a specific impairment of temporal processing at early, automatic processing stages involving auditory sensory memory (ASM). Even though age effects on auditory temporal processing have been well-documented, there is a paucity of research on how ASM processing of more complex tone-patterns is altered by age. In the current study, age effects on ASM processing of temporal and frequency aspects of two-tone patterns were investigated using a passive listening protocol. The P1 component, the mismatch negativity (MMN) and the P3a component of event-related brain potentials (ERPs) to tone frequency and temporal pattern deviants were recorded in younger and older adults as a measure of auditory event detection, ASM processing, and attention switching, respectively. MMN was elicited with smaller amplitude to both frequency and temporal deviants in older adults. Furthermore, P3a was elicited only in the younger adults. In conclusion, the smaller MMN amplitude indicates that automatic processing of both frequency and temporal aspects of two-tone patterns is impaired in older adults. The failure to initiate an attention switch, suggested by the absence of P3a, indicates that impaired ASM processing of patterns may lead to less distractibility in older adults. Our results suggest age-related changes in ASM processing of patterns that cannot be explained by an inhibitory deficit.	\N	\N
19929331	Native language experience plays a critical role in shaping speech categorization, but the exact mechanisms by which it does so are not well understood. Investigating category learning of nonspeech sounds with which listeners have no prior experience allows their experience to be systematically controlled in a way that is impossible to achieve by studying natural speech acquisition, and it provides a means of probing the boundaries and constraints that general auditory perception and cognition bring to the task of speech category learning. In this study, we used a multimodal, video-game-based implicit learning paradigm to train participants to categorize acoustically complex, nonlinguistic sounds. MMN responses to the nonspeech stimuli were collected before and after training, and changes in MMN resulting from the nonspeech category learning closely resemble patterns of change typically observed during speech category learning. Results indicate that changes in mismatch negativity resulting from the nonspeech category learning closely resemble patterns of change typically observed during speech category learning. This suggests that the often-observed "specialized" neural responses to speech sounds may result, at least in part, from the expertise we develop with speech categories through experience rather than from properties unique to speech (e.g., linguistic or vocal tract gestural information). Furthermore, particular characteristics of the training paradigm may inform our understanding of mechanisms that support natural speech acquisition.	\N	\N
20578033	Understanding the basic neural processes that underlie complex higher-order cognitive operations and functional domains is a fundamental goal of cognitive neuroscience. Electroencephalography (EEG) is a non-invasive and relatively inexpensive method for assessing neurophysiological function that can be used to achieve this goal. EEG measures the electrical activity of large, synchronously firing populations of neurons in the brain with electrodes placed on the scalp. This unit outlines the basics of setting up an EEG experiment with human participants, including equipment, and a step-by-step guide to applying and preparing an electrode cap. Also included are support protocols for two event-related potential (ERP) paradigms, P50 suppression, and mismatch negativity (MMN), which are measures of early sensory processing. These paradigms can be used to assess the integrity of early sensory processing in normal individuals and clinical populations, such as individuals with schizophrenia.	\N	\N
20665718	Subjects detected rarely occurring shifts between two simple tone-patterns, in a paradigm that dissociated the effects of rarity from those of pitch, habituation, and attention. Whole-head magnetoencephalography suggested that rare attended pattern-shifts evoked activity first in the superior temporal plane (sTp, peak ~100 ms), then superior temporal sulcus (sTs, peak ~130 ms), then posteroventral prefrontal (pvpF, peak ~230 ms), and anterior temporal cortices (aT, peak ~370 ms). Activity was more prominent in the right hemisphere. After subtracting the effects of nonshift tones (balanced for pitch and habituation status), weak but consistent differential effects of pattern-shifts began in aT at 90-130 ms, spread to sTs and sTp at ∼130 ms, then pvpF, and finally returned to aT. Cingulate activity resembled prefrontal. Responses to pattern shifts were greatly attenuated when the same stimuli were ignored, suggesting that the initial superior temporal activity reflected an attention-related mismatch negativity. The prefrontal activity at ~230 ms corresponded in latency and task correlates with simultaneously recorded event-related potential components N2b and P3a; the subsequent temporal activity corresponded to the P3b. These results were confirmed in sensors specific for frontal or temporal cortex, and thus are independent of the inverse method used. Overall, these results suggest that auditory working memory for temporal patterns begins with detection of the pattern change by an interaction of anterior and superior temporal structures, followed by identification of the event and its consequences led by posteroventral prefrontal and cingulate cortices, and finally, definitive encoding of the event in anterior temporal areas.	\N	\N
20929535	We investigated the processing of task-irrelevant and unexpected novel sounds and its modulation by working-memory load in children aged 9-10 and in adults. Environmental sounds (novels) were embedded amongst frequently presented standard sounds in an auditory-visual distraction paradigm. Each sound was followed by a visual target. In two conditions, participants evaluated the position of a visual stimulus (0-back, low load) or compared the position of the current stimulus with the one two trials before (2-back, high load). Processing of novel sounds were measured with reaction times, hit rates and the auditory event-related brain potentials (ERPs) Mismatch Negativity (MMN), P3a, Reorienting Negativity (RON) and visual P3b. In both memory load conditions novels impaired task performance in adults whereas they improved performance in children. Auditory ERPs reflect age-related differences in the time-window of the MMN as children showed a positive ERP deflection to novels whereas adults lack an MMN. The attention switch towards the task irrelevant novel (reflected by P3a) was comparable between the age groups. Adults showed more efficient reallocation of attention (reflected by RON) under load condition than children. Finally, the P3b elicited by the visual target stimuli was reduced in both age groups when the preceding sound was a novel. Our results give new insights in the development of novelty processing as they (1) reveal that task-irrelevant novel sounds can result in contrary effects on the performance in a visual primary task in children and adults, (2) show a positive ERP deflection to novels rather than an MMN in children, and (3) reveal effects of auditory novels on visual target processing.	\N	\N
21368051	Certain features of objects or events can be represented by more than a single sensory system, such as roughness of a surface (sight, sound, and touch), the location of a speaker (audition and sight), and the rhythm or duration of an event (by all three major sensory systems). Thus, these properties can be said to be sensory-independent or amodal. A key question is whether common multisensory cortical regions process these amodal features, or does each sensory system contain its own specialized region(s) for processing common features? We tackled this issue by investigating simple duration-detection mechanisms across audition and touch; these systems were chosen because fine duration discriminations are possible in both. The mismatch negativity (MMN) component of the human event-related potential provides a sensitive metric of duration processing and has been elicited independently during both auditory and somatosensory investigations. Employing high-density electroencephalographic recordings in conjunction with intracranial subdural recordings, we asked whether fine duration discriminations, represented by the MMN, were generated in the same cortical regions regardless of the sensory modality being probed. Scalp recordings pointed to statistically distinct MMN topographies across senses, implying differential underlying cortical generator configurations. Intracranial recordings confirmed these noninvasive findings, showing generators of the auditory MMN along the superior temporal gyrus with no evidence of a somatosensory MMN in this region, whereas a robust somatosensory MMN was recorded from postcentral gyrus in the absence of an auditory MMN. The current data clearly argue against a common circuitry account for amodal duration processing.	\N	\N
21483666	Acute stress is a stereotypical, but multimodal response to a present or imminent challenge overcharging an organism. Among the different branches of this multimodal response, the consequences of glucocorticoid secretion have been extensively investigated, mostly in connection with long-term memory (LTM). However, stress responses comprise other endocrine signaling and altered neuronal activity wholly independent of pituitary regulation. To date, knowledge of the impact of such "paracorticoidal" stress responses on higher cognitive functions is scarce. We investigated the impact of an ecological stressor on the ability to direct selective attention using event-related potentials in humans. Based on research in rodents, we assumed that a stress-induced imbalance of catecholaminergic transmission would impair this ability. The stressor consisted of a single cold pressor test. Auditory negative difference (Nd) and mismatch negativity (MMN) were recorded in a tonal dichotic listening task. A time series of such tasks confirmed an increased distractibility occurring 4-7 minutes after onset of the stressor as reflected by an attenuated Nd. Salivary cortisol began to rise 8-11 minutes after onset when no further modulations in the event-related potentials (ERP) occurred, thus precluding a causal relationship. This effect may be attributed to a stress-induced activation of mesofrontal dopaminergic projections. It may also be attributed to an activation of noradrenergic projections. Known characteristics of the modulation of ERP by different stress-related ligands were used for further disambiguation of causality. The conjuncture of an attenuated Nd and an increased MMN might be interpreted as indicating a dopaminergic influence. The selective effect on the late portion of the Nd provides another tentative clue for this. Prior studies have deliberately tracked the adrenocortical influence on cognition, as it has proven most influential with respect to LTM. However, current cortisol-optimized study designs would have failed to detect the present findings regarding attention.	\N	\N
21750713	In the present study we investigated the capacity of the memory store underlying the mismatch negativity (MMN) response in musicians and nonmusicians for complex tone patterns. While previous studies have focused either on the kind of information that can be encoded or on the decay of the memory trace over time, we studied capacity in terms of the length of tone sequences, i.e., the number of individual tones that can be fully encoded and maintained. By means of magnetoencephalography (MEG) we recorded MMN responses to deviant tones that could occur at any position of standard tone patterns composed of four, six or eight tones during passive, distracted listening. Whereas there was a reliable MMN response to deviant tones in the four-tone pattern in both musicians and nonmusicians, only some individuals showed MMN responses to the longer patterns. This finding of a reliable capacity of the short-term auditory store underlying the MMN response is in line with estimates of a three to five item capacity of the short-term memory trace from behavioural studies, although pitch and contour complexity covaried with sequence length, which might have led to an understatement of the reported capacity. Whereas there was a tendency for an enhancement of the pattern MMN in musicians compared to nonmusicians, a strong advantage for musicians could be shown in an accompanying behavioural task of detecting the deviants while attending to the stimuli for all pattern lengths, indicating that long-term musical training differentially affects the memory capacity of auditory short-term memory for complex tone patterns with and without attention. Also, a left-hemispheric lateralization of MMN responses in the six-tone pattern suggests that additional networks that help structuring the patterns in the temporal domain might be recruited for demanding auditory processing in the pitch domain.	\N	\N
21808660	Have you ever shouted your child's name from the kitchen while they were watching television in the living room to no avail, so you shout their name again, only louder? Yet, still no response. The current study provides evidence that young children process loudness changes differently than pitch changes when they are engaged in another task such as watching a video. Intensity level changes were physiologically detected only when they were behaviorally relevant, but frequency level changes were physiologically detected without task relevance in younger children. This suggests that changes in pitch rather than changes in volume may be more effective in evoking a response when sounds are unexpected. Further, even though behavioral ability may appear to be similar in younger and older children, attention-based physiologic responses differ from automatic physiologic processes in children. Results indicate that 1) the automatic auditory processes leading to more efficient higher-level skills continue to become refined through childhood; and 2) there are different time courses for the maturation of physiological processes encoding the distinct acoustic attributes of sound pitch and sound intensity. The relevance of these findings to sound perception in real-world environments is discussed.	\N	\N
22163029	The detection of deviant sounds is a crucial function of the auditory system and is reflected by the automatically elicited mismatch negativity (MMN), an auditory evoked potential at 100 to 250 ms from stimulus onset. It has recently been shown that rarely occurring frequency and location deviants in an oddball paradigm trigger a more negative response than standard sounds at very early latencies in the middle latency response of the human auditory evoked potential. This fast and early ability of the auditory system is corroborated by the finding of neurons in the animal auditory cortex and subcortical structures, which restore their adapted responsiveness to standard sounds, when a rare change in a sound feature occurs. In this study, we investigated whether the detection of intensity deviants is also reflected at shorter latencies than those of the MMN. Auditory evoked potentials in response to click sounds were analyzed regarding the auditory brain stem response, the middle latency response (MLR) and the MMN. Rare stimuli with a lower intensity level than standard stimuli elicited (in addition to an MMN) a more negative potential in the MLR at the transition from the Na to the Pa component at circa 24 ms from stimulus onset. This finding, together with the studies about frequency and location changes, suggests that the early automatic detection of deviant sounds in an oddball paradigm is a general property of the auditory system.	\N	\N
22213909	Behavioural and electrophysiological studies give differing impressions of when auditory discrimination is mature. Ability to discriminate frequency and speech contrasts reaches adult levels only around 12 years of age, yet an electrophysiological index of auditory discrimination, the mismatch negativity (MMN), is reported to be as large in children as in adults. Auditory ERPs were measured in 30 children (7 to 12 years), 23 teenagers (13 to 16 years) and 32 adults (35 to 56 years) in an oddball paradigm with tone or syllable stimuli. For each stimulus type, a standard stimulus (1000 Hz tone or syllable [ba]) occurred on 70% of trials, and one of two deviants (1030 or 1200 Hz tone, or syllables [da] or [bi]) equiprobably on the remaining trials. For the traditional MMN interval of 100–250 ms post-onset, size of mismatch responses increased with age, whereas the opposite trend was seen for an interval from 300 to 550 ms post-onset, corresponding to the late discriminative negativity (LDN). Time-frequency analysis of single trials revealed that the MMN resulted from phase-synchronization of oscillations in the theta (4–7 Hz) range, with greater synchronization in adults than children. Furthermore, the amount of synchronization was significantly correlated with frequency discrimination threshold. These results show that neurophysiological processes underlying auditory discrimination continue to develop through childhood and adolescence. Previous reports of adult-like MMN amplitudes in children may be artefactual results of using peak measurements when comparing groups that differ in variance.	\N	\N
22221004	Deviations from repetitive auditory stimuli evoke a mismatch negativity (MMN). Counterintuitively, omissions of repetitive stimuli do not. Violations of patterns reflecting complex rules also evoke MMN. To detect a MMN to missing stimuli, we developed an auditory gestalt task using one stimulus. Groups of six pips (50 ms duration, 330 ms stimulus onset asynchrony [SOA], 400 trials), were presented with an intertrial interval (ITI) of 750 ms while subjects (n=16) watched a silent video. Occasional deviant groups had missing 4th or 6th tones (50 trials each). Missing stimuli evoked a MMN (p<.05). The missing 4th (-0.8 µV, p<.01) and the missing 6th stimuli (-1.1 µV, p<.05) were more negative than standard 6th stimuli (0.3 µV). MMN can be elicited by a missing stimulus at long SOAs by violation of a gestalt grouping rule. Patterned stimuli appear more sensitive to omissions and ITI than homogenous streams.	\N	\N
22551948	Recent studies show that electrophysiological markers of auditory processing such as the cortical 100 ms response (M100) and the mismatch field, derived from magnetoencephalography, might be used to identify children with autism spectrum disorders--M100 peak latency--and to stratify children with autism according to the degree of language impairment--mismatch field peak latency. The present study examined the latency of right superior temporal gyrus M100 and mismatch field in a cohort of children and young adolescents with specific language impairment (n=17), in comparison with age-matched and nonverbal intelligence quotient-matched typically developing controls (n=21). Neither group showed symptoms associated with autism. Although M100 latency (reflecting early auditory processing) did not distinguish controls from children with specific language impairment, the later 'change detection' mismatch field response was significantly delayed (by >50 ms) in the specific language impairment group. Linear discriminant analysis confirmed the role of mismatch field latency (92%) but not M100 latency (8%) in distinguishing groups. The present results lend support to the claim that a delayed M100 is specific to autism spectrum disorders (with relative independence of degree of language impairment) and that a delayed mismatch field reflects an abnormality more generally associated with language impairment, suggesting that mismatch field delay in the present specific language impairment group and previously reported in autistic children with language impairment may be indicative of a common neural system dysfunction.	\N	\N
22570723	Multisensory learning and resulting neural brain plasticity have recently become a topic of renewed interest in human cognitive neuroscience. Music notation reading is an ideal stimulus to study multisensory learning, as it allows studying the integration of visual, auditory and sensorimotor information processing. The present study aimed at answering whether multisensory learning alters uni-sensory structures, interconnections of uni-sensory structures or specific multisensory areas. In a short-term piano training procedure musically naive subjects were trained to play tone sequences from visually presented patterns in a music notation-like system [Auditory-Visual-Somatosensory group (AVS)], while another group received audio-visual training only that involved viewing the patterns and attentively listening to the recordings of the AVS training sessions [Auditory-Visual group (AV)]. Training-related changes in cortical networks were assessed by pre- and post-training magnetoencephalographic (MEG) recordings of an auditory, a visual and an integrated audio-visual mismatch negativity (MMN). The two groups (AVS and AV) were differently affected by the training. The results suggest that multisensory training alters the function of multisensory structures, and not the uni-sensory ones along with their interconnections, and thus provide an answer to an important question presented by cognitive models of multisensory training.	\N	\N
22815876	The precise neural mechanisms underlying speech sound representations are still a matter of debate. Proponents of 'sparse representations' assume that on the level of speech sounds, only contrastive or otherwise not predictable information is stored in long-term memory. Here, in a passive oddball paradigm, we challenge the neural foundations of such a 'sparse' representation; we use words that differ only in their penultimate consonant ("coronal" [t] vs. "dorsal" [k] place of articulation) and for example distinguish between the German nouns Latz ([lats]; bib) and Lachs ([laks]; salmon). Changes from standard [t] to deviant [k] and vice versa elicited a discernible Mismatch Negativity (MMN) response. Crucially, however, the MMN for the deviant [lats] was stronger than the MMN for the deviant [laks]. Source localization showed this difference to be due to enhanced brain activity in right superior temporal cortex. These findings reflect a difference in phonological 'sparsity': Coronal [t] segments, but not dorsal [k] segments, are based on more sparse representations and elicit less specific neural predictions; sensory deviations from this prediction are more readily 'tolerated' and accordingly trigger weaker MMNs. The results foster the neurocomputational reality of 'representationally sparse' models of speech perception that are compatible with more general predictive mechanisms in auditory perception.	\N	\N
22916282	Auditory deviance detection in humans is indexed by the mismatch negativity (MMN), a component of the auditory evoked potential (AEP) of the electroencephalogram (EEG) occurring at a latency of 100-250 ms after stimulus onset. However, by using classic oddball paradigms, differential responses to regularity violations of simple auditory features have been found at the level of the middle latency response (MLR) of the AEP occurring within the first 50 ms after stimulus (deviation) onset. These findings suggest the existence of fast deviance detection mechanisms for simple feature changes, but it is not clear whether deviance detection among more complex acoustic regularities could be observed at such early latencies. To test this, we examined the pre-attentive processing of rare stimulus repetitions in a sequence of tones alternating in frequency in both long and middle latency ranges. Additionally, we introduced occasional changes in the interaural time difference (ITD), so that a simple-feature regularity could be examined in the same paradigm. MMN was obtained for both repetition and ITD deviants, occurring at 150 ms and 100 ms after stimulus onset respectively. At the level of the MLR, a difference was observed between standards and ITD deviants at the Na component (20-30 ms after stimulus onset), for 800 Hz tones, but not for repetition deviants. These findings suggest that detection mechanisms for deviants to simple regularities, but not to more complex regularities, are already activated in the MLR range, supporting the view that the auditory deviance detection system is organized in a hierarchical manner.	\N	\N
23028971	For the perception of timbre of a musical instrument, the attack time is known to hold crucial information. The first 50 to 150 ms of sound onset reflect the excitation mechanism, which generates the sound. Since auditory processing and music perception in particular are known to be hampered in cochlear implant (CI) users, we conducted an electroencephalography (EEG) study with an oddball paradigm to evaluate the processing of small differences in musical sound onset. The first 60 ms of a cornet sound were manipulated in order to examine whether these differences are detected by CI users and normal-hearing controls (NH controls), as revealed by auditory evoked potentials (AEPs). Our analysis focused on the N1 as an exogenous component known to reflect physical stimuli properties as well as on the P2 and the Mismatch Negativity (MMN). Our results revealed different N1 latencies as well as P2 amplitudes and latencies for the onset manipulations in both groups. An MMN could be elicited only in the NH control group. Together with additional findings that suggest an impact of musical training on CI users' AEPs, our findings support the view that impaired timbre perception in CI users is at partly due to altered sound onset feature detection.	\N	\N
23131615	This study investigated whether the mismatch negativity (MMN) event-related brain potential (ERP) could be evoked by purely top-down, attentional control. An infrequently occurring tone was designated as a target prior to presenting a randomized sequence of five equi-probably occurring tones. MMN elicitation to the tones categorized as "high", "medium", or "low" frequency, and designated as the target, would indicate that the change detection process can be driven solely by top-down control. However, MMNs were not elicited by the categorized tones. Only the N2b and P3b attention-driven target detection components were elicited. These results suggest that top-down factors alone cannot generate mismatch negativity. Standard formation by stimulus-driven factors is required.	\N	\N
23241212	Coloured-hearing (CH) synesthesia is a perceptual phenomenon in which an acoustic stimulus (the inducer) initiates a concurrent colour perception (the concurrent). Individuals with CH synesthesia "see" colours when hearing tones, words, or music; this specific phenomenon suggesting a close relationship between auditory and visual representations. To date, it is still unknown whether the perception of colours is associated with a modulation of brain functions in the inducing brain area, namely in the auditory-related cortex and associated brain areas. In addition, there is an on-going debate as to whether attention to the inducer is necessarily required for eliciting a visual concurrent, or whether the latter can emerge in a pre-attentive fashion. By using the EEG technique in the context of a pre-attentive mismatch negativity (MMN) paradigm, we show that the binding of tones and colours in CH synesthetes is associated with increased MMN amplitudes in response to deviant tones supposed to induce novel concurrent colour perceptions. Most notably, the increased MMN amplitudes we revealed in the CH synesthetes were associated with stronger intracerebral current densities originating from the auditory cortex, parietal cortex, and ventral visual areas. The automatic binding of tones and colours in CH synesthetes is accompanied by an early pre-attentive process recruiting the auditory cortex, inferior and superior parietal lobules, as well as ventral occipital areas.	\N	\N
23308266	Computational and experimental research has revealed that auditory sensory predictions are derived from regularities of the current environment by using internal generative models. However, so far, what has not been addressed is how the auditory system handles situations giving rise to redundant or even contradictory predictions derived from different sources of information. To this end, we measured error signals in the event-related brain potentials (ERPs) in response to violations of auditory predictions. Sounds could be predicted on the basis of overall probability, i.e., one sound was presented frequently and another sound rarely. Furthermore, each sound was predicted by an informative visual cue. Participants' task was to use the cue and to discriminate the two sounds as fast as possible. Violations of the probability based prediction (i.e., a rare sound) as well as violations of the visual-auditory prediction (i.e., an incongruent sound) elicited error signals in the ERPs (Mismatch Negativity [MMN] and Incongruency Response [IR]). Particular error signals were observed even in case the overall probability and the visual symbol predicted different sounds. That is, the auditory system concurrently maintains and tests contradictory predictions. Moreover, if the same sound was predicted, we observed an additive error signal (scalp potential and primary current density) equaling the sum of the specific error signals. Thus, the auditory system maintains and tolerates functionally independently represented redundant and contradictory predictions. We argue that the auditory system exploits all currently active regularities in order to optimally prepare for future events.	\N	\N
23585888	To localize the neural generators of the musically elicited mismatch negativity with high temporal resolution we conducted a beamformer analysis (Synthetic Aperture Magnetometry, SAM) on magnetoencephalography (MEG) data from a previous musical mismatch study. The stimuli consisted of a six-tone melodic sequence comprising broken chords in C- and G-major. The musical sequence was presented within an oddball paradigm in which the last tone was lowered occasionally (20%) by a minor third. The beamforming analysis revealed significant right hemispheric neural activation in the superior temporal (STC), inferior frontal (IFC), superior frontal (SFC) and orbitofrontal (OFC) cortices within a time window of 100-200 ms after the occurrence of a deviant tone. IFC and SFC activation was also observed in the left hemisphere. The pronounced early right inferior frontal activation of the auditory mismatch negativity has not been shown in MEG studies so far. The activation in STC and IFC is consistent with earlier electroencephalography (EEG), optical imaging and functional magnetic resonance imaging (fMRI) studies that reveal the auditory and inferior frontal cortices as main generators of the auditory MMN. The observed right hemispheric IFC is also in line with some previous music studies showing similar activation patterns after harmonic syntactic violations. The results demonstrate that a deviant tone within a musical sequence recruits immediately a distributed neural network in frontal and prefrontal areas suggesting that top-down processes are involved when expectation violation occurs within well-known stimuli.	\N	\N
23617597	The human auditory cortex automatically encodes acoustic input from the environment and differentiates regular sound patterns from deviant ones in order to identify important, irregular events. The Mismatch Negativity (MMN) response is a neuronal marker for the detection of sounds that are unexpected, based on the encoded regularities. It is also elicited by violations of more complex regularities and musical expertise has been shown to have an effect on the processing of complex regularities. Using magnetoencephalography (MEG), we investigated the MMN response to salient or less salient deviants by varying the standard probability (70%, 50% and 35%) of a pattern oddball paradigm. To study the effects of musical expertise in the encoding of the patterns, we compared the responses of a group of non-musicians to those of musicians. We observed significant MMN in all conditions, including the least salient condition (35% standards), in response to violations of the predominant tone pattern for both groups. The amplitude of MMN from the right hemisphere was influenced by the standard probability. This effect was modulated by long-term musical training: standard probability changes influenced MMN amplitude in the group of non-musicians only. This study indicates that pattern violations are detected automatically, even if they are of very low salience, both in non-musicians and musicians, with salience having a stronger impact on processing in the right hemisphere of non-musicians. Long-term musical training influences this encoding, in that non-musicians benefit to a greater extent from a good signal-to-noise ratio (i.e. high probability of the standard pattern), while musicians are less dependent on the salience of an acoustic environment.	\N	\N
23708059	The auditory system is organized such that progressively more complex features are represented across successive cortical hierarchical stages. Just when and where the processing of phonemes, fundamental elements of the speech signal, is achieved in this hierarchy remains a matter of vigorous debate. Non-invasive measures of phonemic representation have been somewhat equivocal. While some studies point to a primary role for middle/anterior regions of the superior temporal gyrus (STG), others implicate the posterior STG. Differences in stimulation, task and inter-individual anatomical/functional variability may account for these discrepant findings. Here, we sought to clarify this issue by mapping phonemic representation across left perisylvian cortex, taking advantage of the excellent sampling density afforded by intracranial recordings in humans. We asked whether one or both major divisions of the STG were sensitive to phonemic transitions. The high signal-to-noise characteristics of direct intracranial recordings allowed for analysis at the individual participant level, circumventing issues of inter-individual anatomic and functional variability that may have obscured previous findings at the group level of analysis. The mismatch negativity (MMN), an electrophysiological response elicited by changes in repetitive streams of stimulation, served as our primary dependent measure. Oddball configurations of pairs of phonemes, spectro-temporally matched non-phonemes, and simple tones were presented. The loci of the MMN clearly differed as a function of stimulus type. Phoneme representation was most robust over middle/anterior STG/STS, but was also observed over posterior STG/SMG. These data point to multiple phonemic processing zones along perisylvian cortex, both anterior and posterior to primary auditory cortex. This finding is considered within the context of a dual stream model of auditory processing in which functionally distinct ventral and dorsal auditory processing pathways may be engaged by speech stimuli.	\N	\N
23715097	In this study, we used magnetoencephalography and a mismatch paradigm to investigate speech processing in stroke patients with auditory comprehension deficits and age-matched control subjects. We probed connectivity within and between the two temporal lobes in response to phonemic (different word) and acoustic (same word) oddballs using dynamic causal modelling. We found stronger modulation of self-connections as a function of phonemic differences for control subjects versus aphasics in left primary auditory cortex and bilateral superior temporal gyrus. The patients showed stronger modulation of connections from right primary auditory cortex to right superior temporal gyrus (feed-forward) and from left primary auditory cortex to right primary auditory cortex (interhemispheric). This differential connectivity can be explained on the basis of a predictive coding theory which suggests increased prediction error and decreased sensitivity to phonemic boundaries in the aphasics' speech network in both hemispheres. Within the aphasics, we also found behavioural correlates with connection strengths: a negative correlation between phonemic perception and an inter-hemispheric connection (left superior temporal gyrus to right superior temporal gyrus), and positive correlation between semantic performance and a feedback connection (right superior temporal gyrus to right primary auditory cortex). Our results suggest that aphasics with impaired speech comprehension have less veridical speech representations in both temporal lobes, and rely more on the right hemisphere auditory regions, particularly right superior temporal gyrus, for processing speech. Despite this presumed compensatory shift in network connectivity, the patients remain significantly impaired.	\N	\N
23825422	Hierarchical predictive coding suggests that attention in humans emerges from increased precision in probabilistic inference, whereas expectation biases attention in favor of contextually anticipated stimuli. We test these notions within auditory perception by independently manipulating top-down expectation and attentional precision alongside bottom-up stimulus predictability. Our findings support an integrative interpretation of commonly observed electrophysiological signatures of neurodynamics, namely mismatch negativity (MMN), P300, and contingent negative variation (CNV), as manifestations along successive levels of predictive complexity. Early first-level processing indexed by the MMN was sensitive to stimulus predictability: here, attentional precision enhanced early responses, but explicit top-down expectation diminished it. This pattern was in contrast to later, second-level processing indexed by the P300: although sensitive to the degree of predictability, responses at this level were contingent on attentional engagement and in fact sharpened by top-down expectation. At the highest level, the drift of the CNV was a fine-grained marker of top-down expectation itself. Source reconstruction of high-density EEG, supported by intracranial recordings, implicated temporal and frontal regions differentially active at early and late levels. The cortical generators of the CNV suggested that it might be involved in facilitating the consolidation of context-salient stimuli into conscious perception. These results provide convergent empirical support to promising recent accounts of attention and expectation in predictive coding.	\N	\N
23850664	Over the last four decades, a range of different neuroimaging tools have been used to study human auditory attention, spanning from classic event-related potential studies using electroencephalography to modern multimodal imaging approaches (e.g., combining anatomical information based on magnetic resonance imaging with magneto- and electroencephalography). This review begins by exploring the different strengths and limitations inherent to different neuroimaging methods, and then outlines some common behavioral paradigms that have been adopted to study auditory attention. We argue that in order to design a neuroimaging experiment that produces interpretable, unambiguous results, the experimenter must not only have a deep appreciation of the imaging technique employed, but also a sophisticated understanding of perception and behavior. Only with the proper caveats in mind can one begin to infer how the cortex supports a human in solving the "cocktail party" problem. This article is part of a Special Issue entitled Human Auditory Neuroimaging.	\N	\N
23886958	The purpose of the study was to test the hypothesis that sound context modulates the magnitude of auditory distraction, indexed by behavioral and electrophysiological measures. Participants were asked to identify tone duration, while irrelevant changes occurred in tone frequency, tone intensity, and harmonic structure. Frequency deviants were randomly intermixed with standards (Uni-Condition), with intensity deviants (Bi-Condition), and with both intensity and complex deviants (Tri-Condition). Only in the Tri-Condition did the auditory distraction effect reflect the magnitude difference among the frequency and intensity deviants. The mixture of the different types of deviants in the Tri-Condition modulated the perceived level of distraction, demonstrating that the sound context can modulate the effect of deviance level on processing irrelevant acoustic changes in the environment. These findings thus indicate that perceptual contrast plays a role in change detection processes that leads to auditory distraction.	\N	\N
23920129	A better understanding of melodic pitch perception in cochlear implants (CIs) may guide signal processing and/or rehabilitation techniques to improve music perception and appreciation in CI patients. In this study, the mismatch negativity (MMN) in response to infrequent changes in 5-tone pitch contours was obtained in CI users and normal-hearing (NH) listeners. Melodic contour identification (MCI) was also measured. Results showed that MCI performance was poorer in CI than in NH subjects; the MMNs were missing in all CI subjects for the 1-semitone contours. The MMNs with the 5-semitone contours were observed in a smaller proportion of CI than NH subjects. Results suggest that encoding of pitch contour changes in CI users appears to be degraded, most likely due to the limited pitch cues provided by the CI and deafness-related compromise of brain substrates.	\N	\N
24143195	Unexpected physical increases in the intensity of a frequently occurring "standard" auditory stimulus are experienced as obtrusive. This could either be because of a physical change, the increase in intensity of the "deviant" stimulus, or a psychological change, the violation of the expectancy for the occurrence of the lower intensity standard stimulus. Two experiments were run in which event-related potentials (ERPs) were recorded to determine whether "psychological" increments (violation of an expectancy for a lower intensity) would be processed differently than psychological decrements (violation of an expectancy for a higher intensity). Event-related potentials (ERPs) were recorded while subjects were presented with auditory tones that alternated between low and high intensity. The subjects ignored the auditory stimuli while watching a video. Deviants were created by repeating the same stimulus. In the first experiment, pairs of stimuli alternating in intensity, were presented in separate increment (H-L...H-L...H-H...H-L, in which H = 80 dB SPL and L = 60 dB SPL) and decrement conditions (L-H...L-H...L-L... L-H, in which H = 90 dB SPL and L = 80 dB SPL). The paradigm employed in the second experiment consisted of an alternating intensity pattern (H-L-H-L-H-H-H-L) or (H-L-H-L-L-L-H-L). Importantly, the stimulus prior to the deviant (the standard) and the actual deviants in both increment and decrement conditions in both experiments were physically identical (80 dB SPL tones). The repetition of the lower intensity tone therefore acted as a psychological rather than a physical decrement (a higher intensity tone was expected) while the repetition of the higher intensity tone acted as a psychological increment (a lower intensity tone was expected). The psychological increments in both experiments elicited a larger amplitude mismatch negativity (MMN) than the decrements. Thus, regardless of whether an acoustic change signals a physical increase in intensity or violates an expected decrease in intensity, a large MMN will be elicited.	\N	\N
24158725	The goal of this review article is to redefine what the mismatch negativity (MMN) component of event-related potentials reflects in auditory scene analysis, and to provide an overview of how the MMN serves as a valuable tool in Cognitive Neuroscience research. In doing so, some of the old beliefs (five common 'myths') about MMN will be dispelled, such as the notion that MMN is a simple feature discriminator and that attention itself modulates MMN elicitation. A revised description of what MMN truly reflects will be provided, which includes a principal focus onto the highly context-dependent nature of MMN elicitation and new terminology to discuss MMN and attention. This revised framework will help clarify what has been a long line of seemingly contradictory results from studies in which behavioral ability to hear differences between sounds and passive elicitation of MMN have been inconsistent. Understanding what MMN is will also benefit clinical research efforts by providing a new picture of how to design appropriate paradigms suited to various clinical populations.	\N	\N
24366694	One of the major challenges in human brain science is the functional hemispheric asymmetry of auditory processing. Behavioral and neurophysiological studies have demonstrated that speech processing is dominantly handled in the left hemisphere, whereas music processing dominantly occurs in the right. Using magnetoencephalography, we measured the auditory mismatch negativity elicited by band-pass filtered click-trains, which deviated from frequently presented standard sound signals in a spectral or temporal domain. The results showed that spectral and temporal deviants were dominantly processed in the right and left hemispheres, respectively. Hemispheric asymmetry was not limited to high-level cognitive processes, but also originated from the pre-attentive neural processing stage represented by mismatch negativity.	\N	\N
24475052	The brain response to auditory novelty comprises two main eeg components: an early mismatch negativity and a late P300. Whereas the former has been proposed to reflect a prediction error, the latter is often associated with working memory updating. Interestingly, these two proposals predict fundamentally different dynamics: prediction errors are thought to propagate serially through several distinct brain areas, while working memory supposes that activity is sustained over time within a stable set of brain areas. Here we test this temporal dissociation by showing how the generalization of brain activity patterns across time can characterize the dynamics of the underlying neural processes. This method is applied to magnetoencephalography (MEG) recordings acquired from healthy participants who were presented with two types of auditory novelty. Following our predictions, the results show that the mismatch evoked by a local novelty leads to the sequential recruitment of distinct and short-lived patterns of brain activity. In sharp contrast, the global novelty evoked by an unexpected sequence of five sounds elicits a sustained state of brain activity that lasts for several hundreds of milliseconds. The present results highlight how MEG combined with multivariate pattern analyses can characterize the dynamics of human cortical processes.	\N	\N
24548430	Natural sound environments are dynamic, with overlapping acoustic input originating from simultaneously active sources. A key function of the auditory system is to integrate sensory inputs that belong together and segregate those that come from different sources. We hypothesized that this skill is impaired in individuals with phonological processing difficulties. There is considerable disagreement about whether phonological impairments observed in children with developmental language disorders can be attributed to specific linguistic deficits or to more general acoustic processing deficits. However, most tests of general auditory abilities have been conducted with a single set of sounds. We assessed the ability of school-aged children (7-15 years) to parse complex auditory non-speech input, and determined whether the presence of phonological processing impairments was associated with stream perception performance. A key finding was that children with language impairments did not show the same developmental trajectory for stream perception as typically developing children. In addition, children with language impairments required larger frequency separations between sounds to hear distinct streams compared to age-matched peers. Furthermore, phonological processing ability was a significant predictor of stream perception measures, but only in the older age groups. No such association was found in the youngest children. These results indicate that children with language impairments have difficulty parsing speech streams, or identifying individual sound events when there are competing sound sources. We conclude that language group differences may in part reflect fundamental maturational disparities in the analysis of complex auditory scenes.	\N	\N
24771006	Detecting regularity and change in the environment is crucial for survival, as it enables making predictions about the world and informing goal-directed behavior. In the auditory modality, the detection of regularity involves segregating incoming sounds into distinct perceptual objects (stream segregation). The detection of change from this within-stream regularity is associated with the mismatch negativity, a component of auditory event-related brain potentials (ERPs). A central unanswered question is how the detection of regularity and the detection of change are interrelated, and whether attention affects the former, the latter, or both. Here we show that the detection of regularity and the detection of change can be empirically dissociated, and that attention modulates the detection of change without precluding the detection of regularity, and the perceptual organization of the auditory background into distinct streams. By applying frequency spectra analysis on the EEG of subjects engaged in a selective listening task, we found distinct peaks of ERP synchronization, corresponding to the rhythm of the frequency streams, independently of whether the stream was attended or ignored. Our results provide direct neurophysiological evidence of regularity detection in the auditory background, and show that it can occur independently of change detection and in the absence of attention.	\N	\N
25178752	The ability to read passages of information fluently and with comprehension is a basic component of socioeconomic success. Reading ability depends on the integrity of underlying visual and auditory (phonological) systems. This study investigated the integrity of reading ability in schizophrenia relative to the integrity of underlying visual and auditory function. The participants were 45 schizophrenia patients, 19 clinical high-risk patients, and 65 comparison subjects. Reading was assessed using tests sensitive to visual or phonological reading dysfunction. Sensory, neuropsychological, and functional outcome measures were also obtained. Schizophrenia patients displayed reading deficits that were far more severe (effect size >2.0) than would be predicted based on general neurocognitive impairments (effect size 1.0-1.4). The deficits correlated highly with both visual and auditory sensory measures, including impaired mismatch negativity generation (r=0.62, N=51, p=0.0002). Patients with established schizophrenia displayed both visual and phonological impairments, whereas high-risk patients showed isolated visual impairments. More than 70% of schizophrenia patients met criteria for acquired dyslexia, with 50% reading below eighth grade level despite intact premorbid reading ability. Reading deficits also correlated significantly (rp=0.4, N=30, p=0.03) with failure to match parental socioeconomic achievement, over and above contributions of more general cognitive impairment. Patients with schizophrenia display severe deficits in reading ability that represent a potentially remediable cause of impaired socioeconomic function. Such deficits are not presently captured during routine clinical assessment. Deficits most likely develop during the years immediately surrounding illness onset and may contribute to the reduced educational and occupational achievement associated with schizophrenia.	\N	\N
25231619	In animal models, single-neuron response properties such as stimulus-specific adaptation have been described as possible precursors to mismatch negativity, a human brain response to stimulus change. In the present study, we attempted to bridge the gap between human and animal studies by characterising responses to changes in the frequency of repeated tone series in the anesthetised guinea pig using small-animal magnetoencephalography (MEG). We showed that 1) auditory evoked fields (AEFs) qualitatively similar to those observed in human MEG studies can be detected noninvasively in rodents using small-animal MEG; 2) guinea pig AEF amplitudes reduce rapidly with tone repetition, and this AEF reduction is largely complete by the second tone in a repeated series; and 3) differences between responses to the first (deviant) and later (standard) tones after a frequency transition resemble those previously observed in awake humans using a similar stimulus paradigm.	\N	\N
25342520	Neurofeedback is a strong direct training method for brain function, wherein brain activity patterns are measured and displayed as feedback, and trainees try to stabilize the feedback signal onto certain desirable states to regulate their own mental states. Here, we introduce a novel neurofeedback method, using the mismatch negativity (MMN) responses elicited by similar sounds that cannot be consciously discriminated. Through neurofeedback training, without participants' attention to the auditory stimuli or awareness of what was to be learned, we found that the participants could unconsciously achieve a significant improvement in the auditory discrimination of the applied stimuli. Our method has great potential to provide effortless auditory perceptual training. Based on this method, participants do not need to make an effort to discriminate auditory stimuli, and can choose tasks of interest without boredom due to training. In particular, it could be used to train people to recognize speech sounds that do not exist in their native language and thereby facilitate foreign language learning.	\N	\N
25379456	Although sensory processing abnormalities contribute to widespread cognitive and psychosocial impairments in schizophrenia (SZ) patients, scalp-channel measures of averaged event-related potentials (ERPs) mix contributions from distinct cortical source-area generators, diluting the functional relevance of channel-based ERP measures. SZ patients (n = 42) and non-psychiatric comparison subjects (n = 47) participated in a passive auditory duration oddball paradigm, eliciting a triphasic (Deviant-Standard) tone ERP difference complex, here termed the auditory deviance response (ADR), comprised of a mid-frontal mismatch negativity (MMN), P3a positivity, and re-orienting negativity (RON) peak sequence. To identify its cortical sources and to assess possible relationships between their response contributions and clinical SZ measures, we applied independent component analysis to the continuous 68-channel EEG data and clustered the resulting independent components (ICs) across subjects on spectral, ERP, and topographic similarities. Six IC clusters centered in right superior temporal, right inferior frontal, ventral mid-cingulate, anterior cingulate, medial orbitofrontal, and dorsal mid-cingulate cortex each made triphasic response contributions. Although correlations between measures of SZ clinical, cognitive, and psychosocial functioning and standard (Fz) scalp-channel ADR peak measures were weak or absent, for at least four IC clusters one or more significant correlations emerged. In particular, differences in MMN peak amplitude in the right superior temporal IC cluster accounted for 48% of the variance in SZ-subject performance on tasks necessary for real-world functioning and medial orbitofrontal cluster P3a amplitude accounted for 40%/54% of SZ-subject variance in positive/negative symptoms. Thus, source-resolved auditory deviance response measures including MMN may be highly sensitive to SZ clinical, cognitive, and functional characteristics.	\N	\N
21159322	Phonology is a lower-level structural aspect of language involving the sounds of a language and their organization in that language. Numerous behavioral studies utilizing priming, which refers to an increased sensitivity to a stimulus following prior experience with that or a related stimulus, have provided evidence for the role of phonology in visual word recognition. However, most language studies utilizing priming in conjunction with functional magnetic resonance imaging (fMRI) have focused on lexical-semantic aspects of language processing. The aim of the present study was to investigate the neurobiological substrates of the automatic, implicit stages of phonological processing. While undergoing fMRI, eighteen individuals performed a lexical decision task (LDT) on prime-target pairs including word-word homophone and pseudoword-word pseudohomophone pairs with a prime presentation below perceptual threshold. Whole-brain analyses revealed several cortical regions exhibiting hemodynamic response suppression due to phonological priming including bilateral superior temporal gyri (STG), middle temporal gyri (MTG), and angular gyri (AG) with additional region of interest (ROI) analyses revealing response suppression in the left lateralized supramarginal gyrus (SMG). Homophone and pseudohomophone priming also resulted in different patterns of hemodynamic responses relative to one another. These results suggest that phonological processing plays a key role in visual word recognition. Furthermore, enhanced hemodynamic responses for unrelated stimuli relative to primed stimuli were observed in midline cortical regions corresponding to the default-mode network (DMN) suggesting that DMN activity can be modulated by task requirements within the context of an implicit task.	\N	\N
21500313	The effects of neural activity on cerebral hemodynamics underlie human brain imaging with functional magnetic resonance imaging and positron emission tomography. However, the threshold and characteristics of the converse effects, wherein the cerebral hemodynamic and metabolic milieu influence neural activity, remain unclear. We tested whether mild hypercapnia (5% CO2 ) decreases the magnetoencephalogram response to auditory pattern recognition and visual semantic tasks. Hypercapnia induced statistically significant decreases in event-related fields without affecting behavioral performance. Decreases were observed in early sensory components in both auditory and visual modalities as well as later cognitive components related to memory and language. Effects were distributed across cortical regions. Decreases were comparable in evoked versus spontaneous spectral power. Hypercapnia is commonly used with hemodynamic models to calibrate the blood oxygenation level-dependent response. Modifying model assumptions to incorporate the current findings produce a modest but measurable decrease in the estimated cerebral metabolic rate for oxygen change with activation. Because under normal conditions, low cerebral pH would arise when bloodflow is unable to keep pace with neuronal activity, the cortical depression observed here may reflect a homeostatic mechanism by which neuronal activity is adjusted to a level that can be sustained by available bloodflow. Animal studies suggest that these effects may be mediated by pH-modulating presynaptic adenosine receptors. Although the data is not clear, comparable changes in cortical pH to those induced here may occur during sleep apnea, sleep, and exercise. If so, these results suggest that such activities may in turn have generalized depressive effects on cortical activity.	\N	\N
22496909	Understanding how the brain processes stimuli in a rich natural environment is a fundamental goal of neuroscience. Here, we showed a feature film to 10 healthy volunteers during functional magnetic resonance imaging (fMRI) of hemodynamic brain activity. We then annotated auditory and visual features of the motion picture to inform analysis of the hemodynamic data. The annotations were fitted to both voxel-wise data and brain network time courses extracted by independent component analysis (ICA). Auditory annotations correlated with two independent components (IC) disclosing two functional networks, one responding to variety of auditory stimulation and another responding preferentially to speech but parts of the network also responding to non-verbal communication. Visual feature annotations correlated with four ICs delineating visual areas according to their sensitivity to different visual stimulus features. In comparison, a separate voxel-wise general linear model based analysis disclosed brain areas preferentially responding to sound energy, speech, music, visual contrast edges, body motion and hand motion which largely overlapped the results revealed by ICA. Differences between the results of IC- and voxel-based analyses demonstrate that thorough analysis of voxel time courses is important for understanding the activity of specific sub-areas of the functional networks, while ICA is a valuable tool for revealing novel information about functional connectivity which need not be explained by the predefined model. Our results encourage the use of naturalistic stimuli and tasks in cognitive neuroimaging to study how the brain processes stimuli in rich natural environments.	\N	\N
23777481	Numerous studies have provided clues about the ontogeny of lateralization of auditory processing in humans, but most have employed specific subtypes of stimuli and/or have assessed responses in discrete temporal windows. The present study used near-infrared spectroscopy (NIRS) to establish changes in hemodynamic activity in the neocortex of preverbal infants (aged 4-11 months) while they were exposed to two distinct types of complex auditory stimuli (full sentences and musical phrases). Measurements were taken from bilateral temporal regions, including both anterior and posterior superior temporal gyri. When the infant sample was treated as a homogenous group, no significant effects emerged for stimulus type. However, when infants' hemodynamic responses were categorized according to their overall changes in volume, two very clear neurophysiological patterns emerged. A high-responder group showed a pattern of early and increasing activation, primarily in the left hemisphere, similar to that observed in comparable studies with adults. In contrast, a low-responder group showed a pattern of gradual decreases in activation over time. Although age did track with responder type, no significant differences between these groups emerged for stimulus type, suggesting that the high- versus low-responder characterization generalizes across classes of auditory stimuli. These results highlight a new way to conceptualize the variable cortical blood flow patterns that are frequently observed across infants and stimuli, with hemodynamic response volumes potentially serving as an early indicator of developmental changes in auditory-processing sensitivity.	\N	\N
22786953	Auditory spatial perception plays a critical role in day-to-day communication. For instance, listeners utilize acoustic spatial information to segregate individual talkers into distinct auditory "streams" to improve speech intelligibility. However, spatial localization is an exceedingly difficult task in everyday listening environments with numerous distracting echoes from nearby surfaces, such as walls. Listeners' brains overcome this unique challenge by relying on acoustic timing and, quite surprisingly, visual spatial information to suppress short-latency (1-10 ms) echoes through a process known as "the precedence effect" or "echo suppression." In the present study, we employed electroencephalography (EEG) to investigate the neural time course of echo suppression both with and without the aid of coincident visual stimulation in human listeners. We find that echo suppression is a multistage process initialized during the auditory N1 (70-100 ms) and followed by space-specific suppression mechanisms from 150 to 250 ms. Additionally, we find a robust correlate of listeners' spatial perception (i.e., suppressing or not suppressing the echo) over central electrode sites from 300 to 500 ms. Contrary to our hypothesis, vision's powerful contribution to echo suppression occurs late in processing (250-400 ms), suggesting that vision contributes primarily during late sensory or decision making processes. Together, our findings support growing evidence that echo suppression is a slow, progressive mechanism modifiable by visual influences during late sensory and decision making stages. Furthermore, our findings suggest that audiovisual interactions are not limited to early, sensory-level modulations but extend well into late stages of cortical processing.	\N	\N
25710328	To form a veridical percept of the environment, the brain needs to integrate sensory signals from a common source but segregate those from independent sources. Thus, perception inherently relies on solving the "causal inference problem." Behaviorally, humans solve this problem optimally as predicted by Bayesian Causal Inference; yet, the underlying neural mechanisms are unexplored. Combining psychophysics, Bayesian modeling, functional magnetic resonance imaging (fMRI), and multivariate decoding in an audiovisual spatial localization task, we demonstrate that Bayesian Causal Inference is performed by a hierarchy of multisensory processes in the human brain. At the bottom of the hierarchy, in auditory and visual areas, location is represented on the basis that the two signals are generated by independent sources (= segregation). At the next stage, in posterior intraparietal sulcus, location is estimated under the assumption that the two signals are from a common source (= forced fusion). Only at the top of the hierarchy, in anterior intraparietal sulcus, the uncertainty about the causal structure of the world is taken into account and sensory signals are combined as predicted by Bayesian Causal Inference. Characterizing the computational operations of signal interactions reveals the hierarchical nature of multisensory perception in human neocortex. It unravels how the brain accomplishes Bayesian Causal Inference, a statistical computation fundamental for perception and cognition. Our results demonstrate how the brain combines information in the face of uncertainty about the underlying causal structure of the world.	\N	\N
20146608	The neural responses to sensory consequences of a self-produced motor act are suppressed compared with those in response to a similar but externally generated stimulus. Previous studies in the somatosensory and auditory systems have shown that the motor-induced suppression of the sensory mechanisms is sensitive to delays between the motor act and the onset of the stimulus. The present study investigated time-dependent neural processing of auditory feedback in response to self-produced vocalizations. ERPs were recorded in response to normal and pitch-shifted voice auditory feedback during active vocalization and passive listening to the playback of the same vocalizations. The pitch-shifted stimulus was delivered to the subjects' auditory feedback after a randomly chosen time delay between the vocal onset and the stimulus presentation. Results showed that the neural responses to delayed feedback perturbations were significantly larger than those in response to the pitch-shifted stimulus occurring at vocal onset. Active vocalization was shown to enhance neural responsiveness to feedback alterations only for nonzero delays compared with passive listening to the playback. These findings indicated that the neural mechanisms of auditory feedback processing are sensitive to timing between the vocal motor commands and the incoming auditory feedback. Time-dependent neural processing of auditory feedback may be an important feature of the audio-vocal integration system that helps to improve the feedback-based monitoring and control of voice structure through vocal error detection and correction.	\N	\N
20493828	Magnetoencephalography (MEG) is an increasingly popular non-invasive tool used to record, on a millisecond timescale, the magnetic field changes generated by cortical neural activity. MEG has the advantage, over fMRI for example, that it is a direct measure of neural activity. In the current investigation we used MEG to measure cortical responses to tactile and auditory stimuli in the macaque monkey. We had two aims. First, we sought to determine whether MEG, a technique that may have low spatial accuracy, could be used to distinguish the location and organization of sensory cortical fields in macaque monkeys, a species with a relatively small brain compared to that of the human. Second, we wanted to examine the temporal dynamics of cortical responses in the macaque monkey relative to the human. We recorded MEG data from anesthetized monkeys and, for comparison, from awake humans that were presented with simple tactile and auditory stimuli. Neural source reconstruction of MEG data showed that primary somatosensory and auditory cortex could be differentiated and, further, that separate representations of the digit and lip within somatosensory cortex could be identified in macaque monkeys as well as humans. We compared the latencies of activity from monkey and human data for the three stimulation types and proposed a correspondence between the neural responses of the two species. We thus demonstrate the feasibility of using MEG in the macaque monkey and provide a non-human primate model for examining the relationship between external evoked magnetic fields and their underlying neural sources.	\N	\N
20598152	The detection of any abrupt change in the environment is important to survival. Since memory of preceding sensory conditions is necessary for detecting changes, such a change-detection system relates closely to the memory system. Here we used an auditory change-related N1 subcomponent (change-N1) of event-related brain potentials to investigate cortical mechanisms underlying change detection and echoic memory. Change-N1 was elicited by a simple paradigm with two tones, a standard followed by a deviant, while subjects watched a silent movie. The amplitude of change-N1 elicited by a fixed sound pressure deviance (70 dB vs. 75 dB) was negatively correlated with the logarithm of the interval between the standard sound and deviant sound (1, 10, 100, or 1000 ms), while positively correlated with the logarithm of the duration of the standard sound (25, 100, 500, or 1000 ms). The amplitude of change-N1 elicited by a deviance in sound pressure, sound frequency, and sound location was correlated with the logarithm of the magnitude of physical differences between the standard and deviant sounds. The present findings suggest that temporal representation of echoic memory is non-linear and Weber-Fechner law holds for the automatic cortical response to sound changes within a suprathreshold range. Since the present results show that the behavior of echoic memory can be understood through change-N1, change-N1 would be a useful tool to investigate memory systems.	\N	\N
20633569	Studies in all sensory modalities have demonstrated amplification of early brain responses to attended signals, but less is known about the processes by which listeners selectively ignore stimuli. Here we use MEG and a new paradigm to dissociate the effects of selectively attending, and ignoring in time. Two different tasks were performed successively on the same acoustic stimuli: triplets of tones (A, B, C) with noise-bursts interspersed between the triplets. In the COMPARE task subjects were instructed to respond when tones A and C were of same frequency. In the PASSIVE task they were instructed to respond as fast as possible to noise-bursts. COMPARE requires attending to A and C and actively ignoring tone B, but PASSIVE involves neither attending to nor ignoring the tones. The data were analyzed separately for frontal and auditory-cortical channels to independently address attentional effects on low-level sensory versus putative control processing. We observe the earliest attend/ignore effects as early as 100 ms post-stimulus onset in auditory cortex. These appear to be generated by modulation of exogenous (stimulus-driven) sensory evoked activity. Specifically related to ignoring, we demonstrate that active-ignoring-induced input inhibition involves early selection. We identified a sequence of early (<200 ms post-onset) auditory cortical effects, comprised of onset response attenuation and the emergence of an inhibitory response, and provide new, direct evidence that listeners actively ignoring a sound can reduce their stimulus related activity in auditory cortex by 100 ms after onset when this is required to execute specific behavioral objectives.	\N	\N
21233780	The neural origins of the cortical response to rare sensory events remain poorly understood. Using simultaneous event-related potentials and magnetic resonance imaging, we investigated the anatomical profile of regional activity at various processing stages during performance of auditory and visual variants of an oddball paradigm. The earliest rarity-detection response was found in sensory-specific cortices, rapidly spreading to tertiary association areas, mesial temporal and frontal cortices by 150-200 ms. P3m-related activity was not found in sensory-specific cortices. On the basis of the anatomic distribution of P3m-related activity, this component is likely to reflect more generalized cognitive abilities hosted by association cortical regions.	\N	\N
21261633	Humans must often focus attention onto relevant sensory signals in the presence of simultaneous irrelevant signals. This type of attention has been explored in vision with the N2pc component, and the present study sought to find an analogous auditory effect. In Experiment 1, two 750-ms sounds were presented simultaneously, one from each of two lateral speakers. On each trial, participants indicated whether one of the two sounds was a pre-defined target. We found that targets elicited an N2ac component: a negativity in the N2 latency range at anterior contralateral electrodes. We also observed a later and more posterior contralateral positivity. Experiment 2 replicated these effects and demonstrated that they arose from competition between attended and unattended tones rather than reflecting lateralized effects of attention for individual tones. The N2ac component may provide a useful tool for studying selective attention within auditory scenes.	\N	\N
21305666	Both sighted and blind individuals can readily interpret meaning behind everyday real-world sounds. In sighted listeners, we previously reported that regions along the bilateral posterior superior temporal sulci (pSTS) and middle temporal gyri (pMTG) are preferentially activated when presented with recognizable action sounds. These regions have generally been hypothesized to represent primary loci for complex motion processing, including visual biological motion processing and audio-visual integration. However, it remained unclear whether, or to what degree, life-long visual experience might impact functions related to hearing perception or memory of sound-source actions. Using functional magnetic resonance imaging (fMRI), we compared brain regions activated in congenitally blind versus sighted listeners in response to hearing a wide range of recognizable human-produced action sounds (excluding vocalizations) versus unrecognized, backward-played versions of those sounds. Here, we show that recognized human action sounds commonly evoked activity in both groups along most of the left pSTS/pMTG complex, though with relatively greater activity in the right pSTS/pMTG by the blind group. These results indicate that portions of the postero-lateral temporal cortices contain domain-specific hubs for biological and/or complex motion processing independent of sensory-modality experience. Contrasting the two groups, the sighted listeners preferentially activated bilateral parietal plus medial and lateral frontal networks, whereas the blind listeners preferentially activated left anterior insula plus bilateral anterior calcarine and medial occipital regions, including what would otherwise have been visual-related cortex. These global-level network differences suggest that blind and sighted listeners may preferentially use different memory retrieval strategies when hearing and attempting to recognize action sounds.	\N	\N
21380858	Most ecologically natural sensory inputs are not limited to a single modality. While it is possible to use real ecological materials as experimental stimuli to investigate the neural basis of multi-sensory experience, parametric control of such tokens is limited. By using artificial bimodal stimuli composed of approximations to ecological signals, we aim to observe the interactions between putatively relevant stimulus attributes. Here we use MEG as an electrophysiological tool and employ as a measure the steady-state response (SSR), an experimental paradigm typically applied to unimodal signals. In this experiment we quantify the responses to a bimodal audio-visual signal with different degrees of temporal (phase) congruity, focusing on stimulus properties critical to audiovisual speech. An amplitude modulated auditory signal ('pseudo-speech') is paired with a radius-modulated ellipse ('pseudo-mouth'), with the envelope of low-frequency modulations occurring in phase or at offset phase values across modalities. We observe (i) that it is possible to elicit an SSR to bimodal signals; (ii) that bimodal signals exhibit greater response power than unimodal signals; and (iii) that the SSR power at specific harmonics and sensors differentially reflects the congruity between signal components. Importantly, we argue that effects found at the modulation frequency and second harmonic reflect differential aspects of neural coding of multisensory signals. The experimental paradigm facilitates a quantitative characterization of properties of multi-sensory speech and other bimodal computations.	\N	\N
21807011	In real-world settings, information from multiple sensory modalities is combined to form a complete, behaviorally salient percept - a process known as multisensory integration. While deficits in auditory and visual processing are often observed in schizophrenia, little is known about how multisensory integration is affected by the disorder. The present study examined auditory, visual, and combined audio-visual processing in schizophrenia patients using high-density electrical mapping. An ecologically relevant task was used to compare unisensory and multisensory evoked potentials from schizophrenia patients to potentials from healthy normal volunteers. Analysis of unisensory responses revealed a large decrease in the N100 component of the auditory-evoked potential, as well as early differences in the visual-evoked components in the schizophrenia group. Differences in early evoked responses to multisensory stimuli were also detected. Multisensory facilitation was assessed by comparing the sum of auditory and visual evoked responses to the audio-visual evoked response. Schizophrenia patients showed a significantly greater absolute magnitude response to audio-visual stimuli than to summed unisensory stimuli when compared to healthy volunteers, indicating significantly greater multisensory facilitation in the patient group. Behavioral responses also indicated increased facilitation from multisensory stimuli. The results represent the first report of increased multisensory facilitation in schizophrenia and suggest that, although unisensory deficits are present, compensatory mechanisms may exist under certain conditions that permit improved multisensory integration in individuals afflicted with the disorder.	\N	\N
21958655	Perceptual sensitivities are malleable via learning, even in adults. We trained adults to discriminate complex sounds (periodic, frequency-modulated sweep trains) using two different training procedures, and used psychoacoustic tests and evoked potential measures (the N1-P2 complex) to assess changes in both perceptual and neural sensitivities. Training took place either on a single day, or daily across eight days, and involved discrimination of pairs of stimuli using a single-interval, forced-choice task. In some participants, training started with dissimilar pairs that became progressively more similar across sessions, whereas in others training was constant, involving only one, highly similar, stimulus pair. Participants were better able to discriminate the complex sounds after training, particularly after progressive training, and the evoked potentials elicited by some of the sounds increased in amplitude following training. Significant amplitude changes were restricted to the P2 peak. Our findings indicate that changes in perceptual sensitivities parallel enhanced neural processing. These results are consistent with the proposal that changes in perceptual abilities arise from the brain's capacity to adaptively modify cortical representations of sensory stimuli, and that different training regimens can lead to differences in cortical sensitivities, even after relatively short periods of training.	\N	\N
22367585	In recent years, it has become evident that neural responses previously considered to be unisensory can be modulated by sensory input from other modalities. In this regard, visual neural activity elicited to viewing a face is strongly influenced by concurrent incoming auditory information, particularly speech. Here, we applied an additive-factors paradigm aimed at quantifying the impact that auditory speech has on visual event-related potentials (ERPs) elicited to visual speech. These multisensory interactions were measured across parametrically varied stimulus salience, quantified in terms of signal to noise, to provide novel insights into the neural mechanisms of audiovisual speech perception. First, we measured a monotonic increase of the amplitude of the visual P1-N1-P2 ERP complex during a spoken-word recognition task with increases in stimulus salience. ERP component amplitudes varied directly with stimulus salience for visual, audiovisual, and summed unisensory recordings. Second, we measured changes in multisensory gain across salience levels. During audiovisual speech, the P1 and P1-N1 components exhibited less multisensory gain relative to the summed unisensory components with reduced salience, while N1-P2 amplitude exhibited greater multisensory gain as salience was reduced, consistent with the principle of inverse effectiveness. The amplitude interactions were correlated with behavioral measures of multisensory gain across salience levels as measured by response times, suggesting that change in multisensory gain associated with unisensory salience modulations reflects an increased efficiency of visual speech processing.	\N	\N
22464943	Limited information is available on the relationship between antisocial personality disorder (ASPD) and early filtering, or gating, of information, even though this could contribute to the repeatedly reported impairment in ASPD of higher-order information processing. In order to investigate early filtering in ASPD, we compared electrophysiological measures of auditory sensory gating assessed by the paired-click paradigm in males with ASPD (n = 37) to healthy controls (n = 28). Stimulus encoding was measured by P50, N100, and P200 auditory evoked potentials; auditory sensory gating (ASG) was measured by a reduction in amplitude of evoked potentials following click repetition. Effects were studied of co-existing past alcohol or drug use disorders, ASPD symptom counts, and trait impulsivity. Controls and ASPD did not differ in P50, N100, or P200 amplitude or ASG. Past alcohol or drug use disorders had no effect. In controls, impulsivity related to improved P50 and P200 gating. In ASPD, P50 or N100 gating was impaired with more symptoms or increased impulsivity, respectively, suggesting impaired early filtering of irrelevant information. In controls the relationship between P50 and P200 gating and impulsivity was reversed, suggesting better gating with higher impulsivity scores. This could reflect different roles of ASG in behavioral regulation in controls versus ASPD.	\N	\N
22547804	Bilingualism profoundly affects the brain, yielding functional and structural changes in cortical regions dedicated to language processing and executive function [Crinion J, et al. (2006) Science 312:1537-1540; Kim KHS, et al. (1997) Nature 388:171-174]. Comparatively, musical training, another type of sensory enrichment, translates to expertise in cognitive processing and refined biological processing of sound in both cortical and subcortical structures. Therefore, we asked whether bilingualism can also promote experience-dependent plasticity in subcortical auditory processing. We found that adolescent bilinguals, listening to the speech syllable [da], encoded the stimulus more robustly than age-matched monolinguals. Specifically, bilinguals showed enhanced encoding of the fundamental frequency, a feature known to underlie pitch perception and grouping of auditory objects. This enhancement was associated with executive function advantages. Thus, through experience-related tuning of attention, the bilingual auditory system becomes highly efficient in automatically processing sound. This study provides biological evidence for system-wide neural plasticity in auditory experts that facilitates a tight coupling of sensory and cognitive functions.	\N	\N
22592306	Poor sensitivity to the interaural time difference (ITD) constrains the ability of human bilateral cochlear implant users to listen in everyday noisy acoustic environments. ITD sensitivity to periodic pulse trains degrades sharply with increasing pulse rate but can be restored at high pulse rates by jittering the interpulse intervals in a binaurally coherent manner (Laback and Majdak. Binaural jitter improves interaural time-difference sensitivity of cochlear implantees at high pulse rates. Proc Natl Acad Sci USA 105: 814-817, 2008). We investigated the neural basis of the jitter effect by recording from single inferior colliculus (IC) neurons in bilaterally implanted, anesthetized cats. Neural responses to trains of biphasic pulses were measured as a function of pulse rate, jitter, and ITD. An effect of jitter on neural responses was most prominent for pulse rates above 300 pulses/s. High-rate periodic trains evoked only an onset response in most IC neurons, but introducing jitter increased ongoing firing rates in about half of these neurons. Neurons that had sustained responses to jittered high-rate pulse trains showed ITD tuning comparable with that produced by low-rate periodic pulse trains. Thus, jitter appears to improve neural ITD sensitivity by restoring sustained firing in many IC neurons. The effect of jitter on IC responses is qualitatively consistent with human psychophysics. Action potentials tended to occur reproducibly at sparse, preferred times across repeated presentations of high-rate jittered pulse trains. Spike triggered averaging of responses to jittered pulse trains revealed that firing was triggered by very short interpulse intervals. This suggests it may be possible to restore ITD sensitivity to periodic carriers by simply inserting short interpulse intervals at select times.	\N	\N
22628458	Successful integration of auditory and visual inputs is crucial for both basic perceptual functions and for higher-order processes related to social cognition. Autism spectrum disorders (ASD) are characterized by impairments in social cognition and are associated with abnormalities in sensory and perceptual processes. Several groups have reported that individuals with ASD are impaired in their ability to integrate socially relevant audiovisual (AV) information, and it has been suggested that this contributes to the higher-order social and cognitive deficits observed in ASD. However, successful integration of auditory and visual inputs also influences detection and perception of nonsocial stimuli, and integration deficits may impair earlier stages of information processing, with cascading downstream effects. To assess the integrity of basic AV integration, we recorded high-density electrophysiology from a cohort of high-functioning children with ASD (7-16 years) while they performed a simple AV reaction time task. Children with ASD showed considerably less behavioral facilitation to multisensory inputs, deficits that were paralleled by less effective neural integration. Evidence for processing differences relative to typically developing children was seen as early as 100 ms poststimulation, and topographic analysis suggested that children with ASD relied on different cortical networks during this early multisensory processing stage.	\N	\N
22735387	Decreased blood hemoglobin (HbB) levels and anemia have been associated with abnormal brainstem auditory evoked responses (BAER). Lead (Pb) exposure has also been associated with anemia and aberrant BAER. This study investigated the relationship between HbB level and BAER wave latency and amplitude in Pb-exposed Andean children. Sixty-six children aged 2 to 15 years (mean age: 9.1; SD: 3.3) living in Pb-contaminated villages were screened for HbB levels, blood Pb (PbB) levels and BAER latencies and amplitudes. The mean HbB level observed in the study group was 11.9 g/dL (SD: 1.4; range: 8.6-14.8 g/dL). The mean HbB level corrected for altitude was 10.3g/dL (SD: 1.4; range: 6.9-13.1 g/dL), and suggestive of anemia. The mean PbB level was 49.3 μg/dL (SD: 30.1; range: 4.4-119.1 μg/dL) and indicative of Pb poisoning. Spearman rho correlation analyses revealed significant associations between the BAER absolute latencies and HbB level, indicating that as the HbB level decreased, the BAER wave latency increased. Children with low HbB levels (≤11 g/dL) showed significantly prolonged absolute latencies of waves I, II, III, IV and V compared to the children with normal HbB levels. Although a significant relationship between HbB and BAER waves was observed, no significant associations between PbB level and BAER parameters were found. Low hemoglobin levels may diminish auditory sensory-neural function, and is therefore an important variable to consider when assessing BAER in children with anemia and/or Pb exposure.	\N	\N
22773777	Many neurons adapt their spike output to accommodate the prevailing sensory environment. Although such adaptation is thought to improve coding of relevant stimulus features, the relationship between adaptation at the neural and behavioral levels remains to be established. Here we describe improved discrimination performance for an auditory spatial cue (interaural time differences, ITDs) following adaptation to stimulus statistics. Physiological recordings in the midbrain of anesthetized guinea pigs and measurement of discrimination performance in humans both demonstrate improved coding of the most prevalent ITDs in a distribution, but with highest accuracy maintained for ITDs corresponding to frontal locations, suggesting the existence of a fovea for auditory space. A biologically plausible model accounting for the physiological data suggests that neural tuning is stabilized by inhibition to maintain high discriminability for frontal locations. The data support the notion that adaptive coding in the midbrain is a key element of behaviorally efficient sound localization in dynamic acoustic environments.	\N	\N
22885999	Event-related potentials (ERPs) to tones that are self-initiated are reduced in their magnitude in comparison with ERPs to tones that are externally generated. This phenomenon has been taken as evidence for an efference copy of the motor command acting to suppress the sensory response. However, self-initiation provides a strong temporal cue for the stimulus which might also contribute to the ERP suppression for self-initiated tones. The current experiment sought to investigate the suppression of monaural tones by temporal cueing and also whether the addition of self-initiation enhanced this suppression. Lastly, the experiment sought to investigate the lateralisation of the ERP suppression via presenting these monaural tones to each ear respectively. We examined source waveforms extracted from the lateralised auditory cortices and measured the modulation of the N1 and P2 components by cueing and self-initiation. Self-initiation significantly reduced the amplitude of the N1 component. Temporal cueing without self-initiation significantly reduced the P2 component. There were no significant differences in the amplitude of either the N1 or the P2 between self-initiation and temporal cuing. There was a significant lateralisation effect on the N1-it being significantly larger contralateral to the ear of stimulation. There was no interaction between lateralisation and side of the temporal cue or side of self-initiation suggesting that the effects of self-initiation and temporal cuing are equal bilaterally. We conclude that a significant proportion of ERP suppression by self-initiation is a result of inherent temporal cueing.	\N	\N
23071654	Selectively attending to task-relevant sounds whilst ignoring background noise is one of the most amazing feats performed by the human brain. Here, we studied the underlying neural mechanisms by recording magnetoencephalographic (MEG) responses of 14 healthy human subjects while they performed a near-threshold auditory discrimination task vs. a visual control task of similar difficulty. The auditory stimuli consisted of notch-filtered continuous noise masker sounds, and of 1020-Hz target tones occasionally (p = 0.1) replacing 1000-Hz standard tones of 300-ms duration that were embedded at the center of the notches, the widths of which were parametrically varied. As a control for masker effects, tone-evoked responses were additionally recorded without masker sound. Selective attention to tones significantly increased the amplitude of the onset M100 response at ~100 ms to the standard tones during presence of the masker sounds especially with notches narrower than the critical band. Further, attention modulated sustained response most clearly at 300-400 ms time range from sound onset, with narrower notches than in case of the M100, thus selectively reducing the masker-induced suppression of the tone-evoked response. Our results show evidence of a multiple-stage filtering mechanism of sensory input in the human auditory cortex: 1) one at early (~100 ms) latencies bilaterally in posterior parts of the secondary auditory areas, and 2) adaptive filtering of attended sounds from task-irrelevant background masker at longer latency (~300 ms) in more medial auditory cortical regions, predominantly in the left hemisphere, enhancing processing of near-threshold sounds.	\N	\N
23145143	It has been previously demonstrated by our group that a visual stimulus made of dynamically changing luminance evokes an echo or reverberation at ~10 Hz, lasting up to a second. In this study we aimed to reveal whether similar echoes also exist in the auditory modality. A dynamically changing auditory stimulus equivalent to the visual stimulus was designed and employed in two separate series of experiments, and the presence of reverberations was analyzed based on reverse correlations between stimulus sequences and EEG epochs. The first experiment directly compared visual and auditory stimuli: while previous findings of ~10 Hz visual echoes were verified, no similar echo was found in the auditory modality regardless of frequency. In the second experiment, we tested if auditory sequences would influence the visual echoes when they were congruent or incongruent with the visual sequences. However, the results in that case similarly did not reveal any auditory echoes, nor any change in the characteristics of visual echoes as a function of audio-visual congruence. The negative findings from these experiments suggest that brain oscillations do not equivalently affect early sensory processes in the visual and auditory modalities, and that alpha (8-13 Hz) oscillations play a special role in vision.	\N	\N
23251704	Cognitive task demands in one sensory modality (T1) can have beneficial effects on a secondary task (T2) in a different modality, due to reduced top-down control needed to inhibit the secondary task, as well as crossmodal spread of attention. This contrasts findings of cognitive load compromising a secondary modality's processing. We manipulated cognitive load within one modality (visual) and studied the consequences of cognitive demands on secondary (auditory) processing. 15 healthy participants underwent a simultaneous EEG-fMRI experiment. Data from 8 participants were obtained outside the scanner for validation purposes. The primary task (T1) was to respond to a visual working memory (WM) task with four conditions, while the secondary task (T2) consisted of an auditory oddball stream, which participants were asked to ignore. The fMRI results revealed fronto-parietal WM network activations in response to T1 task manipulation. This was accompanied by significantly higher reaction times and lower hit rates with increasing task difficulty which confirmed successful manipulation of WM load. Amplitudes of auditory evoked potentials, representing fundamental auditory processing showed a continuous augmentation which demonstrated a systematic relation to cross-modal cognitive load. With increasing WM load, primary auditory cortices were increasingly deactivated while psychophysiological interaction results suggested the emergence of auditory cortices connectivity with visual WM regions. These results suggest differential effects of crossmodal attention on fundamental auditory processing. We suggest a continuous allocation of resources to brain regions processing primary tasks when challenging the central executive under high cognitive load.	\N	\N
23281832	If we initiate a sound by our own motor behavior, the N1 component of the auditory event-related brain potential (ERP) that the sound elicits is attenuated compared to the N1 elicited by the same sound when it is initiated externally. It has been suggested that this N1 suppression results from an internal predictive mechanism that is in the service of discriminating the sensory consequences of one's own actions from other sensory input. As the N1-suppression effect is becoming a popular approach to investigate predictive processing in cognitive and social neuroscience, it is important to exclude an alternative interpretation not related to prediction. According to the attentional account, the N1 suppression is due to a difference in the allocation of attention between self- and externally-initiated sounds. To test this hypothesis, we manipulated the allocation of attention to the sounds in different blocks: Attention was directed either to the sounds, to the own motor acts or to visual stimuli. If attention causes the N1-suppression effect, then manipulating attention should affect the effect for self-initiated sounds. We found N1 suppression in all conditions. The N1 per se was affected by attention, but there was no interaction between attention and self-initiation effects. This implies that self-initiation N1 effects are not caused by attention. The present results support the assumption that the N1-suppression effect for self-initiated sounds indicates the operation of an internal predictive mechanism. Furthermore, while attention had an influence on the N1a, N1b, and N1c components, the N1-suppression effect was confined to the N1b and N1c subcomponents suggesting that the major contribution to the auditory N1-suppression effect is circumscribed to late N1 components.	\N	\N
23301775	Using electrophysiology, we have examined two questions in relation to musical training - namely, whether it enhances sensory encoding of the human voice and whether it improves the ability to ignore irrelevant auditory change. Participants performed an auditory distraction task, in which they identified each sound as either short (350 ms) or long (550 ms) and ignored a change in timbre of the sounds. Sounds consisted of a male and a female voice saying a neutral sound [a], and of a cello and a French Horn playing an F3 note. In some blocks, musical sounds occurred on 80% of trials, while voice sounds on 20% of trials. In other blocks, the reverse was true. Participants heard naturally recorded sounds in half of experimental blocks and their spectrally-rotated versions in the other half. Regarding voice perception, we found that musicians had a larger N1 event-related potential component not only to vocal sounds but also to their never before heard spectrally-rotated versions. We therefore conclude that musical training is associated with a general improvement in the early neural encoding of complex sounds. Regarding the ability to ignore irrelevant auditory change, musicians' accuracy tended to suffer less from the change in timbre of the sounds, especially when deviants were musical notes. This behavioral finding was accompanied by a marginally larger re-orienting negativity in musicians, suggesting that their advantage may lie in a more efficient disengagement of attention from the distracting auditory dimension.	\N	\N
23316957	There is an accumulating body of evidence indicating that neuronal functional specificity to basic sensory stimulation is mutable and subject to experience. Although fMRI experiments have investigated changes in brain activity after relative to before perceptual learning, brain activity during perceptual learning has not been explored. This work investigated brain activity related to auditory frequency discrimination learning using a variational Bayesian approach for source localization, during simultaneous EEG and fMRI recording. We investigated whether the practice effects are determined solely by activity in stimulus-driven mechanisms or whether high-level attentional mechanisms, which are linked to the perceptual task, control the learning process. The results of fMRI analyses revealed significant attention and learning related activity in left and right superior temporal gyrus STG as well as the left inferior frontal gyrus IFG. Current source localization of simultaneously recorded EEG data was estimated using a variational Bayesian method. Analysis of current localized to the left inferior frontal gyrus and the right superior temporal gyrus revealed gamma band activity correlated with behavioral performance. Rapid improvement in task performance is accompanied by plastic changes in the sensory cortex as well as superior areas gated by selective attention. Together the fMRI and EEG results suggest that gamma band activity in the right STG and left IFG plays an important role during perceptual learning.	\N	\N
23326548	Auditory distraction is a failure to maintain focus on a stream of sounds. We investigated the neural correlates of distraction in a selective-listening pitch-discrimination task with high (competing speech) or low (white noise) distraction. High-distraction impaired performance and reduced the N1 peak of the auditory Event-Related Potential evoked by probe tones. In a series of simulations, we explored two theories to account for this effect: disruption of sensory gain or a disruption of inter-trial phase consistency. When compared to these simulations, our data were consistent with both effects of distraction. Distraction reduced the gain of the auditory evoked potential and disrupted the inter-trial phase consistency with which the brain responds to stimulus events. Tones at a non-target, unattended frequency were more susceptible to the effects of distraction than tones within an attended frequency band.	\N	\N
23616340	Previous studies on crossmodal spatial orienting typically used simple and stereotyped stimuli in the absence of any meaningful context. This study combined computational models, behavioural measures and functional magnetic resonance imaging to investigate audiovisual spatial interactions in naturalistic settings. We created short videos portraying everyday life situations that included a lateralised visual event and a co-occurring sound, either on the same or on the opposite side of space. Subjects viewed the videos with or without eye-movements allowed (overt or covert orienting). For each video, visual and auditory saliency maps were used to index the strength of stimulus-driven signals, and eye-movements were used as a measure of the efficacy of the audiovisual events for spatial orienting. Results showed that visual salience modulated activity in higher-order visual areas, whereas auditory salience modulated activity in the superior temporal cortex. Auditory salience modulated activity also in the posterior parietal cortex, but only when audiovisual stimuli occurred on the same side of space (multisensory spatial congruence). Orienting efficacy affected activity in the visual cortex, within the same regions modulated by visual salience. These patterns of activation were comparable in overt and covert orienting conditions. Our results demonstrate that, during viewing of complex multisensory stimuli, activity in sensory areas reflects both stimulus-driven signals and their efficacy for spatial orienting; and that the posterior parietal cortex combines spatial information about the visual and the auditory modality.	\N	\N
23624493	Findings in animal models demonstrate that activity within hierarchically early sensory cortical regions can be modulated by cross-sensory inputs through resetting of the phase of ongoing intrinsic neural oscillations. Here, subdural recordings evaluated whether phase resetting by auditory inputs would impact multisensory integration processes in human visual cortex. Results clearly showed auditory-driven phase reset in visual cortices and, in some cases, frank auditory event-related potentials (ERP) were also observed over these regions. Further, when audiovisual bisensory stimuli were presented, this led to robust multisensory integration effects which were observed in both the ERP and in measures of phase concentration. These results extend findings from animal models to human visual cortices, and highlight the impact of cross-sensory phase resetting by a non-primary stimulus on multisensory integration in ostensibly unisensory cortices.	\N	\N
23647558	In the visual modality, perceptual demand on a goal-directed task has been shown to modulate the extent to which irrelevant information can be disregarded at a sensory-perceptual stage of processing. In the auditory modality, the effect of perceptual demand on neural representations of task-irrelevant sounds is unclear. We compared simultaneous ERPs and fMRI responses associated with task-irrelevant sounds across parametrically modulated perceptual task demands in a dichotic-listening paradigm. Participants performed a signal detection task in one ear (Attend ear) while ignoring task-irrelevant syllable sounds in the other ear (Ignore ear). Results revealed modulation of syllable processing by auditory perceptual demand in an ROI in middle left superior temporal gyrus and in negative ERP activity 130-230 msec post stimulus onset. Increasing the perceptual demand in the Attend ear was associated with a reduced neural response in both fMRI and ERP to task-irrelevant sounds. These findings are in support of a selection model whereby ongoing perceptual demands modulate task-irrelevant sound processing in auditory cortex.	\N	\N
23664703	Both faces and voices are rich in socially-relevant information, which humans are remarkably adept at extracting, including a person's identity, age, gender, affective state, personality, etc. Here, we review accumulating evidence from behavioral, neuropsychological, electrophysiological, and neuroimaging studies which suggest that the cognitive and neural processing mechanisms engaged by perceiving faces or voices are highly similar, despite the very different nature of their sensory input. The similarity between the two mechanisms likely facilitates the multi-modal integration of facial and vocal information during everyday social interactions. These findings emphasize a parsimonious principle of cerebral organization, where similar computational problems in different modalities are solved using similar solutions.	\N	\N
23827717	Learning and maintaining the sounds we use in vocal communication require accurate perception of the sounds we hear performed by others and feedback-dependent imitation of those sounds to produce our own vocalizations. Understanding how the central nervous system integrates auditory and vocal-motor information to enable communication is a fundamental goal of systems neuroscience, and insights into the mechanisms of those processes will profoundly enhance clinical therapies for communication disorders. Gaining the high-resolution insight necessary to define the circuits and cellular mechanisms underlying human vocal communication is presently impractical. Songbirds are the best animal model of human speech, and this review highlights recent insights into the neural basis of auditory perception and feedback-dependent imitation in those animals. Neural correlates of song perception are present in auditory areas, and those correlates are preserved in the auditory responses of downstream neurons that are also active when the bird sings. Initial tests indicate that singing-related activity in those downstream neurons is associated with vocal-motor performance as opposed to the bird simply hearing itself sing. Therefore, action potentials related to auditory perception and action potentials related to vocal performance are co-localized in individual neurons. Conceptual models of song learning involve comparison of vocal commands and the associated auditory feedback to compute an error signal that is used to guide refinement of subsequent song performances, yet the sites of that comparison remain unknown. Convergence of sensory and motor activity onto individual neurons points to a possible mechanism through which auditory and vocal-motor signals may be linked to enable learning and maintenance of the sounds used in vocal communication. This article is part of a Special Issue entitled "Communication Sounds and the Brain: New Directions and Perspectives".	\N	\N
23988583	Experience-dependent characteristics of auditory function, especially with regard to speech-evoked auditory neurophysiology, have garnered increasing attention in recent years. This interest stems from both pragmatic and theoretical concerns as it bears implications for the prevention and remediation of language-based learning impairment in addition to providing insight into mechanisms engendering experience-dependent changes in human sensory function. Musicians provide an attractive model for studying the experience-dependency of auditory processing in humans due to their distinctive neural enhancements compared to nonmusicians. We have only recently begun to address whether these enhancements are observable early in life, during the initial years of music training when the auditory system is under rapid development, as well as later in life, after the onset of the aging process. Here we review neural enhancements in musically trained individuals across the life span in the context of cellular mechanisms that underlie learning, identified in animal models. Musicians' subcortical physiologic enhancements are interpreted according to a cognitive framework for auditory learning, providing a model in which to study mechanisms of experience-dependent changes in human auditory function.	\N	\N
24072639	Neurobiological underpinnings of unusual sensory features in individuals with autism are unknown. Event-related potentials elicited by task-irrelevant sounds were used to elucidate neural correlates of auditory processing and associations with three common sensory response patterns (hyperresponsiveness; hyporesponsiveness; sensory seeking). Twenty-eight children with autism and 39 typically developing children (4-12 year-olds) completed an auditory oddball paradigm. Results revealed marginally attenuated P1 and N2 to standard tones and attenuated P3a to novel sounds in autism versus controls. Exploratory analyses suggested that within the autism group, attenuated N2 and P3a amplitudes were associated with greater sensory seeking behaviors for specific ranges of P1 responses. Findings suggest that attenuated early sensory as well as later attention-orienting neural responses to stimuli may underlie selective sensory features via complex mechanisms.	\N	\N
24119225	Humans are able to extract regularities from complex auditory scenes in order to form perceptually meaningful elements. It has been shown previously that this process depends critically on both the temporal integration of the sensory input over time and the degree of frequency separation between concurrent sound sources. Our goal was to examine the relationship between these two aspects by means of magnetoencephalography (MEG). To achieve this aim, we combined time-frequency analysis on a sensor space level with source analysis. Our paradigm consisted of asymmetric ABA-tone triplets wherein the B-tones were presented temporally closer to the first A-tones, providing different tempi within the same sequence. Participants attended to the slowest B-rhythm whilst the frequency separation between tones was manipulated (0-, 2-, 4- and 10-semitones). The results revealed that the asymmetric ABA-triplets spontaneously elicited periodic-sustained responses corresponding to the temporal distribution of the A-B and B-A tone intervals in all conditions. Moreover, when attending to the B-tones, the neural representations of the A- and B-streams were both detectable in the scenarios which allow perceptual streaming (2-, 4- and 10-semitones). Alongside this, the steady-state responses tuned to the presentation of the B-tones enhanced significantly with increase of the frequency separation between tones. However, the strength of the B-tones related steady-state responses dominated the strength of the A-tones responses in the 10-semitones condition. Conversely, the representation of the A-tones dominated the B-tones in the cases of 2- and 4-semitones conditions, in which a greater effort was required for completing the task. Additionally, the P1 evoked fields' component following the B-tones increased in magnitude with the increase of inter-tonal frequency difference. The enhancement of the evoked fields in the source space, along with the B-tones related activity of the time-frequency results, likely reflect the selective enhancement of the attended B-stream. The results also suggested a dissimilar efficiency of the temporal integration of separate streams depending on the degree of frequency separation between the sounds. Overall, the present findings suggest that the neural effects of auditory streaming could be directly captured in the time-frequency spectrum at the sensor-space level.	\N	\N
24314010	Auditory perceptual learning persistently modifies neural networks in the central nervous system. Central auditory processing comprises a hierarchy of sound analysis and integration, which transforms an acoustical signal into a meaningful object for perception. Based on latencies and source locations of auditory evoked responses, we investigated which stage of central processing undergoes neuroplastic changes when gaining auditory experience during passive listening and active perceptual training. Young healthy volunteers participated in a five-day training program to identify two pre-voiced versions of the stop-consonant syllable 'ba', which is an unusual speech sound to English listeners. Magnetoencephalographic (MEG) brain responses were recorded during two pre-training and one post-training sessions. Underlying cortical sources were localized, and the temporal dynamics of auditory evoked responses were analyzed. After both passive listening and active training, the amplitude of the P2m wave with latency of 200 ms increased considerably. By this latency, the integration of stimulus features into an auditory object for further conscious perception is considered to be complete. Therefore the P2m changes were discussed in the light of auditory object representation. Moreover, P2m sources were localized in anterior auditory association cortex, which is part of the antero-ventral pathway for object identification. The amplitude of the earlier N1m wave, which is related to processing of sensory information, did not change over the time course of the study. The P2m amplitude increase and its persistence over time constitute a neuroplastic change. The P2m gain likely reflects enhanced object representation after stimulus experience and training, which enables listeners to improve their ability for scrutinizing fine differences in pre-voicing time. Different trajectories of brain and behaviour changes suggest that the preceding effect of a P2m increase relates to brain processes, which are necessary precursors of perceptual learning. Cautious discussion is required when interpreting the finding of a P2 amplitude increase between recordings before and after training and learning.	\N	\N
24423729	Across the animal kingdom, sensations resulting from an animal's own actions are processed differently from sensations resulting from external sources, with self-generated sensations being suppressed. A forward model has been proposed to explain this process across sensorimotor domains. During vocalization, reduced processing of one's own speech is believed to result from a comparison of speech sounds to corollary discharges of intended speech production generated from efference copies of commands to speak. Until now, anatomical and functional evidence validating this model in humans has been indirect. Using EEG with anatomical MRI to facilitate source localization, we demonstrate that inferior frontal gyrus activity during the 300ms before speaking was associated with suppressed processing of speech sounds in auditory cortex around 100ms after speech onset (N1). These findings indicate that an efference copy from speech areas in prefrontal cortex is transmitted to auditory cortex, where it is used to suppress processing of anticipated speech sounds. About 100ms after N1, a subsequent auditory cortical component (P2) was not suppressed during talking. The combined N1 and P2 effects suggest that although sensory processing is suppressed as reflected in N1, perceptual gaps may be filled as reflected in the lack of P2 suppression, explaining the discrepancy between sensory suppression and preserved sensory experiences. These findings, coupled with the coherence between relevant brain regions before and during speech, provide new mechanistic understanding of the complex interactions between action planning and sensory processing that provide for differentiated tagging and monitoring of one's own speech, processes disrupted in neuropsychiatric disorders.	\N	\N
24695717	Detecting the location of salient sounds in the environment rests on the brain's ability to use differences in sounds arriving at both ears. Functional neuroimaging studies in humans indicate that the left and right auditory hemispaces are coded asymmetrically, with a rightward attentional bias that reflects spatial attention in vision. Neuropsychological observations in patients with spatial neglect have led to the formulation of two competing models: the orientation bias and right-hemisphere dominance models. The orientation bias model posits a symmetrical mapping between one side of the sensorium and the contralateral hemisphere, with mutual inhibition of the ipsilateral hemisphere. The right-hemisphere dominance model introduces a functional asymmetry in the brain's coding of space: the left hemisphere represents the right side, whereas the right hemisphere represents both sides of the sensorium. We used Dynamic Causal Modeling of effective connectivity and Bayesian model comparison to adjudicate between these alternative network architectures, based on human electroencephalographic data acquired during an auditory location oddball paradigm. Our results support a hemispheric asymmetry in a frontoparietal network that conforms to the right-hemisphere dominance model. We show that, within this frontoparietal network, forward connectivity increases selectively in the hemisphere contralateral to the side of sensory stimulation. We interpret this finding in light of hierarchical predictive coding as a selective increase in attentional gain, which is mediated by feedforward connections that carry precision-weighted prediction errors during perceptual inference. This finding supports the disconnection hypothesis of unilateral neglect and has implications for theories of its etiology.	\N	\N
24956028	Listening situations with multiple talkers or background noise are common in everyday communication and are particularly demanding for older adults. Here we review current research on auditory perception in aging individuals in order to gain insights into the challenges of listening under noisy conditions. Informationally rich temporal structure in auditory signals--over a range of time scales from milliseconds to seconds--renders temporal processing central to perception in the auditory domain. We discuss the role of temporal structure in auditory processing, in particular from a perspective relevant for hearing in background noise, and focusing on sensory memory, auditory scene analysis, and speech perception. Interestingly, these auditory processes, usually studied in an independent manner, show considerable overlap of processing time scales, even though each has its own 'privileged' temporal regimes. By integrating perspectives on temporal structure processing in these three areas of investigation, we aim to highlight similarities typically not recognized.	\N	\N
25245785	Atypical processing and integration of sensory inputs are hypothesized to play a role in unusual sensory reactions and social-cognitive deficits in autism spectrum disorder (ASD). Reports on the relationship between objective metrics of sensory processing and clinical symptoms, however, are surprisingly sparse. Here we examined the relationship between neurophysiological assays of sensory processing and (1) autism severity and (2) sensory sensitivities, in individuals with ASD aged 6-17. Multiple linear regression indicated significant associations between neural markers of auditory processing and multisensory integration, and autism severity. No such relationships were apparent for clinical measures of visual/auditory sensitivities. These data support that aberrant early sensory processing contributes to autism symptoms, and reveal the potential of electrophysiology to objectively subtype autism.	\N	\N
25259525	Auditory selective attention plays an essential role for identifying sounds of interest in a scene, but the neural underpinnings are still incompletely understood. Recent findings demonstrate that neural activity that is time-locked to a particular amplitude-modulation (AM) is enhanced in the auditory cortex when the modulated stream of sounds is selectively attended to under sensory competition with other streams. However, the target sounds used in the previous studies differed not only in their AM, but also in other sound features, such as carrier frequency or location. Thus, it remains uncertain whether the observed enhancements reflect AM-selective attention. The present study aims at dissociating the effect of AM frequency on response enhancement in auditory cortex by using an ongoing auditory stimulus that contains two competing targets differing exclusively in their AM frequency. Electroencephalography results showed a sustained response enhancement for auditory attention compared to visual attention, but not for AM-selective attention (attended AM frequency vs. ignored AM frequency). In contrast, the response to the ignored AM frequency was enhanced, although a brief trend toward response enhancement occurred during the initial 15 s. Together with the previous findings, these observations indicate that selective enhancement of attended AMs in auditory cortex is adaptive under sustained AM-selective attention. This finding has implications for our understanding of cortical mechanisms for feature-based attentional gain control.	\N	\N
25535356	When social animals communicate, the onset of informative content in one modality varies considerably relative to the other, such as when visual orofacial movements precede a vocalization. These naturally occurring asynchronies do not disrupt intelligibility or perceptual coherence. However, they occur on time scales where they likely affect integrative neuronal activity in ways that have remained unclear, especially for hierarchically downstream regions in which neurons exhibit temporally imprecise but highly selective responses to communication signals. To address this, we exploited naturally occurring face- and voice-onset asynchronies in primate vocalizations. Using these as stimuli we recorded cortical oscillations and neuronal spiking responses from functional MRI (fMRI)-localized voice-sensitive cortex in the anterior temporal lobe of macaques. We show that the onset of the visual face stimulus resets the phase of low-frequency oscillations, and that the face-voice asynchrony affects the prominence of two key types of neuronal multisensory responses: enhancement or suppression. Our findings show a three-way association between temporal delays in audiovisual communication signals, phase-resetting of ongoing oscillations, and the sign of multisensory responses. The results reveal how natural onset asynchronies in cross-sensory inputs regulate network oscillations and neuronal excitability in the voice-sensitive cortex of macaques, a suggested animal model for human voice areas. These findings also advance predictions on the impact of multisensory input on neuronal processes in face areas and other brain regions.	\N	\N
25948269	Sensory processing involves identification of stimulus features, but also integration with the surrounding sensory and cognitive context. Previous work in animals and humans has shown fine-scale sensitivity to context in the form of learned knowledge about the statistics of the sensory environment, including relative probabilities of discrete units in a stream of sequential auditory input. These statistics are a defining characteristic of one of the most important sequential signals humans encounter: speech. For speech, extensive exposure to a language tunes listeners to the statistics of sound sequences. To address how speech sequence statistics are neurally encoded, we used high-resolution direct cortical recordings from human lateral superior temporal cortex as subjects listened to words and nonwords with varying transition probabilities between sound segments. In addition to their sensitivity to acoustic features (including contextual features, such as coarticulation), we found that neural responses dynamically encoded the language-level probability of both preceding and upcoming speech sounds. Transition probability first negatively modulated neural responses, followed by positive modulation of neural responses, consistent with coordinated predictive and retrospective recognition processes, respectively. Furthermore, transition probability encoding was different for real English words compared with nonwords, providing evidence for online interactions with high-order linguistic knowledge. These results demonstrate that sensory processing of deeply learned stimuli involves integrating physical stimulus features with their contextual sequential structure. Despite not being consciously aware of phoneme sequence statistics, listeners use this information to process spoken input and to link low-level acoustic representations with linguistic information about word identity and meaning.	\N	\N
22803512	Existing 67-channel event-related potentials, obtained during recognition and working memory paradigms with words or faces, were used to examine early visual processing in schizophrenia patients prone to auditory hallucinations (AH, n = 26) or not (NH, n = 49) and healthy controls (HC, n = 46). Current source density (CSD) transforms revealed distinct, strongly left- (words) or right-lateralized (faces; N170) inferior-temporal N1 sinks (150 ms) in each group. N1 was quantified by temporal PCA of peak-adjusted CSDs. For words and faces in both paradigms, N1 was substantially reduced in AH compared with NH and HC, who did not differ from each other. The difference in N1 between AH and NH was not due to overall symptom severity or performance accuracy, with both groups showing comparable memory deficits. Our findings extend prior reports of reduced auditory N1 in AH, suggesting a broader early perceptual integration deficit that is not limited to the auditory modality.	\N	\N
25231612	Atypical medial olivocochlear (MOC) feedback from brain stem to cochlea has been proposed to play a role in tinnitus, but even well-constructed tests of this idea have yielded inconsistent results. In the present study, it was hypothesized that low sound tolerance (mild to moderate hyperacusis), which can accompany tinnitus or occur on its own, might contribute to the inconsistency. Sound-level tolerance (SLT) was assessed in subjects (all men) with clinically normal or near-normal thresholds to form threshold-, age-, and sex-matched groups: 1) no tinnitus/high SLT, 2) no tinnitus/low SLT, 3) tinnitus/high SLT, and 4) tinnitus/low SLT. MOC function was measured from the ear canal as the change in magnitude of distortion-product otoacoustic emissions (DPOAE) elicited by broadband noise presented to the contralateral ear. The noise reduced DPOAE magnitude in all groups ("contralateral suppression"), but significantly more reduction occurred in groups with tinnitus and/or low SLT, indicating hyperresponsiveness of the MOC system compared with the group with no tinnitus/high SLT. The results suggest hyperresponsiveness of the interneurons of the MOC system residing in the cochlear nucleus and/or MOC neurons themselves. The present data, combined with previous human and animal data, indicate that neural pathways involving every major division of the cochlear nucleus manifest hyperactivity and/or hyperresponsiveness in tinnitus and/or low SLT. The overactivation may develop in each pathway separately. However, a more parsimonious hypothesis is that top-down neuromodulation is the driving force behind ubiquitous overactivation of the auditory brain stem and may correspond to attentional spotlighting on the auditory domain in tinnitus and hyperacusis.	\N	\N
21909378	Speech is the most important form of human communication but ambient sounds and competing talkers often degrade its acoustics. Fortunately the brain can use visual information, especially its highly precise spatial information, to improve speech comprehension in noisy environments. Previous studies have demonstrated that audiovisual integration depends strongly on spatiotemporal factors. However, some integrative phenomena such as McGurk interference persist even with gross spatial disparities, suggesting that spatial alignment is not necessary for robust integration of audiovisual place-of-articulation cues. It is therefore unclear how speech-cues interact with audiovisual spatial integration mechanisms. Here, we combine two well established psychophysical phenomena, the McGurk effect and the ventriloquist's illusion, to explore this dependency. Our results demonstrate that conflicting spatial cues may not interfere with audiovisual integration of speech, but conflicting speech-cues can impede integration in space. This suggests a direct but asymmetrical influence between ventral 'what' and dorsal 'where' pathways.	\N	\N
22390292	Human multisensory systems are known to bind inputs from the different sensory modalities into a unified percept, a process that leads to measurable behavioral benefits. This integrative process can be observed through multisensory illusions, including the McGurk effect and the sound-induced flash illusion, both of which demonstrate the ability of one sensory modality to modulate perception in a second modality. Such multisensory integration is highly dependent upon the temporal relationship of the different sensory inputs, with perceptual binding occurring within a limited range of asynchronies known as the temporal binding window (TBW). Previous studies have shown that this window is highly variable across individuals, but it is unclear how these variations in the TBW relate to an individual's ability to integrate multisensory cues. Here we provide evidence linking individual differences in multisensory temporal processes to differences in the individual's audiovisual integration of illusory stimuli. Our data provide strong evidence that the temporal processing of multiple sensory signals and the merging of multiple signals into a single, unified perception, are highly related. Specifically, the width of right side of an individuals' TBW, where the auditory stimulus follows the visual, is significantly correlated with the strength of illusory percepts, as indexed via both an increase in the strength of binding synchronous sensory signals and in an improvement in correctly dissociating asynchronous signals. These findings are discussed in terms of their possible neurobiological basis, relevance to the development of sensory integration, and possible importance for clinical conditions in which there is growing evidence that multisensory integration is compromised.	\N	\N
23664001	The sight and sound of a person speaking or a ball bouncing may seem simultaneous, but their corresponding neural signals are spread out over time as they arrive at different multisensory brain sites. How subjective timing relates to such neural timing remains a fundamental neuroscientific and philosophical puzzle. A dominant assumption is that temporal coherence is achieved by sensory resynchronisation or recalibration across asynchronous brain events. This assumption is easily confirmed by estimating subjective audiovisual timing for groups of subjects, which is on average similar across different measures and stimuli, and approximately veridical. But few studies have examined normal and pathological individual differences in such measures. Case PH, with lesions in pons and basal ganglia, hears people speak before seeing their lips move. Temporal order judgements (TOJs) confirmed this: voices had to lag lip-movements (by ∼200 msec) to seem synchronous to PH. Curiously, voices had to lead lips (also by ∼200 msec) to maximise the McGurk illusion (a measure of audiovisual speech integration). On average across these measures, PH's timing was therefore still veridical. Age-matched control participants showed similar discrepancies. Indeed, normal individual differences in TOJ and McGurk timing correlated negatively: subjects needing an auditory lag for subjective simultaneity needed an auditory lead for maximal McGurk, and vice versa. This generalised to the Stream-Bounce illusion. Such surprising antagonism seems opposed to good sensory resynchronisation, yet average timing across tasks was still near-veridical. Our findings reveal remarkable disunity of audiovisual timing within and between subjects. To explain this we propose that the timing of audiovisual signals within different brain mechanisms is perceived relative to the average timing across mechanisms. Such renormalisation fully explains the curious antagonistic relationship between disparate timing estimates in PH and healthy participants, and how they can still perceive the timing of external events correctly, on average.	\N	\N
24974346	We investigated whether visual speech fills in non-intact auditory speech (excised consonant onsets) in typically developing children from 4 to 14 years of age. Stimuli with the excised auditory onsets were presented in the audiovisual (AV) and auditory-only (AO) modes. A visual speech fill-in effect occurs when listeners experience hearing the same non-intact auditory stimulus (e.g., /-b/ag) as different depending on the presence/absence of visual speech such as hearing /bag/ in the AV mode but hearing /ag/ in the AO mode. We quantified the visual speech fill-in effect by the difference in the number of correct consonant onset responses between the modes. We found that easy visual speech cues /b/ provided greater filling in than difficult cues /g/. Only older children benefited from difficult visual speech cues, whereas all children benefited from easy visual speech cues, although 4- and 5-year-olds did not benefit as much as older children. To explore task demands, we compared results on our new task with those on the McGurk task. The influence of visual speech was uniquely associated with age and vocabulary abilities for the visual speech fill--in effect but was uniquely associated with speechreading skills for the McGurk effect. This dissociation implies that visual speech--as processed by children-is a complicated and multifaceted phenomenon underpinned by heterogeneous abilities. These results emphasize that children perceive a speaker's utterance rather than the auditory stimulus per se. In children, as in adults, there is more to speech perception than meets the ear.	\N	\N
24996043	The brain improves speech processing through the integration of audiovisual (AV) signals. Situations involving AV speech integration may be crudely dichotomized into those where auditory and visual inputs contain (1) equivalent, complementary signals (validating AV speech) or (2) inconsistent, different signals (conflicting AV speech). This simple framework may allow the systematic examination of broad commonalities and differences between AV neural processes engaged by various experimental paradigms frequently used to study AV speech integration. We conducted an activation likelihood estimation metaanalysis of 22 functional imaging studies comprising 33 experiments, 311 subjects, and 347 foci examining "conflicting" versus "validating" AV speech. Experimental paradigms included content congruency, timing synchrony, and perceptual measures, such as the McGurk effect or synchrony judgments, across AV speech stimulus types (sublexical to sentence). Colocalization of conflicting AV speech experiments revealed consistency across at least two contrast types (e.g., synchrony and congruency) in a network of dorsal stream regions in the frontal, parietal, and temporal lobes. There was consistency across all contrast types (synchrony, congruency, and percept) in the bilateral posterior superior/middle temporal cortex. Although fewer studies were available, validating AV speech experiments were localized to other regions, such as ventral stream visual areas in the occipital and inferior temporal cortex. These results suggest that while equivalent, complementary AV speech signals may evoke activity in regions related to the corroboration of sensory input, conflicting AV speech signals recruit widespread dorsal stream areas likely involved in the resolution of conflicting sensory signals.	\N	\N
20541597	Auditory perceptual 'restoration' occurs when the auditory system restores an occluded or masked sound of interest. Behavioral work on auditory restoration in humans began over 50 years ago using it to model a noisy environmental scene with competing sounds. It has become clear that not only humans experience auditory restoration: restoration has been broadly conserved in many species. Behavioral studies in humans and animals provide a necessary foundation to link the insights being obtained from human EEG and fMRI to those from animal neurophysiology. The aggregate of data resulting from multiple approaches across species has begun to clarify the neuronal bases of auditory restoration. Different types of neural responses supporting restoration have been found, supportive of multiple mechanisms working within a species. Yet a general principle has emerged that responses correlated with restoration mimic the response that would have been given to the uninterrupted sound of interest. Using the same technology to study different species will help us to better harness animal models of 'auditory scene analysis' to clarify the conserved neural mechanisms shaping the perceptual organization of sound and to advance strategies to improve hearing in natural environmental settings.	\N	\N
20826671	Processing of complex acoustic scenes depends critically on the temporal integration of sensory information as sounds evolve naturally over time. It has been previously speculated that this process is guided by both innate mechanisms of temporal processing in the auditory system, as well as top-down mechanisms of attention and possibly other schema-based processes. In an effort to unravel the neural underpinnings of these processes and their role in scene analysis, we combine magnetoencephalography (MEG) with behavioral measures in humans in the context of polyrhythmic tone sequences. While maintaining unchanged sensory input, we manipulate subjects' attention to one of two competing rhythmic streams in the same sequence. The results reveal that the neural representation of the attended rhythm is significantly enhanced in both its steady-state power and spatial phase coherence relative to its unattended state, closely correlating with its perceptual detectability for each listener. Interestingly, the data reveal a differential efficiency of rhythmic rates of the order of few hertz during the streaming process, closely following known neural and behavioral measures of temporal modulation sensitivity in the auditory system. These findings establish a direct link between known temporal modulation tuning in the auditory system (particularly at the level of auditory cortex) and the temporal integration of perceptual features in a complex acoustic scene, while mediated by processes of attention.	\N	\N
20844143	Segregation of concurrent sounds in complex acoustic environments is a fundamental feature of auditory scene analysis. A powerful cue used by the auditory system to segregate concurrent sounds, such as speakers' voices at a cocktail party, is inharmonicity. This can be demonstrated when a component of a harmonic complex tone is perceived as a separate tone "popping out" from the complex as a whole when it is sufficiently mistuned from its harmonic value. The neural bases of perceptual "pop out" of mistuned harmonics are unclear. We recorded multiunit activity from primary auditory cortex (A1) of behaving monkeys elicited by harmonic complex tones that were either "in tune" or that contained a mistuned third harmonic set at the best frequency of the neural populations. Responses to mistuned sounds were enhanced relative to responses to "in-tune" sounds, thus correlating with the enhanced perceptual salience of the mistuned component. Consistent with human psychophysics of "pop out," response enhancements increased with the degree of mistuning, were maximal for neural populations tuned to the frequency of the mistuned component, and were not observed under comparable stimulus conditions that do not elicit perceptual "pop out." Mistuning was also associated with changes in neuronal temporal response patterns phase locked to "beats" in the stimuli. Intracortical auditory evoked potentials paralleled noninvasive neurophysiological correlates of perceptual "pop out" in humans, further augmenting the translational relevance of the results. Findings suggest two complementary neural mechanisms for "pop out," based on the detection of local differences in activation level or coherence of temporal response patterns across A1.	\N	\N
20975559	Analysis of the auditory environment, source identification and vocal communication all require efficient brain mechanisms for disambiguating, representing and understanding complex natural sounds as 'auditory objects'. Failure of these mechanisms leads to a diverse spectrum of clinical deficits. Here we review current evidence concerning the phenomenology, mechanisms and brain substrates of auditory agnosias and related disorders of auditory object processing. Analysis of lesions causing auditory object deficits has revealed certain broad anatomical correlations: deficient parsing of the auditory scene is associated with lesions involving the parieto-temporal junction, while selective disorders of sound recognition occur with more anterior temporal lobe or extra-temporal damage. Distributed neural networks have been increasingly implicated in the pathogenesis of such disorders as developmental dyslexia, congenital amusia and tinnitus. Auditory category deficits may arise from defective interaction of spectrotemporal encoding and executive and mnestic processes. Dedicated brain mechanisms are likely to process specialized sound objects such as voices and melodies. Emerging empirical evidence suggests a clinically relevant, hierarchical and modular neuropsychological model of auditory object processing that provides a framework for understanding auditory agnosias and makes specific predictions to direct future work.	\N	\N
21196054	Humans and other animals can attend to one of multiple sounds and follow it selectively over time. The neural underpinnings of this perceptual feat remain mysterious. Some studies have concluded that sounds are heard as separate streams when they activate well-separated populations of central auditory neurons, and that this process is largely pre-attentive. Here, we argue instead that stream formation depends primarily on temporal coherence between responses that encode various features of a sound source. Furthermore, we postulate that only when attention is directed towards a particular feature (e.g. pitch) do all other temporally coherent features of that source (e.g. timbre and location) become bound together as a stream that is segregated from the incoherent features of other sources.	\N	\N
21209201	Auditory figure-ground segregation, listeners' ability to selectively hear out a sound of interest from a background of competing sounds, is a fundamental aspect of scene analysis. In contrast to the disordered acoustic environment we experience during everyday listening, most studies of auditory segregation have used relatively simple, temporally regular signals. We developed a new figure-ground stimulus that incorporates stochastic variation of the figure and background that captures the rich spectrotemporal complexity of natural acoustic scenes. Figure and background signals overlap in spectrotemporal space, but vary in the statistics of fluctuation, such that the only way to extract the figure is by integrating the patterns over time and frequency. Our behavioral results demonstrate that human listeners are remarkably sensitive to the appearance of such figures. In a functional magnetic resonance imaging experiment, aimed at investigating preattentive, stimulus-driven, auditory segregation mechanisms, naive subjects listened to these stimuli while performing an irrelevant task. Results demonstrate significant activations in the intraparietal sulcus (IPS) and the superior temporal sulcus related to bottom-up, stimulus-driven figure-ground decomposition. We did not observe any significant activation in the primary auditory cortex. Our results support a role for automatic, bottom-up mechanisms in the IPS in mediating stimulus-driven, auditory figure-ground segregation, which is consistent with accumulating evidence implicating the IPS in structuring sensory input and perceptual organization.	\N	\N
21355664	The effect of context on the identification of common environmental sounds (e.g., dogs barking or cars honking) was tested by embedding them in familiar auditory background scenes (street ambience, restaurants). Initial results with subjects trained on both the scenes and the sounds to be identified showed a significant advantage of about five percentage points better accuracy for sounds that were contextually incongruous with the background scene (e.g., a rooster crowing in a hospital). Further studies with naive (untrained) listeners showed that this incongruency advantage (IA) is level-dependent: there is no advantage for incongruent sounds lower than a Sound/Scene ratio (So/Sc) of -7.5 dB, but there is about five percentage points better accuracy for sounds with greater So/Sc. Testing a new group of trained listeners on a larger corpus of sounds and scenes showed that the effect is robust and not confined to a specific stimulus set. Modeling using spectral-temporal measures showed that neither analyses based on acoustic features, nor semantic assessments of sound-scene congruency can account for this difference, indicating the IA is a complex effect, possibly arising from the sensitivity of the auditory system to new and unexpected events, under particular listening conditions.	\N	\N
21387016	Important sounds can be easily missed or misidentified in the presence of extraneous noise. We describe an auditory illusion in which a continuous ongoing tone becomes inaudible during a brief, non-masking noise burst more than one octave away, which is unexpected given the frequency resolution of human hearing. Participants strongly susceptible to this illusory discontinuity did not perceive illusory auditory continuity (in which a sound subjectively continues during a burst of masking noise) when the noises were short, yet did so at longer noise durations. Participants who were not prone to illusory discontinuity showed robust early electroencephalographic responses at 40-66 ms after noise burst onset, whereas those prone to the illusion lacked these early responses. These data suggest that short-latency neural responses to auditory scene components reflect subsequent individual differences in the parsing of auditory scenes.	\N	\N
21428515	The precedence effect (PE) describes the ability to localize a direct, leading sound correctly when its delayed copy (lag) is present, though not separately audible. The relative contribution of binaural cues in the temporal fine structure (TFS) of lead-lag signals was compared to that of interaural level differences (ILDs) and interaural time differences (ITDs) carried in the envelope. In a localization dominance paradigm participants indicated the spatial location of lead-lag stimuli processed with a binaural noise-band vocoder whose noise carriers introduced random TFS. The PE appeared for noise bursts of 10 ms duration, indicating dominance of envelope information. However, for three test words the PE often failed even at short lead-lag delays, producing two images, one toward the lead and one toward the lag. When interaural correlation in the carrier was increased, the images appeared more centered, but often remained split. Although previous studies suggest dominance of TFS cues, no image is lateralized in accord with the ITD in the TFS. An interpretation in the context of auditory scene analysis is proposed: By replacing the TFS with that of noise the auditory system loses the ability to fuse lead and lag into one object, and thus to show the PE.	\N	\N
21945789	This study investigates how acoustic change-events are represented in a listener's brain when attention is strongly focused elsewhere. Using magneto-encephalography (MEG) we examine whether cortical responses to different kinds of changes in stimulus statistics are similarly influenced by attentional load, and whether the processing of such acoustic changes in auditory cortex depends on modality-specific or general processing resources. We investigated these issues by examining cortical responses to two basic forms of acoustic transitions: (1) Violations of a simple acoustic pattern and (2) the emergence of a regular pattern from a random one. To simulate a complex sensory environment, these patterns were presented concurrently with streams of auditory and visual decoys. Listeners were required to perform tasks of high- and low-attentional-load in these domains. Results demonstrate that while auditory attentional-load does not influence the cortical representation of simple violations of regularity, it significantly reduces the magnitude of responses to the emergence of a regular acoustic pattern, suggesting a fundamentally skewed representation of the unattended auditory scene. In contrast, visual attentional-load had no effect on either transition response, consistent with the hypothesis that processing resources necessary for change detection are modality-specific.	\N	\N
22036957	Parsing of sound sources in the auditory environment or 'auditory scene analysis' is a computationally demanding cognitive operation that is likely to be vulnerable to the neurodegenerative process in Alzheimer's disease. However, little information is available concerning auditory scene analysis in Alzheimer's disease. Here we undertook a detailed neuropsychological and neuroanatomical characterization of auditory scene analysis in a cohort of 21 patients with clinically typical Alzheimer's disease versus age-matched healthy control subjects. We designed a novel auditory dual stream paradigm based on synthetic sound sequences to assess two key generic operations in auditory scene analysis (object segregation and grouping) in relation to simpler auditory perceptual, task and general neuropsychological factors. In order to assess neuroanatomical associations of performance on auditory scene analysis tasks, structural brain magnetic resonance imaging data from the patient cohort were analysed using voxel-based morphometry. Compared with healthy controls, patients with Alzheimer's disease had impairments of auditory scene analysis, and segregation and grouping operations were comparably affected. Auditory scene analysis impairments in Alzheimer's disease were not wholly attributable to simple auditory perceptual or task factors; however, the between-group difference relative to healthy controls was attenuated after accounting for non-verbal (visuospatial) working memory capacity. These findings demonstrate that clinically typical Alzheimer's disease is associated with a generic deficit of auditory scene analysis. Neuroanatomical associations of auditory scene analysis performance were identified in posterior cortical areas including the posterior superior temporal lobes and posterior cingulate. This work suggests a basis for understanding a class of clinical symptoms in Alzheimer's disease and for delineating cognitive mechanisms that mediate auditory scene analysis both in health and in neurodegenerative disease.	\N	\N
22280585	Despite many studies investigating auditory spatial impressions in rooms, few have addressed the impact of simultaneous visual cues on localization and the perception of spaciousness. The current research presents an immersive audiovisual environment in which participants were instructed to make auditory width judgments in dynamic bi-modal settings. The results of these psychophysical tests suggest the importance of congruent audio visual presentation to the ecological interpretation of an auditory scene. Supporting data were accumulated in five rooms of ascending volumes and varying reverberation times. Participants were given an audiovisual matching test in which they were instructed to pan the auditory width of a performing ensemble to a varying set of audio and visual cues in rooms. Results show that both auditory and visual factors affect the collected responses and that the two sensory modalities coincide in distinct interactions. The greatest differences between the panned audio stimuli given a fixed visual width were found in the physical space with the largest volume and the greatest source distance. These results suggest, in this specific instance, a predominance of auditory cues in the spatial analysis of the bi-modal scene.	\N	\N
22371616	Auditory streaming and visual plaids have been used extensively to study perceptual organization in each modality. Both stimuli can produce bistable alternations between grouped (one object) and split (two objects) interpretations. They also share two peculiar features: (i) at the onset of stimulus presentation, organization starts with a systematic bias towards the grouped interpretation; (ii) this first percept has 'inertia'; it lasts longer than the subsequent ones. As a result, the probability of forming different objects builds up over time, a landmark of both behavioural and neurophysiological data on auditory streaming. Here we show that first percept bias and inertia are independent. In plaid perception, inertia is due to a depth ordering ambiguity in the transparent (split) interpretation that makes plaid perception tristable rather than bistable: experimental manipulations removing the depth ambiguity suppressed inertia. However, the first percept bias persisted. We attempted a similar manipulation for auditory streaming by introducing level differences between streams, to bias which stream would appear in the perceptual foreground. Here both inertia and first percept bias persisted. We thus argue that the critical common feature of the onset of perceptual organization is the grouping bias, which may be related to the transition from temporally/spatially local to temporally/spatially global computation.	\N	\N
22371619	Recent studies have shown that auditory scene analysis involves distributed neural sites below, in, and beyond the auditory cortex (AC). However, it remains unclear what role each site plays and how they interact in the formation and selection of auditory percepts. We addressed this issue through perceptual multistability phenomena, namely, spontaneous perceptual switching in auditory streaming (AS) for a sequence of repeated triplet tones, and perceptual changes for a repeated word, known as verbal transformations (VTs). An event-related fMRI analysis revealed brain activity timelocked to perceptual switching in the cerebellum for AS, in frontal areas for VT, and the AC and thalamus for both. The results suggest that motor-based prediction, produced by neural networks outside the auditory system, plays essential roles in the segmentation of acoustic sequences both in AS and VT. The frequency of perceptual switching was determined by a balance between the activation of two sites, which are proposed to be involved in exploring novel perceptual organization and stabilizing current perceptual organization. The effect of the gene polymorphism of catechol-O-methyltransferase (COMT) on individual variations in switching frequency suggests that the balance of exploration and stabilization is modulated by catecholamines such as dopamine and noradrenalin. These mechanisms would support the noteworthy flexibility of auditory scene analysis.	\N	\N
22371621	Auditory stream segregation involves linking temporally separate acoustic events into one or more coherent sequences. For any non-trivial sequence of sounds, many alternative descriptions can be formed, only one or very few of which emerge in awareness at any time. Evidence from studies showing bi-/multistability in auditory streaming suggest that some, perhaps many of the alternative descriptions are represented in the brain in parallel and that they continuously vie for conscious perception. Here, based on a predictive coding view, we consider the nature of these sound representations and how they compete with each other. Predictive processing helps to maintain perceptual stability by signalling the continuation of previously established patterns as well as the emergence of new sound sources. It also provides a measure of how well each of the competing representations describes the current acoustic scene. This account of auditory stream segregation has been tested on perceptual data obtained in the auditory streaming paradigm.	\N	\N
22612172	Observers often remember a scene as containing information that was not presented but that would have likely been located just beyond the observed boundaries of the scene. This effect is called boundary extension (BE; e.g., Intraub & Richardson, 1989). Previous studies have observed BE in memory for visual and haptic stimuli, and the present experiments examined whether BE occurred in memory for auditory stimuli (prose, music). Experiments 1 and 2 varied the amount of auditory content to be remembered. BE was not observed, but when auditory targets contained more content, boundary restriction (BR) occurred. Experiment 3 presented auditory stimuli with less content and BR also occurred. In Experiment 4, white noise was added to stimuli with less content to equalize the durations of auditory stimuli, and BR still occurred. Experiments 5 and 6 presented trained stories and popular music, and BR still occurred. This latter finding ruled out the hypothesis that the lack of BE in Experiments 1-4 reflected a lack of familiarity with the stimuli. Overall, memory for auditory content exhibited BR rather than BE, and this pattern was stronger if auditory stimuli contained more content. Implications for the understanding of general perceptual processing and directions for future research are discussed.	\N	\N
22753470	A visual scene is perceived in terms of visual objects. Similar ideas have been proposed for the analogous case of auditory scene analysis, although their hypothesized neural underpinnings have not yet been established. Here, we address this question by recording from subjects selectively listening to one of two competing speakers, either of different or the same sex, using magnetoencephalography. Individual neural representations are seen for the speech of the two speakers, with each being selectively phase locked to the rhythm of the corresponding speech stream and from which can be exclusively reconstructed the temporal envelope of that speech stream. The neural representation of the attended speech dominates responses (with latency near 100 ms) in posterior auditory cortex. Furthermore, when the intensity of the attended and background speakers is separately varied over an 8-dB range, the neural representation of the attended speech adapts only to the intensity of that speaker but not to the intensity of the background speaker, suggesting an object-level intensity gain control. In summary, these results indicate that concurrent auditory objects, even if spectrotemporally overlapping and not resolvable at the auditory periphery, are neurally encoded individually in auditory cortex and emerge as fundamental representational units for top-down attentional modulation and bottom-up neural adaptation.	\N	\N
22829899	In natural environments, sensory information is embedded in temporally contiguous streams of events. This is typically the case when seeing and listening to a speaker or when engaged in scene analysis. In such contexts, two mechanisms are needed to single out and build a reliable representation of an event (or object): the temporal parsing of information and the selection of relevant information in the stream. It has previously been shown that rhythmic events naturally build temporal expectations that improve sensory processing at predictable points in time. Here, we asked to which extent temporal regularities can improve the detection and identification of events across sensory modalities. To do so, we used a dynamic visual conjunction search task accompanied by auditory cues synchronized or not with the color change of the target (horizontal or vertical bar). Sounds synchronized with the visual target improved search efficiency for temporal rates below 1.4 Hz but did not affect efficiency above that stimulation rate. Desynchronized auditory cues consistently impaired visual search below 3.3 Hz. Our results are interpreted in the context of the Dynamic Attending Theory: specifically, we suggest that a cognitive operation structures events in time irrespective of the sensory modality of input. Our results further support and specify recent neurophysiological findings by showing strong temporal selectivity for audiovisual integration in the auditory-driven improvement of visual search efficiency.	\N	\N
22844509	In auditory scene analysis, population separation and temporal coherence have been proposed to explain how auditory features are grouped together and streamed over time. The present study investigated whether these two theories can be applied to tactile streaming and whether temporal coherence theory can be applied to crossmodal streaming. The results show that synchrony detection between two tones/taps at different frequencies/locations became difficult when one of the tones/taps was embedded in a perceptual stream. While the taps applied to the same location were streamed over time, the taps applied to different locations were not. This observation suggests that tactile stream formation can be explained by population-separation theory. On the other hand, temporally coherent auditory stimuli at different frequencies were streamed over time, but temporally coherent tactile stimuli applied to different locations were not. When there was within-modality streaming, temporally coherent auditory stimuli and tactile stimuli were not streamed over time, either. This observation suggests the limitation of temporal coherence theory when it is applied to perceptual grouping over time.	\N	\N
23029426	The ability to detect sudden changes in the environment is critical for survival. Hearing is hypothesized to play a major role in this process by serving as an "early warning device," rapidly directing attention to new events. Here, we investigate listeners' sensitivity to changes in complex acoustic scenes-what makes certain events "pop-out" and grab attention while others remain unnoticed? We use artificial "scenes" populated by multiple pure-tone components, each with a unique frequency and amplitude modulation rate. Importantly, these scenes lack semantic attributes, which may have confounded previous studies, thus allowing us to probe low-level processes involved in auditory change perception. Our results reveal a striking difference between "appear" and "disappear" events. Listeners are remarkably tuned to object appearance: change detection and identification performance are at ceiling; response times are short, with little effect of scene-size, suggesting a pop-out process. In contrast, listeners have difficulty detecting disappearing objects, even in small scenes: performance rapidly deteriorates with growing scene-size; response times are slow, and even when change is detected, the changed component is rarely successfully identified. We also measured change detection performance when a noise or silent gap was inserted at the time of change or when the scene was interrupted by a distractor that occurred at the time of change but did not mask any scene elements. Gaps adversely affected the processing of item appearance but not disappearance. However, distractors reduced both appearance and disappearance detection. Together, our results suggest a role for neural adaptation and sensitivity to transients in the process of auditory change detection, similar to what has been demonstrated for visual change detection. Importantly, listeners consistently performed better for item addition (relative to deletion) across all scene interruptions used, suggesting a robust perceptual representation of item appearance.	\N	\N
23145699	Listeners are good at attending to one auditory stream in a crowded environment. However, is there an upper limit of streams present in an auditory scene at which this selective attention breaks down? Here, participants were asked to attend one stream of spoken letters amidst other letter streams. In half of the trials, an initial primer was played, cueing subjects to the sound configuration. Results indicate that performance increases with token repetitions. Priming provided a performance benefit, suggesting that stream selection, not formation, is the bottleneck associated with attention in an overcrowded scene. Results' implications for brain-computer interfaces are discussed.	\N	\N
23423817	A variety of perceptual correspondences between auditory and visual features have been reported, but few studies have investigated how rhythm, an auditory feature defined purely by dynamics relevant to speech and music, interacts with visual features. Here, we demonstrate a novel crossmodal association between auditory rhythm and visual clutter. Participants were shown a variety of visual scenes from diverse categories and asked to report the auditory rhythm that perceptually matched each scene by adjusting the rate of amplitude modulation (AM) of a sound. Participants matched each scene to a specific AM rate with surprising consistency. A spatial-frequency analysis showed that scenes with greater contrast energy in midrange spatial frequencies were matched to faster AM rates. Bandpass-filtering the scenes indicated that greater contrast energy in this spatial-frequency range was associated with an abundance of object boundaries and contours, suggesting that participants matched more cluttered scenes to faster AM rates. Consistent with this hypothesis, AM-rate matches were strongly correlated with perceived clutter. Additional results indicated that both AM-rate matches and perceived clutter depend on object-based (cycles per object) rather than retinal (cycles per degree of visual angle) spatial frequency. Taken together, these results suggest a systematic crossmodal association between auditory rhythm, representing density in the temporal domain, and visual clutter, representing object-based density in the spatial domain. This association may allow for the use of auditory rhythm to influence how visual clutter is perceived and attended.	\N	\N
23516340	Many sound sources can only be recognised from the pattern of sounds they emit, and not from the individual sound events that make up their emission sequences. Auditory scene analysis addresses the difficult task of interpreting the sound world in terms of an unknown number of discrete sound sources (causes) with possibly overlapping signals, and therefore of associating each event with the appropriate source. There are potentially many different ways in which incoming events can be assigned to different causes, which means that the auditory system has to choose between them. This problem has been studied for many years using the auditory streaming paradigm, and recently it has become apparent that instead of making one fixed perceptual decision, given sufficient time, auditory perception switches back and forth between the alternatives-a phenomenon known as perceptual bi- or multi-stability. We propose a new model of auditory scene analysis at the core of which is a process that seeks to discover predictable patterns in the ongoing sound sequence. Representations of predictable fragments are created on the fly, and are maintained, strengthened or weakened on the basis of their predictive success, and conflict with other representations. Auditory perceptual organisation emerges spontaneously from the nature of the competition between these representations. We present detailed comparisons between the model simulations and data from an auditory streaming experiment, and show that the model accounts for many important findings, including: the emergence of, and switching between, alternative organisations; the influence of stimulus parameters on perceptual dominance, switching rate and perceptual phase durations; and the build-up of auditory streaming. The principal contribution of the model is to show that a two-stage process of pattern discovery and competition between incompatible patterns can account for both the contents (perceptual organisations) and the dynamics of human perception in auditory streaming.	\N	\N
23527271	The auditory system creates a neuronal representation of the acoustic world based on spectral and temporal cues present at the listener's ears, including cues that potentially signal the locations of sounds. Discrimination of concurrent sounds from multiple sources is especially challenging. The current study is part of an effort to better understand the neuronal mechanisms governing this process, which has been termed "auditory scene analysis". In particular, we are interested in spatial release from masking by which spatial cues can segregate signals from other competing sounds, thereby overcoming the tendency of overlapping spectra and/or common temporal envelopes to fuse signals with maskers. We studied detection of pulsed tones in free-field conditions in the presence of concurrent multi-tone non-speech maskers. In "energetic" masking conditions, in which the frequencies of maskers fell within the ± 1/3-octave band containing the signal, spatial release from masking at low frequencies (~600 Hz) was found to be about 10 dB. In contrast, negligible spatial release from energetic masking was seen at high frequencies (~4000 Hz). We observed robust spatial release from masking in broadband "informational" masking conditions, in which listeners could confuse signal with masker even though there was no spectral overlap. Substantial spatial release was observed in conditions in which the onsets of the signal and all masker components were synchronized, and spatial release was even greater under asynchronous conditions. Spatial cues limited to high frequencies (>1500 Hz), which could have included interaural level differences and the better-ear effect, produced only limited improvement in signal detection. Substantially greater improvement was seen for low-frequency sounds, for which interaural time differences are the dominant spatial cue.	\N	\N
23691185	Listening to and understanding people in a "cocktail-party situation" is a remarkable feature of the human auditory system. Here we investigated the neural correlates of the ability to localize a particular sound among others in an acoustically cluttered environment with healthy subjects. In a sound localization task, five different natural sounds were presented from five virtual spatial locations during functional magnetic resonance imaging (fMRI). Activity related to auditory stream segregation was revealed in posterior superior temporal gyrus bilaterally, anterior insula, supplementary motor area, and frontoparietal network. Moreover, the results indicated critical roles of left planum temporale in extracting the sound of interest among acoustical distracters and the precuneus in orienting spatial attention to the target sound. We hypothesized that the left-sided lateralization of the planum temporale activation is related to the higher specialization of the left hemisphere for analysis of spectrotemporal sound features. Furthermore, the precuneus - a brain area known to be involved in the computation of spatial coordinates across diverse frames of reference for reaching to objects - seems to be also a crucial area for accurately determining locations of auditory targets in an acoustically complex scene of multiple sound sources. The precuneus thus may not only be involved in visuo-motor processes, but may also subserve related functions in the auditory modality.	\N	\N
23825404	In a complex auditory scene, a "cocktail party" for example, listeners can disentangle multiple competing sequences of sounds. A recent psychophysical study in our laboratory demonstrated a robust spatial component of stream segregation showing ∼8° acuity. Here, we recorded single- and multiple-neuron responses from the primary auditory cortex of anesthetized cats while presenting interleaved sound sequences that human listeners would experience as segregated streams. Sequences of broadband sounds alternated between pairs of locations. Neurons synchronized preferentially to sounds from one or the other location, thereby segregating competing sound sequences. Neurons favoring one source location or the other tended to aggregate within the cortex, suggestive of modular organization. The spatial acuity of stream segregation was as narrow as ∼10°, markedly sharper than the broad spatial tuning for single sources that is well known in the literature. Spatial sensitivity was sharpest among neurons having high characteristic frequencies. Neural stream segregation was predicted well by a parameter-free model that incorporated single-source spatial sensitivity and a measured forward-suppression term. We found that the forward suppression was not due to post discharge adaptation in the cortex and, therefore, must have arisen in the subcortical pathway or at the level of thalamocortical synapses. A linear-classifier analysis of single-neuron responses to rhythmic stimuli like those used in our psychophysical study yielded thresholds overlapping those of human listeners. Overall, the results indicate that the ascending auditory system does the work of segregating auditory streams, bringing them to discrete modules in the cortex for selection by top-down processes.	\N	\N
23926291	Previously, Gygi and Shafiro (2011) found that when environmental sounds are semantically incongruent with the background scene (e.g., horse galloping in a restaurant), they can be identified more accurately by young normal-hearing listeners (YNH) than sounds congruent with the scene (e.g., horse galloping at a racetrack). This study investigated how age and high-frequency audibility affect this Incongruency Advantage (IA) effect. In Experiments 1a and 1b, elderly listeners ( N = 18 for 1a; N = 10 for 1b) with age-appropriate hearing (EAH) were tested on target sounds and auditory scenes in 5 sound-to-scene ratios (So/Sc) between -3 and -18 dB. Experiment 2 tested 11 YNH on the same sound-scene pairings lowpass-filtered at 4 kHz (YNH-4k). The EAH and YNH-4k groups exhibited an almost identical pattern of significant IA effects, but both were at approximately 3.9 dB higher So/Sc than the previously tested YNH listeners. However, the psychometric functions revealed a shallower slope for EAH listeners compared with YNH listeners for the congruent stimuli only, suggesting a greater difficulty for the EAH listeners in attending to sounds expected to occur in a scene. These findings indicate that semantic relationships between environmental sounds in soundscapes are mediated by both audibility and cognitive factors and suggest a method for dissociating these factors.	\N	\N
24003112	After hearing a tone, the human auditory system becomes more sensitive to similar tones than to other tones. Current auditory models explain this phenomenon by a simple bandpass attention filter. Here, we demonstrate that auditory attention involves multiple pass-bands around octave-related frequencies above and below the cued tone. Intriguingly, this "octave effect" not only occurs for physically presented tones, but even persists for the missing fundamental in complex tones, and for imagined tones. Our results suggest neural interactions combining octave-related frequencies, likely located in nonprimary cortical regions. We speculate that this connectivity scheme evolved from exposure to natural vibrations containing octave-related spectral peaks, e.g., as produced by vocal cords.	\N	\N
24052177	The fundamental perceptual unit in hearing is the 'auditory object'. Similar to visual objects, auditory objects are the computational result of the auditory system's capacity to detect, extract, segregate and group spectrotemporal regularities in the acoustic environment; the multitude of acoustic stimuli around us together form the auditory scene. However, unlike the visual scene, resolving the component objects within the auditory scene crucially depends on their temporal structure. Neural correlates of auditory objects are found throughout the auditory system. However, neural responses do not become correlated with a listener's perceptual reports until the level of the cortex. The roles of different neural structures and the contribution of different cognitive states to the perception of auditory objects are not yet fully understood.	\N	\N
24239869	Perceptual representations of auditory stimuli (i.e., sounds) are derived from the auditory system's ability to segregate and group the spectral, temporal, and spatial features of auditory stimuli-a process called "auditory scene analysis". Psychophysical studies have identified several of the principles and mechanisms that underlie a listener's ability to segregate and group acoustic stimuli. One important psychophysical task that has illuminated many of these principles and mechanisms is the "streaming" task. Despite the wide use of this task to study psychophysical mechanisms of human audition, no studies have explicitly tested the streaming abilities of non-human animals using the standard methodologies employed in human-audition studies. Here, we trained rhesus macaques to participate in the streaming task using methodologies and controls similar to those presented in previous human studies. Overall, we found that the monkeys' behavioral reports were qualitatively consistent with those of human listeners, thus suggesting that this task may be a valuable tool for future neurophysiological studies.	\N	\N
24475030	In our daily lives, auditory stream segregation allows us to differentiate concurrent sound sources and to make sense of the scene we are experiencing. However, a combination of segregation and the concurrent integration of auditory streams is necessary in order to analyze the relationship between streams and thus perceive a coherent auditory scene. The present functional magnetic resonance imaging study investigates the relative role and neural underpinnings of these listening strategies in multi-part musical stimuli. We compare a real human performance of a piano duet and a synthetic stimulus of the same duet in a prioritized integrative attention paradigm that required the simultaneous segregation and integration of auditory streams. In so doing, we manipulate the degree to which the attended part of the duet led either structurally (attend melody vs. attend accompaniment) or temporally (asynchronies vs. no asynchronies between parts), and thus the relative contributions of integration and segregation used to make an assessment of the leader-follower relationship. We show that perceptually the relationship between parts is biased towards the conventional structural hierarchy in western music in which the melody generally dominates (leads) the accompaniment. Moreover, the assessment varies as a function of both cognitive load, as shown through difficulty ratings and the interaction of the temporal and the structural relationship factors. Neurally, we see that the temporal relationship between parts, as one important cue for stream segregation, revealed distinct neural activity in the planum temporale. By contrast, integration used when listening to both the temporally separated performance stimulus and the temporally fused synthetic stimulus resulted in activation of the intraparietal sulcus. These results support the hypothesis that the planum temporale and IPS are key structures underlying the mechanisms of segregation and integration of auditory streams, respectively.	\N	\N
24478375	Adaptation to both common and rare sounds has been independently reported in neurophysiological studies using probabilistic stimulus paradigms in small mammals. However, the apparent sensitivity of the mammalian auditory system to the statistics of incoming sound has not yet been generalized to task-related human auditory perception. Here, we show that human listeners selectively adapt to novel sounds within scenes unfolding over minutes. Listeners' performance in an auditory discrimination task remains steady for the most common elements within the scene but, after the first minute, performance improves for distinct and rare (oddball) sound elements, at the expense of rare sounds that are relatively less distinct. Our data provide the first evidence of enhanced coding of oddball sounds in a human auditory discrimination task and suggest the existence of an adaptive mechanism that tracks the long-term statistics of sounds and deploys coding resources accordingly.	\N	\N
24681354	The auditory system is designed to transform acoustic information from low-level sensory representations into perceptual representations. These perceptual representations are the computational result of the auditory system's ability to group and segregate spectral, spatial and temporal regularities in the acoustic environment into stable perceptual units (i.e., sounds or auditory objects). Current evidence suggests that the cortex-specifically, the ventral auditory pathway-is responsible for the computations most closely related to perceptual representations. Here, we discuss how the transformations along the ventral auditory pathway relate to auditory percepts, with special attention paid to the processing of vocalizations and categorization, and explore recent models of how these areas may carry out these computations.	\N	\N
24711409	Human perception, cognition, and action are laced with seemingly arbitrary mappings. In particular, sound has a strong spatial connotation: Sounds are high and low, melodies rise and fall, and pitch systematically biases perceived sound elevation. The origins of such mappings are unknown. Are they the result of physiological constraints, do they reflect natural environmental statistics, or are they truly arbitrary? We recorded natural sounds from the environment, analyzed the elevation-dependent filtering of the outer ear, and measured frequency-dependent biases in human sound localization. We find that auditory scene statistics reveals a clear mapping between frequency and elevation. Perhaps more interestingly, this natural statistical mapping is tightly mirrored in both ear-filtering properties and in perceived sound location. This suggests that both sound localization behavior and ear anatomy are fine-tuned to the statistics of natural auditory scenes, likely providing the basis for the spatial connotation of human hearing.	\N	\N
24788808	This work analyzed the perceptual attributes of natural dynamic audiovisual scenes. We presented thirty participants with 19 natural scenes in a similarity categorization task, followed by a semi-structured interview. The scenes were reproduced with an immersive audiovisual display. Natural scene perception has been studied mainly with unimodal settings, which have identified motion as one of the most salient attributes related to visual scenes, and sound intensity along with pitch trajectories related to auditory scenes. However, controlled laboratory experiments with natural multimodal stimuli are still scarce. Our results show that humans pay attention to similar perceptual attributes in natural scenes, and a two-dimensional perceptual map of the stimulus scenes and perceptual attributes was obtained in this work. The exploratory results show the amount of movement, perceived noisiness, and eventfulness of the scene to be the most important perceptual attributes in naturalistically reproduced real-world urban environments. We found the scene gist properties openness and expansion to remain as important factors in scenes with no salient auditory or visual events. We propose that the study of scene perception should move forward to understand better the processes behind multimodal scene processing in real-world environments. We publish our stimulus scenes as spherical video recordings and sound field recordings in a publicly available database.	\N	\N
24821552	Many studies have shown that attention modulates the cortical representation of an auditory scene, emphasizing an attended source while suppressing competing sources. Yet, individual differences in the strength of this attentional modulation and their relationship with selective attention ability are poorly understood. Here, we ask whether differences in how strongly attention modulates cortical responses reflect differences in normal-hearing listeners' selective auditory attention ability. We asked listeners to attend to one of three competing melodies and identify its pitch contour while we measured cortical electroencephalographic responses. The three melodies were either from widely separated pitch ranges ("easy trials"), or from a narrow, overlapping pitch range ("hard trials"). The melodies started at slightly different times; listeners attended either the leading or lagging melody. Because of the timing of the onsets, the leading melody drew attention exogenously. In contrast, attending the lagging melody required listeners to direct top-down attention volitionally. We quantified how attention amplified auditory N1 response to the attended melody and found large individual differences in the N1 amplification, even though only correctly answered trials were used to quantify the ERP gain. Importantly, listeners with the strongest amplification of N1 response to the lagging melody in the easy trials were the best performers across other types of trials. Our results raise the possibility that individual differences in the strength of top-down gain control reflect inherent differences in the ability to control top-down attention.	\N	\N
24841996	Auditory objects, like their visual counterparts, are perceptually defined constructs, but nevertheless must arise from underlying neural circuitry. Using magnetoencephalography (MEG) recordings of the neural responses of human subjects listening to complex auditory scenes, we review studies that demonstrate that auditory objects are indeed neurally represented in auditory cortex. The studies use neural responses obtained from different experiments in which subjects selectively listen to one of two competing auditory streams embedded in a variety of auditory scenes. The auditory streams overlap spatially and often spectrally. In particular, the studies demonstrate that selective attentional gain does not act globally on the entire auditory scene, but rather acts differentially on the separate auditory streams. This stream-based attentional gain is then used as a tool to individually analyze the different neural representations of the competing auditory streams. The neural representation of the attended stream, located in posterior auditory cortex, dominates the neural responses. Critically, when the intensities of the attended and background streams are separately varied over a wide intensity range, the neural representation of the attended speech adapts only to the intensity of that speaker, irrespective of the intensity of the background speaker. This demonstrates object-level intensity gain control in addition to the above object-level selective attentional gain. Overall, these results indicate that concurrently streaming auditory objects, even if spectrally overlapping and not resolvable at the auditory periphery, are individually neurally encoded in auditory cortex, as separate objects.	\N	\N
25433224	Pitch plays a fundamental role in audition, from speech and music perception to auditory scene analysis. Congenital amusia is a neurogenetic disorder that appears to affect primarily pitch and melody perception. Pitch is normally conveyed by the spectro-temporal fine structure of low harmonics, but some pitch information is available in the temporal envelope produced by the interactions of higher harmonics. Using 10 amusic subjects and 10 matched controls, we tested the hypothesis that amusics suffer exclusively from impaired processing of spectro-temporal fine structure. We also tested whether the inability of amusics to process acoustic temporal fine structure extends beyond pitch by measuring sensitivity to interaural time differences, which also rely on temporal fine structure. Further tests were carried out on basic intensity and spectral resolution. As expected, pitch perception based on spectro-temporal fine structure was impaired in amusics; however, no significant deficits were observed in amusics' ability to perceive the pitch conveyed via temporal-envelope cues. Sensitivity to interaural time differences was also not significantly different between the amusic and control groups, ruling out deficits in the peripheral coding of temporal fine structure. Finally, no significant differences in intensity or spectral resolution were found between the amusic and control groups. The results demonstrate a pitch-specific deficit in fine spectro-temporal information processing in amusia that seems unrelated to temporal or spectral coding in the auditory periphery. These results are consistent with the view that there are distinct mechanisms dedicated to processing resolved and unresolved harmonics in the general population, the former being altered in congenital amusia while the latter is spared.	\N	\N
25654748	In noisy settings, listening is aided by correlated dynamic visual cues gleaned from a talker's face-an improvement often attributed to visually reinforced linguistic information. In this study, we aimed to test the effect of audio-visual temporal coherence alone on selective listening, free of linguistic confounds. We presented listeners with competing auditory streams whose amplitude varied independently and a visual stimulus with varying radius, while manipulating the cross-modal temporal relationships. Performance improved when the auditory target's timecourse matched that of the visual stimulus. The fact that the coherence was between task-irrelevant stimulus features suggests that the observed improvement stemmed from the integration of auditory and visual streams into cross-modal objects, enabling listeners to better attend the target. These findings suggest that in everyday conditions, where listeners can often see the source of a sound, temporal cues provided by vision can help listeners to select one sound source from a mixture.	\N	\N
25659464	To probe sensitivity to the time structure of ongoing sound sequences, we measured MEG responses, in human listeners, to the offset of long tone-pip sequences containing various forms of temporal regularity. If listeners learn sequence temporal properties and form expectancies about the arrival time of an upcoming tone, sequence offset should be detectable as soon as an expected tone fails to arrive. Therefore, latencies of offset responses are indicative of the extent to which the temporal pattern has been acquired. In Exp1, sequences were isochronous with tone inter-onset-interval (IOI) set to 75, 125 or 225ms. Exp2 comprised of non-isochronous, temporally regular sequences, comprised of the IOIs above. Exp3 used the same sequences as Exp2 but listeners were required to monitor them for occasional frequency deviants. Analysis of the latency of offset responses revealed that the temporal structure of (even rather simple) regular sequences is not learnt precisely when the sequences are ignored. Pattern coding, supported by a network of temporal, parietal and frontal sources, improved considerably when the signals were made behaviourally pertinent. Thus, contrary to what might be expected in the context of an 'early warning system' framework, learning of temporal structure is not automatic, but affected by the signal's behavioural relevance.	\N	\N
25726262	Auditory development involves changes in the peripheral and central nervous system along the auditory pathways, and these occur naturally, and in response to stimulation. Human development occurs along a trajectory that can last decades, and is studied using behavioral psychophysics, as well as physiologic measurements with neural imaging. The auditory system constructs a perceptual space that takes information from objects and groups, segregates sounds, and provides meaning and access to communication tools such as language. Auditory signals are processed in a series of analysis stages, from peripheral to central. Coding of information has been studied for features of sound, including frequency, intensity, loudness, and location, in quiet and in the presence of maskers. In the latter case, the ability of the auditory system to perform an analysis of the scene becomes highly relevant. While some basic abilities are well developed at birth, there is a clear prolonged maturation of auditory development well into the teenage years. Maturation involves auditory pathways. However, non-auditory changes (attention, memory, cognition) play an important role in auditory development. The ability of the auditory system to adapt in response to novel stimuli is a key feature of development throughout the nervous system, known as neural plasticity.	\N	\N
22240459	Humans and other animals often communicate acoustically in noisy social groups, in which the background noise generated by other individuals can mask signals of interest. When listening to speech in the presence of speech-like noise, humans experience a release from auditory masking when target and masker are spatially separated. We investigated spatial release from masking (SRM) in a free-field call recognition task in Cope's gray treefrog (Hyla chrysoscelis). In this species, reproduction requires that females successfully detect, recognize, and localize a conspecific male in the noisy social environment of a breeding chorus. Using no-choice phonotaxis assays, we measured females' signal recognition thresholds in response to a target signal (an advertisement call) in the presence and absence of chorus-shaped noise. Females experienced about 3 dB of masking release, compared with a co-localized condition, when the masker was displaced 90° in azimuth from the target. The magnitude of masking release was independent of the spectral composition of the target (carriers of 1.3 kHz, 2.6 kHz, or both). Our results indicate that frogs experience a modest degree of spatial unmasking when performing a call recognition task in the free-field, and suggest that variation in signal spectral content has small effects on both source identification and spatial unmasking. We discuss these results in the context of spatial unmasking in vertebrates and call recognition in frogs.	\N	\N
20649227	The lateralization of 250-ms trains of brief noise bursts was measured using an acoustic pointing technique. Stimuli were designed to assess the contribution of the interaural time delay (ITD) of the onset binaural burst relative to that of the ITDs in the ongoing part of the train. Lateralization was measured by listeners' adjustments of the ITD of a pointer stimulus, a 50-ms burst of noise, to match the lateral position of the target train. Results confirmed previous reports of lateralization dominance by the onset burst under conditions in which the train is composed of frozen tokens and the ongoing part contains multiple ambiguous interaural delays. In contrast, lateralization of ongoing trains in which fresh noise tokens were used for each set of two alternating (left-leading/right-leading) binaural pairs followed the ITD of the first pair in each set, regardless of the ITD of the onset burst of the entire stimulus and even when the onset burst was removed by gradual gating. This clear lateralization of a long-duration stimulus with ambiguous interaural delay cues suggests precedence mechanisms that involve not only the interaural cues at the beginning of a sound, but also the pattern of cues within an ongoing sound.	\N	\N
21131368	The thalamic reticular nucleus (TRN) is a shell-shaped gamma amino butyric acid (GABA)ergic nucleus, which is uniquely placed between the thalamus and the cortex, because it receives excitatory afferents from both cortical and thalamic neurons and sends inhibitory projections to all nuclei of the dorsal thalamus. A review of the evidence suggesting that the TRN is implicated in the neurobiology of schizophrenia. TRN-thalamus circuits are implicated in bottom-up as well as top-down processing. TRN projections to nonspecific nuclei of the dorsal thalamus mediate top-down processes, including attentional modulation, which are initiated by cortical afferents to the TRN. TRN-thalamus circuits are also involved in bottom-up activities, including sensory gating and the transfer to the cortex of sleep spindles. Intriguingly, deficits in attention and sensory gating have been consistently found in schizophrenics, including first-break and chronic patients. Furthermore, high-density electroencephalographic studies have revealed a marked reduction in sleep spindles in schizophrenics. On the basis of our current knowledge on the molecular and anatomo-functional properties of the TRN, we suggest that this thalamic GABAergic nucleus may be involved in the neurobiology of schizophrenia.	\N	\N
22087275	How quickly do listeners recognize emotions from a speaker's voice, and does the time course for recognition vary by emotion type? To address these questions, we adapted the auditory gating paradigm to estimate how much vocal information is needed for listeners to categorize five basic emotions (anger, disgust, fear, sadness, happiness) and neutral utterances produced by male and female speakers of English. Semantically-anomalous pseudo-utterances (e.g., The rivix jolled the silling) conveying each emotion were divided into seven gate intervals according to the number of syllables that listeners heard from sentence onset. Participants (n = 48) judged the emotional meaning of stimuli presented at each gate duration interval, in a successive, blocked presentation format. Analyses looked at how recognition of each emotion evolves as an utterance unfolds and estimated the "identification point" for each emotion. Results showed that anger, sadness, fear, and neutral expressions are recognized more accurately at short gate intervals than happiness, and particularly disgust; however, as speech unfolds, recognition of happiness improves significantly towards the end of the utterance (and fear is recognized more accurately than other emotions). When the gate associated with the emotion identification point of each stimulus was calculated, data indicated that fear (M = 517 ms), sadness (M = 576 ms), and neutral (M = 510 ms) expressions were identified from shorter acoustic events than the other emotions. These data reveal differences in the underlying time course for conscious recognition of basic emotions from vocal expressions, which should be accounted for in studies of emotional speech processing.	\N	\N
22384211	Recent behavioral neuroscience research revealed that elementary reactive behavior can be improved in the case of cross-modal sensory interactions thanks to underlying multisensory integration mechanisms. Can this benefit be generalized to an ongoing coordination of movements under severe physical constraints? We choose a juggling task to examine this question. A central issue well-known in juggling lies in establishing and maintaining a specific temporal coordination among balls, hands, eyes and posture. Here, we tested whether providing additional timing information about the balls and hands motions by using external sound and tactile periodic stimulations, the later presented at the wrists, improved the behavior of jugglers. One specific combination of auditory and tactile metronome led to a decrease of the spatiotemporal variability of the juggler's performance: a simple sound associated to left and right tactile cues presented antiphase to each other, which corresponded to the temporal pattern of hands movement in the juggling task. A contrario, no improvements were obtained in the case of other auditory and tactile combinations. We even found a degraded performance when tactile events were presented alone. The nervous system thus appears able to integrate in efficient way environmental information brought by different sensory modalities, but only if the information specified matches specific features of the coordination pattern. We discuss the possible implications of these results for the understanding of the neuronal integration process implied in audio-tactile interaction in the context of complex voluntary movement, and considering the well-known gating effect of movement on vibrotactile perception.	\N	\N
22896044	Thresholds of school-aged children are elevated relative to those of adults for intensity discrimination and amplitude modulation (AM) detection. It is unclear how these findings are related or what role stimulus gating and dynamic envelope cues play in these results. Two experiments assessed the development of sensitivity to intensity increments in different stimulus contexts. Thresholds for detecting an increment in level were estimated for normal-hearing children (5- to 10-year-olds) and adults. Experiment 1 compared intensity discrimination for gated and continuous presentation of a 1-kHz tone, with a 65-dB-SPL standard level. Experiment 2 compared increment detection and 16-Hz AM detection introduced into a continuous 1-kHz tone, with either 35- or 75-dB-SPL standard levels. Children had higher thresholds than adults overall. All listeners were more sensitive to increments in the continuous than the gated stimulus and performed better at the 75- than at the 35-dB-SPL standard level. Both effects were comparable for children and adults. There was some evidence that children's AM detection was more adultlike than increment detection. These results imply that memory for loudness across gated intervals is not responsible for children's poor performance but that multiple dynamic envelope cues may benefit children more than adults.	\N	\N
23716244	This study investigated monaural envelope correlation perception (Richards 1987) for noise bandwidths ranging from 25 to 1,600 Hz. The high-frequency side of the low band was fixed at 3,000 Hz and the low-frequency side of the high band was fixed at 3,500 Hz. When comodulated, the magnitude spectra of the pair of noise bands were either identical or reflected around the midpoint. Six listeners with normal hearing participated. Listeners showed similar performance for identical and reflected-spectrum conditions, with best performance usually occurring for bandwidths between 200 and 800 Hz. Results were considered in terms of envelope comparisons of waveforms at the outputs of multiple peripheral filters or envelope comparisons of waveforms at the outputs of central filters set to the bandwidths of the noise stimuli. Some aspects of the results were incompatible with the account based on multiple peripheral filters. However, the results of a supplementary condition involving the gating of band subregions indicated that this incompatibility could be accounted for by nonoptimal weighting of peripheral filter outputs.	\N	\N
24298171	While watching movies, the brain integrates the visual information and the musical soundtrack into a coherent percept. Multisensory integration can lead to emotion elicitation on which soundtrack valences may have a modulatory impact. Here, dynamic kissing scenes from romantic comedies were presented to 22 participants (13 females) during functional magnetic resonance imaging scanning. The kissing scenes were either accompanied by happy music, sad music or no music. Evidence from cross-modal studies motivated a predefined three-region network for multisensory integration of emotion, consisting of fusiform gyrus (FG), amygdala (AMY) and anterior superior temporal gyrus (aSTG). The interactions in this network were investigated using dynamic causal models of effective connectivity. This revealed bilinear modulations by happy and sad music with suppression effects on the connectivity from FG and AMY to aSTG. Non-linear dynamic causal modeling showed a suppressive gating effect of aSTG on fusiform-amygdalar connectivity. In conclusion, fusiform to amygdala coupling strength is modulated via feedback through aSTG as region for multisensory integration of emotional material. This mechanism was emotion-specific and more pronounced for sad music. Therefore, soundtrack valences may modulate emotion elicitation in movies by differentially changing preprocessed visual information to the amygdala.	\N	\N
24736181	Although a number of recent studies have examined functional connectivity at rest, few have assessed differences between connectivity both during rest and across active task paradigms. Therefore, the question of whether cortical connectivity patterns remain stable or change with task engagement continues to be unaddressed. We collected multi-scan fMRI data on healthy controls (N=53) and schizophrenia patients (N=42) during rest and across paradigms arranged hierarchically by sensory load. We measured functional network connectivity among 45 non-artifactual distinct brain networks. Then, we applied a novel analysis to assess cross paradigm connectivity patterns applied to healthy controls and patients with schizophrenia. To detect these patterns, we fit a group by task full factorial ANOVA model to the group average functional network connectivity values. Our approach identified both stable (static effects) and state-based differences (dynamic effects) in brain connectivity providing a better understanding of how individuals' reactions to simple sensory stimuli are conditioned by the context within which they are presented. Our findings suggest that not all group differences observed during rest are detectable in other cognitive states. In addition, the stable differences of heightened connectivity between multiple brain areas with thalamus across tasks underscore the importance of the thalamus as a gateway to sensory input and provide new insight into schizophrenia.	\N	\N
24801767	Despite advances in the treatment of schizophrenia spectrum disorders with atypical antipsychotics (AAPs), there is still need for compounds with improved efficacy/side-effect ratios. Evidence from challenge studies suggests that the assessment of gating functions in humans and rodents with naturally low-gating levels might be a useful model to screen for novel compounds with antipsychotic properties. To further evaluate and extend this translational approach, three AAPs were examined. Compounds without antipsychotic properties served as negative control treatments. In a placebo-controlled, within-subject design, healthy males received either single doses of aripiprazole and risperidone (n=28), amisulpride and lorazepam (n=30), or modafinil and valproate (n=30), and placebo. Prepulse inhibiton (PPI) and P50 suppression were assessed. Clinically associated symptoms were evaluated using the SCL-90-R. Aripiprazole, risperidone, and amisulpride increased P50 suppression in low P50 gaters. Lorazepam, modafinil, and valproate did not influence P50 suppression in low gaters. Furthermore, low P50 gaters scored significantly higher on the SCL-90-R than high P50 gaters. Aripiprazole increased PPI in low PPI gaters, whereas modafinil and lorazepam attenuated PPI in both groups. Risperidone, amisulpride, and valproate did not influence PPI. P50 suppression in low gaters appears to be an antipsychotic-sensitive neurophysiologic marker. This conclusion is supported by the association of low P50 suppression and higher clinically associated scores. Furthermore, PPI might be sensitive for atypical mechanisms of antipsychotic medication. The translational model investigating differential effects of AAPs on gating in healthy subjects with naturally low gating can be beneficial for phase II/III development plans by providing additional information for critical decision making.	\N	\N
25024207	Historic theories of speech perception (Motor Theory and Analysis by Synthesis) invoked listeners' knowledge of speech production to explain speech perception. Neuroimaging data show that adult listeners activate motor brain areas during speech perception. In two experiments using magnetoencephalography (MEG), we investigated motor brain activation, as well as auditory brain activation, during discrimination of native and nonnative syllables in infants at two ages that straddle the developmental transition from language-universal to language-specific speech perception. Adults are also tested in Exp. 1. MEG data revealed that 7-mo-old infants activate auditory (superior temporal) as well as motor brain areas (Broca's area, cerebellum) in response to speech, and equivalently for native and nonnative syllables. However, in 11- and 12-mo-old infants, native speech activates auditory brain areas to a greater degree than nonnative, whereas nonnative speech activates motor brain areas to a greater degree than native speech. This double dissociation in 11- to 12-mo-old infants matches the pattern of results obtained in adult listeners. Our infant data are consistent with Analysis by Synthesis: auditory analysis of speech is coupled with synthesis of the motor plans necessary to produce the speech signal. The findings have implications for: (i) perception-action theories of speech perception, (ii) the impact of "motherese" on early language learning, and (iii) the "social-gating" hypothesis and humans' development of social understanding.	\N	\N
25544613	Perception routinely integrates inputs from different senses. Stimulus temporal proximity critically determines whether or not these inputs are bound together. Despite the temporal window of integration being a widely accepted notion, its neurophysiological substrate remains unclear. Many types of common audio-visual interactions occur within a time window of ∼100 ms. For example, in the sound-induced double-flash illusion, when two beeps are presented within ∼100 ms together with one flash, a second illusory flash is often perceived. Due to their intrinsic rhythmic nature, brain oscillations are one candidate mechanism for gating the temporal window of integration. Interestingly, occipital alpha band oscillations cycle on average every ∼100 ms, with peak frequencies ranging between 8 and 14 Hz (i.e., 120-60 ms cycle). Moreover, presenting a brief tone can phase-reset such oscillations in visual cortex. Based on these observations, we hypothesized that the duration of each alpha cycle might provide the temporal unit to bind audio-visual events. Here, we first recorded EEG while participants performed the sound-induced double-flash illusion task and found positive correlation between individual alpha frequency (IAF) peak and the size of the temporal window of the illusion. Participants then performed the same task while receiving occipital transcranial alternating current stimulation (tACS), to modulate oscillatory activity either at their IAF or at off-peak alpha frequencies (IAF±2 Hz). Compared to IAF tACS, IAF-2 Hz and IAF+2 Hz tACS, respectively, enlarged and shrunk the temporal window of illusion, suggesting that alpha oscillations might represent the temporal unit of visual processing that cyclically gates perception and the neurophysiological substrate promoting audio-visual interactions.	\N	\N
19616325	A patient with ankylosing spondylitis, migraine, Parkinson syndrome, renal insufficiency and myopathy, received an implantable-cardioverter-defibrillator because of asymptomatic left ventricular hypertrabeculation/noncompaction as primary prophylaxis against sudden cardiac death. Inadvertently the ventricular lead was placed in a cardiac vein, the patient suffered from pericardial effusion and it was impossible to remove the lead. Implantation of an implantable-cardioverter-defibrillator simply upon the presence of LVHT appears not justified and may be more harmful than beneficial. Studies about the risk of SCD in adults with LVHT are necessary and will hopefully clarify if primary prevention of SCD is indicated.	\N	\N
19770797	FX06 is a naturally occurring fibrin-derived peptide demonstrated to confer cytoprotection in the setting of primary percutaneous coronary intervention. Because the effect of FX06 on human platelet, coagulation, and fibrinolysis biomarkers (PCFB) is unknown but is important for further clinical development, we evaluated how FX06 affects PCFB. The in vitro effects of the whole-blood pre-incubation with escalating concentrations of FX06 (4, 25, and 75 μg/mL) were assessed in aspirin-naïve healthy volunteers (n = 10), those with multiple risk factors for vascular disease (n = 10), and patients with documented coronary artery disease (n = 10). The last two groups were treated with aspirin (81 mg/daily). Thirty-two variables of PCFB were measured with the vehicle and for each chosen FX06 dose. Pretreatment of blood samples with FX06 resulted in a moderate but significant and mostly dose-dependent increases of platelet aggregation induced by adenosine diphosphate and collagen. Similarly, the closure time was reduced, suggesting share-induced activation, PECAM-1, GP Ib, GP IIb/IIIa activity, and vitronectin receptors, which were also up-regulated. In contrast, P-selectin and GPIIb antigen expression were reduced after FX06. All other PCFB were predominantly unaffected by FX06, with the exception of the increased plasminogen, decreased protein C activity, and activated von Willebrand factor. We conclude that in the therapeutic range, FX06 in vitro mildly affects hemostasis by way of mostly activating platelets. Applying moderate concomitant antiplatelet strategies should be considered for the adequate protection from vascular thrombotic events in patients treated with FX06. Similar ex vivo study in patients receiving aspirin and clopidogrel is warranted.	\N	\N
19854042	Upper urinary tract urothelial carcinoma (UUTUC) is relatively rare, occurring in only 5% of all urothelial cancers. It has not been as extensively studied and reviewed as carcinoma of the bladder. UUTUC has a propensity for multifocality, local recurrence, and development of metastases, which argues for an aggressive treatment approach. Open radical nephroureterectomy (ORNU) with removal of an ipsilateral bladder cuff still remains the gold standard treatment for patients with UUTUC and a normal contralateral kidney, which, however, is being challenged by minimally invasive approaches, such as endoscopic and laparoscopic approaches. They are rapidly evolving as reasonable alternatives of care depending on grade and stage of disease. Adjuvant therapy seems to be safe, although its efficacy is debatable. Immunotherapy appears to be most effective in patients with upper-tract carcinoma in situ. Chemotherapy and radiotherapy also show some improvement in recurrence rates, but there have been no randomized, prospective trials. Gene and molecular-targeted therapy is expected. Several controversies remain in our management, including a selection of endoscopic versus laparoscopic approaches, management strategies on the distal ureter, the role of lymphadenectomy, and the value of immunotherapy, chemotherapy, radiotherapy and genetics and molecular markers in UUTUC. Aims of this paper are to critically review the treatment of UUTUC.	\N	\N
20049455	Relapsing polychondritis (RP) is a rare disease which presents chondritis in multiple organs. Characteristic features include auricular chondritis, arthritis, nasal chondritis, ocular inflammation, respiratory tract involvement and audiovestibular damage. Fifty percent of cases of RP are associated with inner ear symptoms such as dizziness and hearing loss. We have recently encountered a case of RP in a 34-year-old man who had recurrent chondritis of both auricles and progressive bilateral profound sensorineural hearing loss; he had been treated many times with steroids, immunosuppressants, plasmapheresis treatments. We perfomed a successful cochlear implant surgery on the left ear of this patient. This raises the possibility of using cochlear implants in treating patients with immune-mediated inner ear disease as well as such RP patients.	\N	\N
20373123	Juvenile dermatomyositis (JDM) is a rare childhood disease with autoimmune association. Environmental factors are known to trigger JDM in genetically susceptible individuals (Schmieder et al., Dermatol Online 6:3, 2009). Calcinosis is a well-established complication of JDM. Prevalence is higher in children (30-70%; Özkaya et al., Erciyes Med J 30(1):40-43, 2008). Hyperimmunoglobulin E syndrome is a primary immunodeficiency syndrome with multiple recurrent abscess formation and raised serum immunoglobulin E levels. We report a case of JDM with calcinosis cutis universalis with hyperimmunoglobulin E syndrome. With a previous similar case report (Min et al., Korean J Intern Med 14:95-98, 1999), this could well be a new sequence syndrome where abscesses are the trigger for the onset of JDM.	\N	\N
20390341	The estrogen signal is mediated by the estrogen receptor (ER). The specific role of ER-beta, a second ER, in breast carcinogenesis is not known. A number of association studies have been carried out to investigate the relationship between polymorphic sites in the ESR2 gene and breast cancer risk, however, the results are inconsistent. We searched PubMed, Medline, and Web of Science database (updated to 10 January 2010) and identified 13 relevant case-control studies, and approximately 28 single-nucleotide polymorphisms (SNPs) and one micro-satellite marker were reported in the literature. The median number of study subjects was 776 (range 158-13,550). Three genetic variants [(CA)n, rs2987983, and rs4986938] showed significant overall associations with breast cancer, and rs4986938 was reported twice. Because rs4986938 and rs1256049 were the most extensively studied polymorphisms, we subsequently conducted a meta-analysis to evaluate their relationship with breast cancer risk (9 studies of 10,837 cases and 16,021 controls for rs4986938; 8 studies of 11,652 cases and 15,726 controls for rs1256049). For rs4986938, the women harboring variant allele seemed to be associated with a decreased risk either in the dominant model [pooled OR = 0.944, 95% confidence interval (95% CI) 0.897-0.993, fixed-effects] or in the co-dominant model (AG vs. GG) (OR = 0.944, 95% CI 0.895-0.997, fixed-effects). rs1256049 was not associated with breast cancer risk in any model. Five studies had investigated the effect of haplotypes in the ESR2 gene on breast cancer risk, and four of them had positive outcomes. In summary, the present systematic review suggests that SNP rs4986938 as well as haplotypes in the ESR2 gene might be associated with breast cancer. The need for additional studies examining these issues seems of vital importance.	\N	\N
20434804	The pathophysiology of tinnitus is obscure and its treatment is therefore elusive. Significant progress in this field can only be achieved by determining the mechanisms of tinnitus generation, and thus, histopathologic findings of the cochlea in presbycusis with tinnitus become crucial. We revealed the histopathologic findings of the cochlea in subjects with presbycusis and tinnitus. The subjects were divided into 2 groups, presbycusis with tinnitus (tinnitus) group and presbycusis without tinnitus (control) group, with each group comprising 8 temporal bones from 8 subjects. We quantitatively analyzed the number of spiral ganglion cells, loss of cochlear inner and outer hair cells, and areas of the stria vascularis and spiral ligament. There was a significantly greater loss of outer hair cells in the tinnitus group compared with the control group in the basal and upper middle turns. The stria vascularis was more atrophic in the tinnitus group compared with the control group in the basal turn. Tinnitus is more common in patients with presbycusis who have more severe degeneration of outer hair cells and stria vascularis.	\N	\N
20512338	Hoarseness due to left recurrent laryngeal nerve paralysis (LRLN) caused by identifiable cardiovascular disease is described as Ortner's syndrome or cardiovocal syndrome. This was first reported by Ortner in 1897 to describe left recurrent laryngeal nerve palsy secondary to mitral stenosis. This case report describe a patient with giant cell arteritis with initial presentation of Ortner's syndrome.	\N	\N
20579773	Oligomeric β-amyloid (Aβ) has recently been linked to synaptic plasticity deficits, which play a major role in progressive cognitive decline in Alzheimer's disease (AD). Here we present evidence that chronic oral administration of carvedilol, a nonselective β-adrenergic receptor blocker, significantly attenuates brain oligomeric β-amyloid content and cognitive deterioration in 2 independent AD mouse models. We found that carvedilol treatment significantly improved neuronal transmission, and that this improvement was associated with the maintenance of number of the less stable "learning" thin spines in the brains of AD mice. Our novel observation that carvedilol interferes with the neuropathologic, biochemical, and electrophysiological mechanisms underlying cognitive deterioration in AD supports the potential development of carvedilol as a treatment for AD.	\N	\N
20678147	Psoriasis is today generally considered a systemic disease. Systemic therapies are used frequently. In Germany fumaric acid esters - FAE (Fumaderm(®) ) - are employed in more than 50 % of the patients requiring such therapy. We report for the first time the development of melanoma in two patients during their treatment with FAE. The logical question is - are the tumors coincidental or might they be treatment-related? Further investigations of pathways and immunologic effects as well as careful reports of side effects are necessary to estimate the risks of malignancy of FAE.	\N	\N
20696610	This study investigates the relationship between neck muscle coactivation, neck strength and perceived pain and disability in women with neck pain. Surface electromyography (EMG) was acquired from the sternocleidomastoid (SCM) and splenius capitis (SC) muscles of 13 women with chronic neck pain and 10 controls as they performed 1) maximal voluntary contractions (MVC) in flexion, extension and left and right lateral flexion, 2) ramped contractions from 0% to 50% MVC in flexion and extension and 3) circular contractions in the horizontal plane at 15N and 30N force. Higher values of EMG amplitude were observed for the SC (antagonist) during ramped neck flexion and for the SCM during ramped extension in the patient group (P<0.05). The patients displayed reduced values of directional specificity in the surface EMG of the SCM and SC for the circular contractions (P<0.05). The EMG amplitude of SC during cervical flexion was positively correlated with the patients' pain (R² =0.35, P<0.05) and perceived disability (R² 0.53, P<0.01). An inverse correlation was evident between the amount of activation of SC during cervical flexion and strength (R² =0.54, P<0.01). These observations indicate a relationship between alterations in neuromuscular control in patients with neck pain and functional consequences, including impaired motor performance and increased levels of perceived disability.	\N	\N
20733020	To report the clinical course, treatment response and prognosis of eight cases which developed acute-onset postoperative endophthalmitis over a 1-month period. 8 patients who were operated on over a period of 1 month and developed acute postoperative endophthalmitis were evaluated. Five of the patients had cataract surgery, one had cataract surgery combined with silicone extraction, and two patients had pars plana vitrectomy (PPV). Clinical patterns were observed, intraocular cultures were obtained, and the source of the organisms causing the epidemic was investigated. All patients had intravitreal antibiotic injections, three had PPV, and in two patients anterior chamber irrigation was performed. Vitreous cultures showed Cellulosimicrobium cellulans in three cases and Stenotrophomonas maltophilia in one case. Four of the cases were culture negative. Stenotrophomonas maltophilia were also isolated from unused bottles of irrigating solutions. The final visual acuity of the patients ranged between HM and 7/10. All three patients with Cellulosimicrobium cellulans had a final visual acuity of ≥ 5/10. The available irrigating solutions were changed, and the endophthalmitis did not recur. The authors are unaware of any previous reports of postoperative endophthalmitis associated with Cellulosimicrobium cellulans. Prompt management with microbiological support, intravitreal antibiotics and PPV when needed were the key to good visual outcomes in this endophthalmitis outbreak.	\N	\N
20849277	The ability for public/veterinary health agencies to assess the risks posed by tick-borne pathogens is reliant on an understanding of the main tick vector species. Crucially, the status, distribution, and changing trends in tick distribution and abundance are implicit requirements of any risk assessment; however, this is contingent on the quality of tick distribution data. Since 2005 the Health Protection Agency has promoted an enhanced tick surveillance program. Through engagement with a variety of public and veterinary health agencies and practitioners (e.g., clinicians and veterinarians), wildlife groups (deer society, zoos, animal refuge centers, and academics), and amateur entomologists, >4000 ticks from 900 separate records across Great Britain have been submitted, representing 14 tick species (Ixodes ricinus, Ixodes hexagonus, Ixodes acuminatus, Ixodes arboricola, Ixodes canisuga, Ixodes frontalis, Ixodes lividus, Ixodes trianguliceps, Ixodes ventalloi, Carios vespertilionis, Dermacentor reticulatus, Haemaphysalis punctata, Hyalomma marginatum, and Amblyomma species). The majority of ticks submitted were I. ricinus (81%), followed by I. hexagonus (10%) and I. frontalis (2.5%). Predominant host groups include companion animals (411 records), humans (198 records), wild birds (111 records), and large wild mammals (88 records), with records also from small/medium wild mammals, livestock, the environment and domestic/aviary birds. The scheme has elucidated the detection of two nonnative tick species, the expansion of previously geographically restricted D. reticulatus and produced ground data on the spread of I. ricinus in southwest England. It has also provided a forum for submission of ticks from the concerned public and particularly those infected with Lyme borreliosis, thus raising awareness among public health agencies of the increased peri-urban tick problem in Britain. Our results demonstrate that it is possible to run a cost-effective nationwide surveillance program to successfully monitor endemic tick species, identify subtle changes in their distribution, and detect the arrival and presence of exotic species.	\N	\N
20853354	We report our 10-year experience with percutaneous closure of adult congenital and acquired (non-post-infarct) ventricular septal defects (VSDs) using different types of Amplatzer occluder devices. Adult congenital and acquired VSDs may produce significant morbidity and mortality. Furthermore, such VSDs pose a significant surgical challenge. Between February 2000 and August 2009, data were retrospectively reviewed from 28 patients who underwent 29 procedures for percutaneous device closure of hemodynamically significant VSDs. Seventeen had unrepaired congenital VSDs, 10 had post-operative VSDs (5 with residual patch-margin defects, 4 post-aortic valve replacement, 1 post-myomectomy), and one had an acquired traumatic VSD. INDICATIONS FOR CLOSURE INCLUDED: symptoms related to significant shunt (dyspnea on exertion); unexplained deterioration of LV function, and/or LV dilation; recurrent endocarditis, and pulmonary hypertension. Outcome parameters were procedural success, procedure-related complications, evidence of residual shunt by echocardiography, and improvement in the signs/symptoms for which the procedure was performed. The mean follow-up interval was 68 months. Of the 28 patients studied, a single VSD was present in 26 patients, while one patient had two defects, and one patient had one defect on the LV side with three openings at the RV side. The median size of the defects by echocardiography was 6 mm. A device was successfully implanted in 28 of 29 (97%) procedures and 28 of 28 (100%) patients. PROCEDURE-RELATED COMPLICATIONS OCCURRED IN TWO CASES: one involving an access site hematoma not requiring transfusion as well as nonsustained ventricular tachycardia that resolved spontaneously and the other involving acute mitral regurgitation due to inadvertent trapping of the anterior mitral valve leaflet between the left ventricular disk and the septum that was resolved by recapturing of the disk. There was immediate complete closure in 20 patients (71%). In six cases there was trivial residual shunt and in two patients the residual shunt was mild. At the latest follow-up, four of the eight with a residual shunt had no shunt and in the remaining four the residual shunt was trivial. Among symptomatic patients 18 (64%), there was marked improvement in symptoms and for those patients 17 (61%) for whom the procedure was performed to address left ventricular enlargement, there was reduction or stabilization in LV size on serial echoes. Percutaneous closure of VSDs in the adult patient appears to be safe and effective.	\N	\N
20853359	A significant proportion (~ 20%) of patients with complex tibial artery occlusions cannot be treated using a conventional antegrade approach. We report our experience using the retrograde approach for the treatment of complex tibial artery occlusive disease using retrograde pedal/tibial access in 13 limbs from 12 patients. Retrograde pedal/tibial access was achieved in all cases (facilitated by surgical cutdown in one case), and procedural success was achieved in 11 of 13 limbs (85%). Based on this experience, a discussion of clinical and technical aspects of the retrograde pedal/tibial approach is provided, and a new classification for tibial artery occlusive disease is proposed.	\N	\N
20878712	Endoscopic evaluation plays a pivotal role in the assessment of treatment response in ulcerative colitis (UC). This study aimed to determine the interobserver agreement (IOA) for assessment of mucosal lesions, and to determine lesions predictive of global assessment of endoscopic severity (GAES). Fifty-one UC patients had digital videorecording of their colonoscopic examinations, edited into videoclips representative of five colonic segments (rectum, sigmoid, descending, transverse, ascending/cecum). Seven gastroenterologists specializing in inflammatory bowel disease (IBD) independently and blindly rated individual lesions and endoscopic severity for each segment and globally. Edema, erythema, stricture, loss of haustral folds, rigidity, and pseudopolyps were scored as absent or present while vascular pattern, granularity, ulceration, and bleeding-friability were scored using a predefined severity scale. The GAES was based on a 4-point scale and a 10-cm visual analog scale (VAS). The IOA among raters was estimated using Lin's concordance correlation coefficient (CCC). Strength of agreement was categorized as excellent (0.81-1.00), good (0.61-0.80), moderate (0.41-0.60), and fair (0.21-0.40). Linear regression analysis was used to identify lesions predictive of overall endoscopic severity and develop a scoring system for clinical use. Granularity, vascular pattern, ulceration, bleeding/friability, and pseudopolyps had good IOA in most segments. There was excellent agreement for VAS and good agreement for GAES and the VAS was significantly associated with GAES (P < 0.001). Granularity, vascular pattern, ulceration, and bleeding-friability were significant predictors of overall endoscopic severity. Granularity, vascular pattern, ulceration, and bleeding-friability demonstrated good reproducibility and were predictors of the GAES in UC patients.	\N	\N
20881290	Mutations in PITX2 are associated with Axenfeld-Rieger syndrome (ARS), which involves ocular, dental, and umbilical abnormalities. Identification of cis-regulatory elements of PITX2 is important to better understand the mechanisms of disease. Conserved noncoding elements surrounding PITX2/pitx2 were identified and examined through transgenic analysis in zebrafish; expression pattern was studied by in situ hybridization. Patient samples were screened for deletion/duplication of the PITX2 upstream region using arrays and probes. Zebrafish pitx2 demonstrates conserved expression during ocular and craniofacial development. Thirteen conserved noncoding sequences positioned within a gene desert as far as 1.1 Mb upstream of the human PITX2 gene were identified; 11 have enhancer activities consistent with pitx2 expression. Ten elements mediated expression in the developing brain, four regions were active during eye formation, and two sequences were associated with craniofacial expression. One region, CE4, located approximately 111 kb upstream of PITX2, directed a complex pattern including expression in the developing eye and craniofacial region, the classic sites affected in ARS. Screening of ARS patients identified an approximately 7600-kb deletion that began 106 to 108 kb upstream of the PITX2 gene, leaving PITX2 intact while removing regulatory elements CE4 to CE13. These data suggest the presence of a complex distant regulatory matrix within the gene desert located upstream of PITX2 with an essential role in its activity and provides a possible mechanism for the previous reports of ARS in patients with balanced translocations involving the 4q25 region upstream of PITX2 and the current patient with an upstream deletion.	\N	\N
20936300	In Huntington's disease (HD) atrophy of the caudate nucleus and putamen has been described many years before clinical manifestation. Volume changes of the pallidum, thalamus, brainstem, accumbens nucleus, hippocampus, and amygdala are less well investigated, or reported with contradicting results. The aim of our study is to provide a more precise view of the specific atrophy of the subcortical grey matter structures in different stages of Huntington's disease, and secondly to investigate how this influences the clinical manifestations. All TRACK-HD subjects underwent standardised T1-weighted 3T MRI scans encompassing 123 manifest HD (stage 1, n = 77; stage 2, n = 46), 120 premanifest HD (close to onset n = 58, far from onset n = 62) and 123 controls. Using FMRIB's FIRST and SIENAX tools the accumbens nucleus, amygdala, brainstem, caudate nucleus, hippocampus, pallidum, putamen, thalamus and whole brain volume were extracted. Results showed that volumes of the caudate nucleus and putamen were reduced in premanifest HD far from predicted onset (>10.8 years). Atrophy of accumbens nucleus and pallidum was apparent in premanifest HD in the close to onset group (0-10.8 years). All other structures were affected to some degree in the manifest group, although brainstem, thalamus and amygdala were relatively spared. The accumbens nucleus, putamen, pallidum and hippocampus had a strong significant correlation with functional and motor scores. We conclude that volume changes may be a sensitive and reliable measure for early disease detection and in this way serve as a biomarker for Huntington's disease. Besides the caudate nucleus and putamen, the pallidum and the accumbens nucleus show great potential in this respect.	\N	\N
20938704	We describe an outbreak of Bacillus cereus bacteremia that occurred at Jichi Medical University Hospital in 2006. This study aimed to identify the source of this outbreak and to implement appropriate control measures. We reviewed the charts of patients with blood cultures positive for B. cereus, and investigated B. cereus contamination within the hospital environment. Genetic relationships among B. cereus isolates were analyzed. Eleven patients developed B. cereus bacteremia between January and August 2006. The hospital linens and the washing machine were highly contaminated with B. cereus, which was also isolated from the intravenous fluid. All of the contaminated linens were autoclaved, the washing machine was cleaned with a detergent, and hand hygiene was promoted among the hospital staff. The number of patients per month that developed new B. cereus bacteremia rapidly decreased after implementing these measures. The source of this outbreak was B. cereus contamination of hospital linens, and B. cereus was transmitted from the linens to patients via catheter infection. Our findings demonstrated that bacterial contamination of hospital linens can cause nosocomial bacteremia. Thus, blood cultures that are positive for B. cereus should not be regarded as false positives in the clinical setting.	\N	\N
20950346	Aldosterone plays an important role in the pathophysiology of heart failure. Aldosterone receptor blockade has been shown to reduce morbidity and mortality in human patients with advanced congestive left ventricular heart failure. This study was designed to assess the efficacy and tolerance of long-term low-dose spironolactone when added to conventional heart failure treatment in dogs with advanced heart failure. Eighteen client-owned dogs with advanced congestive heart failure due to either degenerative valve disease (n=11) or dilated cardiomyopathy (n=7) were included in this prospective, placebo-controlled, double-blinded, randomized clinical study. After initial stabilization including furosemide, angiotensin-converting enzyme inhibitors, pimobendan and digoxin, spironolactone at a median dose of 0.52 mg/kg (range 0.49-0.8 mg/kg) once daily (n=9) or placebo (n=9) was added to the treatment, and the dogs were reassessed 3 and 6 months later. Clinical scoring, echocardiography, electrocardiogram, systolic blood pressure measurement, thoracic radiography, sodium, potassium, urea, creatinine, alanine aminotransferase, aldosterone and aminoterminal atrial natriuretic propeptide were assessed at baseline, 3 and 6 months. Survival times were not significantly different between the two treatment groups. Spironolactone was well tolerated when combined with conventional heart failure treatment.	\N	\N
20981578	Alzheimer's disease (AD) is a progressive neurodegenerative disorder leading to slow neuronal loss in several brain regions. It is characterised by the presence of cerebral senile plaques comprised of aggregated amyloid-β peptides. Transcriptional regulation of the γ-secretase complex, which cleaves the β-amyloid precursor protein to produce Aβ-peptides, could modulate the pathological phenotype of AD patients. This study investigates whether rosuvastatin, an HMG-CoA reductase inhibitor, modulates the expression of genes involved in the function of the γ-secretase complex, in a human cellular model for Aβ peptide accumulation. In particular, we analysed the effect of the statin combined with apoptotic induction. Experimental apoptosis was induced by thapsigargin treatment, a drug that depletes intracellular calcium stores via inhibition of the calcium ATPase pump. Notably, systemic calcium dysregulation accompanies almost all of the brain pathology processes observed in AD. We found differential transcriptional regulation of some γ-secretase cofactors relative to rosuvastatin treatment, in cells expressing Swedish mutant APP. Interestingly, this statin down-regulated the transcription of some enzyme cofactors, similar to treatment with thapsigargin. However, rosuvastatin neither affected the basal Aβ levels nor counteracted APP processing or Aβ over-production triggered by the thapsigargin. Our results provide evidence that rosuvastatin alters gene expression of the γ-secretase complex without affecting enzyme activity.	\N	\N
21040232	Febrile seizures (FSs) relatively represent the most common form of childhood seizures. FSs are not thought of as a true epileptic disease but rather as a special syndrome characterized by its provoking factor (fever) and a typical range of 3 months to 5 years. Although specific genes affecting the majority of FS cases have not been identified yet, several genetic loci for FSs have been reported recently. The aim of this report is to search for the gene responsible for FSs in six affected Tunisian families. A microsatellite marker analysis was performed on the known FS and generalized epilepsy with febrile seizures plus (GEFS+) loci. According to the results obtained by statistical analyses for the six studied families and in agreement with the involvement of SCN1B gene in the GEFS+ syndrome in previous studies, SCN1B on GEFS+1 locus was considered as one of the potential candidate genes and was tested for mutations by direct sequencing. A sequencing analysis of the SCN1B gene revealed a novel mutation (c.374G>T) that changed an arginine residue with leucine at position 125 of the protein. We consider that the variation R125L may affect the protein structure and stability by the loss of hydrogen bonding. Two identified single nucleotide polymorphisms that are located in a neighboring hypothetical polyadenylation were assumed to compose a putative disease-associated haplotype. Our results support that SCN1B is the gene responsible in one amongst the six FS Tunisian families studied and might contribute to the FS susceptibility for the five others.	\N	\N
21055462	Environmental factors have a significant impact on biology. Therefore, environmental toxicants through similar mechanisms can modulate biological systems to influence physiology and promote disease states. The majority of environmental toxicants do not have the capacity to modulate DNA sequence, but can alter the epigenome. In the event an environmental toxicant such as an endocrine disruptor modifies the epigenome of a somatic cell, this may promote disease in the individual exposed, but not be transmitted to the next generation. In the event a toxicant modifies the epigenome of the germ line permanently, then the disease promoted can become transgenerationaly transmitted to subsequent progeny. The current review focuses on the ability of environmental factors such as endocrine disruptors to promote transgenerational phenotypes.	\N	\N
21073934	Two mouse models, the Coch(G88E/G88E) or "knock-in" and the Coch(-/-) or "knock-out" (Coch null), have been developed to study the human late-onset, progressive, sensorineural hearing loss and vestibular dysfunction known as DFNA9. This disorder results from missense and in-frame deletion mutations in COCH (coagulation factor C homology), encoding cochlin, the most abundantly detected protein in the inner ear. We have performed hearing and vestibular analyses by auditory brainstem response (ABR) and vestibular evoked potential (VsEP) testing of the Coch(-/-) and Coch(G88E/G88E) mouse models. Both Coch(-/-) and Coch(G88E/G88E) mice show substantially elevated ABRs at 21 months of age, but only at the highest frequency tested for the former and all frequencies for the latter. At 21 months, 9 of 11 Coch(-/-) mice and 4 of 8 Coch(G88E/G88E) mice have absent ABRs. Interestingly Coch(-/+) mice do not show hearing deficits, in contrast to Coch(G88E/+), which demonstrate elevated ABR thresholds similar to homozyotes. These results corroborate the DFNA9 autosomal dominant mode of inheritance, in addition to the observation that haploinsufficiency of Coch does not result in impaired hearing. Vestibular evoked potential (VsEP) thresholds were analyzed using a two factor ANOVA (Age X Genotype). Elevated VsEP thresholds are detected in Coch(-/-) mice at 13 and 21 months, the two ages tested, and as early as seven months in the Coch(G88E/G88E) mice. These results indicate that in both mouse models, vestibular function is compromised before cochlear function. Analysis and comparison of hearing and vestibular function in these two DFNA9 mouse models, where deficits occur at such an advanced age, provide insight into the pathology of DFNA9 and age-related hearing loss and vestibular dysfunction as well as an opportunity to investigate potential interventional therapies.	\N	\N
21084426	We performed a three-stage genome-wide association study (GWAS) to identify common Parkinson's disease (PD) risk variants in the European population. The initial genome-wide scan was conducted in a French sample of 1039 cases and 1984 controls, using almost 500 000 single nucleotide polymorphisms (SNPs). Two SNPs at SNCA were found to be associated with PD at the genome-wide significance level (P < 3 × 10(-8)). An additional set of promising and new association signals was identified and submitted for immediate replication in two independent case-control studies of subjects of European descent. We first carried out an in silico replication study using GWAS data from the WTCCC2 PD study sample (1705 cases, 5200 WTCCC controls). Nominally replicated SNPs were further genotyped in a third sample of 1527 cases and 1864 controls from France and Australia. We found converging evidence of association with PD on 12q24 (rs4964469, combined P = 2.4 × 10(-7)) and confirmed the association on 4p15/BST1 (rs4698412, combined P = 1.8 × 10(-6)), previously reported in Japanese data. The 12q24 locus includes RFX4, an isoform of which, named RFX4_v3, encodes brain-specific transcription factors that regulate many genes involved in brain morphogenesis and intracellular calcium homeostasis.	\N	\N
21085051	The Centers for Disease Control and Prevention recommend hospitals develop guidelines for the appropriate use of vancomycin as part of comprehensive antimicrobial stewardship. The objective of this study was to evaluate the effectiveness and safety of a guideline to restrict vancomycin use in the neonatal intensive care unit (NICU). A vancomycin use guideline was introduced in 2 tertiary care NICUs with low incidences of methicillin-resistant Staphylococcus aureus infections. We compared all infants >72 hours of age who were evaluated for late-onset infection before and after implementation of this guideline. Vancomycin start rates were reduced from 6.9 to 4.5 per 1000 patient-days (35% reduction; P = 0.01) at Brigham and Women's Hospital, and from 17 to 6.4 per 1000 patient-days (62% reduction; P < 0.0001) at Massachusetts General Hospital. The number of infants exposed to vancomycin decreased from 5.2 to 3.1 per 1000 patient-days (40% reduction; P = 0.008) at Brigham and Women's Hospital, and 10.8 to 5.5 per 1000 patient-days (49% reduction; P = 0.009) at Massachusetts General Hospital. Causes of infection, duration of bacteremia, and incidence of complications or deaths attributable to late-onset infection did not change significantly at either institution. Implementation of a NICU vancomycin use guideline significantly reduced exposure of newborns to vancomycin without adversely affecting short-term patient safety. Further studies are required to evaluate the long-term effect of vancomycin restriction on NICU patient safety and microbial ecology, particularly among institutions with higher rates of methicillin-resistant Staphylococcus aureus infections.	\N	\N
21102561	Human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) have the potential to differentiate into all cell lineages, including hepatocytes, in vitro. Induced hepatocytes have a wide range of potential application in biomedical research, drug discovery, and the treatment of liver disease. However, the existing protocols for hepatic differentiation of PSCs are not very efficient. In this study, we developed an efficient method to induce hepatoblasts, which are progenitors of hepatocytes, from human ESCs and iPSCs by overexpression of the HEX gene, which is a homeotic gene and also essential for hepatic differentiation, using a HEX-expressing adenovirus (Ad) vector under serum/feeder cell-free chemically defined conditions. Ad-HEX-transduced cells expressed α-fetoprotein (AFP) at day 9 and then expressed albumin (ALB) at day 12. Furthermore, the Ad-HEX-transduced cells derived from human iPSCs also produced several cytochrome P450 (CYP) isozymes, and these P450 isozymes were capable of converting the substrates to metabolites and responding to the chemical stimulation. Our differentiation protocol using Ad vector-mediated transient HEX transduction under chemically defined conditions efficiently generates hepatoblasts from human ESCs and iPSCs. Thus, our methods would be useful for not only drug screening but also therapeutic applications.	\N	\N
21104183	Crohn disease is a chronic granulomatous inflammatory disorder that most commonly affects the gastrointestinal tract, particularly the distal small bowel and colon. While certain extraintestinal manifestations of Crohn disease are relatively common and well-known, others, such as metastatic cutaneous involvement, are quite rare and may be difficult to recognize, particularly in the pediatric population. This case report illustrates the magnetic resonance imaging (MRI) appearance of vulvar region cutaneous Crohn disease in an 11-year-old girl.	\N	\N
21106231	The purpose of this study was (1) to investigate the association between BMI self-reported at three time points (during their 20s, 5 years before diagnosis, and post-diagnosis) and mortality among 388 women with newly diagnosed epithelial ovarian cancer and (2) weight change between these 3 time points and mortality. Women completed interview-administered questionnaires on average 9 months post-diagnosis. Women were followed 5 years after diagnosis or until death, whichever came first. Cox proportional hazard regression was used to estimate associations between BMI during the 20s, BMI 5 years prior to diagnosis, BMI post-diagnosis (i.e., at the time of interview) and weight changes between these time points and mortality. The 5-year survival rate was 54% (178 deaths, 146 from ovarian cancer). BMI measured continuously at all three time points was associated with a higher risk of ovarian cancer mortality (P≤0.05). The strongest association was observed with BMI in the 20s and all-cause mortality comparing women with BMI≥25 kg/m(2) to BMI<25 kg/m(2) (HR=1.82; 95% CI, 1.02-3.27; P for trend=0.045). For weight change from the 20s to 5 years prior to diagnosis and ovarian cancer specific mortality, we observed a 68% higher risk of ovarian cancer mortality (HR=1.68; 95% CI, 1.11-2.55; P for trend=0.015, comparing women with <10 lbs weight gain to women with ≥10 lbs weight gain). BMI prior to and after diagnosis and weight gain throughout adulthood is associated with ovarian cancer mortality.	\N	\N
21135704	To study the role of probiotics on gut permeability and endotoxemia in patients with acute pancreatitis (AP). Bacterial translocation has been implicated in infective complications in AP, which has been shown to be prevented by probiotics. A double-blind, randomized placebo-controlled trial was conducted. Consecutive patients with AP presenting within 72 hours after the onset of abdominal pain or who had been nil orally at the time of presentation for up to 5 days were included in the study. The probiotic group received 4 sachets of Probiotics (2.5 billion bacteria per sachet) whereas the placebo group received 4 sachets of placebo for 7 days. Primary outcome measures were effect on gut permeability [assessed by lactulose/mannitol (L/M) excretion in urine] and endotoxemia assessed by endotoxin-core antibody types IgG and IgM (EndoCab IgG and IgM). Secondary outcome measures were mortality, total hospital/intensive care unit stay, abdominal discomfort, organ failure, C-reactive protein, and prealbumin levels. The study was prematurely stopped after the publication of probiotic prophylaxis in patients with predicted severe acute pancreatitis trial. From March 2007 to May 2008, 50 patients with AP were included in the study (26 in placebo group and 24 in probiotic group). There was no difference after intervention in gut permeability, whereas values of C-reactive protein and immunoglobulins decreased significantly [IgG: 140 (20-920) to 90 (20-600) GGU/mL and IgM: 65 (13-230) to 51 (9-240) GMU/mL] in the probiotic group. No difference was observed in prealbumin values, duration of hospital/intensive care unit stay, and mortality in both the groups. No significant trend was identified for an effect of probiotics on gut permeability or endotoxemia in AP. However, the study was underpowered owing to premature study termination.	\N	\N
21172349	Visceral leishmaniasis (VL) is a health issue in Sudan. Our aim was to investigate the involvement of eosinophils and neutrophils in VL by serum and plasma measurements of eosinophil cationic protein (ECP) and myeloperoxidase (MPO) and some key cytokines and chemokines. Blood was collected from 125 VL patients and 181 healthy Sudanese controls from the same rural area. Results showed reduced eosinophil and neutrophil counts in the VL group (P=0.0001 and P=0.002, respectively). Serum-ECP levels were higher in the controls (P<0.0001), while plasma MPO levels were higher in the VL group (P<0.0001). Levels of IL-5, granulocyte macrophage-colony stimulating factor (GM-CSF) and IL-17 were increased among the VL group (P<0.0001, P=0.017 and P=0.03, respectively), whereas eotaxin and IL-8 levels were reduced (P<0.0001 and P=0.002, respectively). Positive correlations were found between IL-8 and ECP/MPO (P<0.0001). We conclude that eosinophil and neutrophil turnover and activity are increased in subjects in rural areas of Sudan. In VL the turnover was further increased, but the relatively low secretory activity of eosinophils and neutrophils in VL may relate to the reduced production and availability of the chemokines eotaxin and IL-8. The combined assay of ECP and MPO in serum and plasma provides further insight into the mechanisms of eosinophil and neutrophil involvement in disease and constitutes a novel approach to the study of disease processes.	\N	\N
21184197	The significance of the cerebrospinal fluid (CSF) Apolipoprotein E (APOE) level and whether it might have differential effects on brain function due to the presence of APOE ε 4 allele(s) in HIV-infected patients are unknown. However, APOE ε 4 allele has been associated with greater incidence of HIV-associated dementia and accelerated progression of HIV infection. Here, we show further evidence for the role of APOE ε 4 in promoting cognitive impairment. We measured the APOE levels in the CSF of HIV-infected individuals. HIV+ subjects showed lower CSF APOE proteins than SN controls (-19%, p= 0.03). While SN subjects with or without ε 4 allele showed no difference in CSF APOE levels, ε 4+ HIV+ subjects had similar levels to the SN subjects but higher levels than ε 4- HIV+ subjects (+34%, p= 0.01). Furthermore, while HIV+ subjects with ε 2 or ε 3 allele(s) showed a positive relationship between their CSF APOE levels and cognitive performance on the speed of processing domain (r= +0.35, p= 0.05), ε 4+ HIV+ subjects, in contrast, exhibited a negative relationship such that those with higher levels of CSF APOE(4) performed worse on the HIV Dementia Scale (r= -0.61, p= 0.02), had lower Global Cognitive Scores (r= -0.57, p= 0.03), and had poorer performance on tests involving learning (ε 4 allele x [APOE] interaction, p = 0.01). Our findings also suggest that the relatively higher levels of CSF APOE in ε 4+ HIV+ (having primarily APOE4 isoforms) may negatively impact the brain and lead to poorer cognitive outcomes, while those individuals without the ε 4 allele (with primarily APOE2 or APOE3 isoforms) may show compensatory responses that lead to better cognitive performance.	\N	\N
21190758	Assuming selective vulnerability of short association U-fibers in early Alzheimer's disease (AD), we quantified demyelination of the surface white matter (dSWM) with magnetization transfer ratio (MTR) in 15 patients (Clinical Dementia Rating Scale [CDR] 0.5-1; Functional Assessment Staging [FAST]: 3-4) compared with 15 controls. MTRs were computed for 39 areas in each hemisphere. We found a bilateral MTR decrease in the temporal, cingulate, parietal, and prefrontal areas. With linear discriminant analysis, we successfully classified all the participants with 3 variates including the cuneus, parahippocampal, and superior temporal regions of the left hemisphere. The pattern of dSWM changed with the age of AD onset. In early onset patients, we found bilateral posterior demyelination spreading to the temporal areas in the left hemisphere. The late onset patients showed a distributed bilateral pattern with the temporal and cingulate areas strongly affected. A correlation with Mini Mental State Examination (MMSE), Lexis, and memory tests revealed the dSWM impact on cognition. A specific landscape of dSWM in early AD shows the potential of MTR imaging as an in vivo biomarker superior to currently used techniques.	\N	\N
21211565	Nuclear receptors (NRs) are ligand-activated transcriptional factors that are involved in various physiological, developmental, and toxicological processes. Farnesoid X receptor (FXR) is a NR that belongs to the NR superfamily. The endogenous ligands of FXR are bile acids. FXR is essential in regulating a network of genes involved in maintaining bile acid and lipid homeostasis. It is clear that FXR is critical for liver and intestinal function. In mice FXR deficiency leads to the development of cholestasis, gallstone disease, nonalcoholic steatohepatitis, liver tumor, and colon tumor. Using mouse models where FXR is deleted either in the whole-body, or selectively in hepatocytes or enterocytes, we start to reveal the importance of tissue-specific FXR function in regulating bile acid and lipid homeostasis. However, a great challenge exists for developing tissue-specific FXR modulators to prevent and treat diseases associated with bile acid or lipid disorders. With further understanding of FXR function in both rodents and humans, this nuclear receptor may emerge as a novel target to prevent and treat liver, gastrointestinal and systemic diseases.	\N	\N
21220035	We retrospectively compared the outcomes of 225 patients with adult acquired aplastic anemia (AA) who underwent allogeneic hematopoietic stem cell transplantation (alloHSCT) from matched related donors (MRDs), and those treated by alloHSCT from alternative donors (ADs). Univariate and multivariate analyses of factors associated with survival were performed. Multivariate analysis showed that age at alloHSCT of ≤ 31 years, MRD, successful engraftment, absence of acute graft-versus-host disease (aGVHD), and platelet engraftment at ≤ 21 days, were independent predictors of longer survival. In addition, time to aGVHD and cumulative nonrelapse mortality (NRM) were better in MRD than in AD recipients. Using propensity score matching (PSM), we performed a case-control study comparing 25 patients in each group who underwent alloHSCT from MRDs and ADs. Pretransplantation clinical factors were well balanced in either group. Median survival time was similar, and no statistically significant difference in transplantation outcomes was apparent when MRD and AD recipients were compared. In conclusion, our results suggest that alloHSCT from an AD should be considered earlier in adult patients with AA who do not have an MRD.	\N	\N
21224840	Despite little supporting data, thiopurine use is common in pediatric ulcerative colitis (UC). Our aim was to determine outcome following thiopurine use in a multicenter inception cohort of children diagnosed with UC. Data were obtained from a prospective observational study of newly diagnosed children <16 years of age. Data are recorded at diagnosis, 30 days, and quarterly. Patients are managed by physician dictates not protocol. Disease activity is classified by physician global assessment. The primary outcome was corticosteroid (CS)-free inactive UC at 1 year following thiopurine initiation without the need for rescue therapy (infliximab, calcineurin inhibitors, or colectomy). Of 1,490 patients in our registry, 394 have UC (mean age at diagnosis 11.3±3.7 years); 197 (50%) received thiopurine (49% ≤3 months from diagnosis). Also, 84% were receiving CSs and 60% 5-aminosalicylates at thiopurine start. Of the 197 patients, there was insufficient follow-up (41), previous or concomitant use of infliximab (16), or calcineurin inhibitor (7), leaving 133 patients evaluable at 1 year. Of these, 65 (49%) had CS-free inactive UC without rescue therapy. CS-free inactive disease at 1 year after initiating thiopurine was not affected by starting thiopurine ≤3 months vs. >3 months from diagnosis, gender, age, or concomitant treatment with 5-aminosalicylates. Kaplan-Meier analysis showed that the likelihood of remaining free of rescue therapy in the thiopurine-treated patients was 73% at 1 year. Approximately 50% of children with UC starting thiopurine without previous or concomitant biologic or calcineurin inhibitor therapy have CS-free inactive disease 1 year later without the need for rescue therapy.	\N	\N
21240517	We investigated whether there exists a hierarchical vulnerability of subcortical structures with respect to the severity of Alzheimer's disease (AD). A total of 236 subjects (179 with AD and 57 with normal cognition) underwent 1.5-T magnetic resonance (MR) imaging. The volumes of the five subcortical structures (amygdala, thalamus, putamen, globus pallidus, and caudate nucleus) and hippocampus were analyzed using a large deformation diffeomorphic metric mapping algorithm. The volume changes were evaluated according to the Clinical Dementia Rating (CDR). Correlation between the volumes of the subcortical structures and scores of the cognitive domain-specific neuropsychological tests were evaluated. Volume loss of the amygdala occurred even in the very mild stage of AD (CDR 0.5), as did volume loss in the hippocampus. Similar reductions in volume occurred in the thalamus and putamen, however during the mild (CDR 1) and moderate (CDR 2) stages of AD, respectively. The globus pallidus and caudate nucleus remained devoid of changes until the moderate stage of AD (p < 0.01). Volume loss in those subcortical structures correlated with the neuropsychological test scores (p < 0.01). Our results suggest that there is a hierarchical vulnerability in subcortical structures according to the clinical severity of AD and that subcortical volume reductions correlate with cognitive impairment.	\N	\N
21242863	A retrospective clinical and radiographic study was performed. The purpose of this study was to compare outcomes of patients with degenerative spondylolisthesis and a preexisting degenerative L5-S1 disc treated with a lumbar floating fusion (LFF) versus lumbosacral fusion (LSF). Fusion for treatment of degenerative spondylolisthesis often ends at the L5 level. These patients usually had a preexisting L5-S1 disc degeneration; however, no literature mentions the role of prophylactic LSF in degenerative spondylolisthesis associated with L5-S1 disc degeneration. A total of 107 patients with a minimum 5-year follow-up who had lumbosacral or LFF with pedicle instrumentation for degenerative spondylolisthesis were included. UCLA (University of California, Los Angeles) classification was used to evaluate the radiographic results of the L5-S1 segment. The Oswestry Disability Index (ODI) and modified Brodsky's criteria were used to evaluate patients' clinical results. The incidence of adjacent segment disease (ASD) (includes radiographic and clinical ASD) of both ends was recorded. There were no statistically significant differences in sex, age distribution, or amount of follow-up between the LFF and LSF groups. The LSF group had a higher percentage of patients that underwent total L5 laminectomy with loss of L5-S1 posterior ligament integrity (LSF = 92% vs. LFF = 67%, P = 0.019). The higher incidence of cephalic ASD in the LSF group was statistically significant (LSF = 25% vs. LFF = 9.7%, P = 0.049). Although no patient in the LSF group developed L5-S1 ASD, need for L5-S1 segment revision surgery was not prevented with LSF. Clinical outcomes on the basis of the success rate (LFF = 85.5% vs.LSF = 70.8%, P = 0.103) and ODI difference (LFF = 28.97 ± 15.82 vs. LSF = 23.04 ± 10.97, P = 0.109), there were no statistically significant difference between these two groups. Posterior instrumentation with posterolateral LFF for the treatment of degenerative spondylolisthesis with concomitant L5-S1 disc degeneration results in a high percentage of satisfactory clinical results. Extended fusion to the sacrum did not provide a better clinical result. LSF could not reduce the incidence of revision surgery at the L5-S1 segment and involved greater incidence of cephalic ASD.	\N	\N
21246519	Concurrent inhibition of epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) is an active and well tolerated regimen in recurrent head and neck cancer (HNC). In the current phase 1 trial, the authors sought to determine the maximum tolerated dose (MTD) and efficacy of concurrent erlotinib and celecoxib as a radiosensitizing regimen. Fourteen patients with previously irradiated HNC with no distant metastases who required reirradiation were eligible. Treatment consisted of daily erlotinib 150 mg and twice daily celecoxib (escalated from 200 mg to 600 mg using a 3 + 3 design with an expanded cohort at the MTD) starting on Day 1 and was continued during radiation. Daily radiation was started on Day 15, and maintenance erlotinib was recommended. The recommended phase 2 dose of celecoxib was 400 mg. Three dose-limiting toxicities included late in-field orocutaneous fistula (Dose Level 2), osteonecrosis (Dose Level 3), and trismus (Dose Level 3). Acute grade ≥ 3 toxicities were uncommon and included mucositis (21%) and dermatitis (14%). At a median follow-up of 11 months, the 1-year locoregional control, progression-free survival, and overall survival rates were 60%, 37%, and 55%, respectively. Concurrent erlotinib, celecoxib, and reirradiation was a feasible and clinically active regimen in a population of patients with recurrent HNC who had a poor prognosis.	\N	\N
21251542	In recent years, a common strategy for the prevention of postsurgical intra-abdominal adhesions has been intrasurgical placement of adhesion barriers into the peritoneal cavity. Osmotic agents, such as various polysaccharides, frequently are used as antiadhesive materials. The effects of these materials on kidney function have not yet been studied. We report a case of an individual with pre-existing chronic kidney disease who developed acute kidney injury after surgical placement of an antiadhesive barrier of macromolecular polysaccharides. A kidney biopsy, performed because of persistent kidney failure, showed tubular cell lesions compatible with osmotic nephrosis lesions. This case suggests that use of polysaccharide-containing antiadhesive barriers can induce severe kidney damage. Such barriers should be used with caution in patients with abnormal kidney function to prevent irreversible damage.	\N	\N
21262922	A 2005 report from the Centers for Medicare and Medicaid Services and the Centers for Disease Control Surgical Infection Prevention program indicated that only 41% of prophylactic antibacterials were correctly stopped within 24 h of the end of surgery. Electronic order sets have shown promise as a means of integrating guideline information with electronic order entry systems and facilitating safer, more effective care. The aim was to study the effectiveness of a computer-based antibacterial order set on increasing the proportion of patients who have antibacterial wound prophylaxis discontinued in the appropriate time frame. The authors conducted a quasi-experimental interrupted time-series analysis over an 8-month study period with the implementation of a computer-based order system designed to prevent excessive duration of surgical prophylaxis antibacterials. The primary outcome was the proportion of surgeries with antibacterials discontinued in the appropriate time frame. Additionally, we evaluated the percent of surgeries after implementation of the electronic intervention with chart documentation of infection among surgeries where the prescriber indicated the reason for antibacterial therapy was treatment. The computer-based order intervention significantly improved the proportion of surgeries with timely discontinuation of antibacterials from 38.8% to 55.7% (p < 0.001) in the intervention hospital, while the control hospital remained at 56-57% (p = 0.006 for the difference between treated and control hospitals). In surgeries after intervention implementation where a prescriber indicated the reason for antibacterial therapy was treatment, the prevalence of chart documented infection was only 14%. A computer-based electronic order set intervention increased timely discontinuation of postoperative antibacterials.	\N	\N
21278729	Optogenetics is a technique for controlling subpopulations of neurons in the intact brain using light. This technique has the potential to enhance basic systems neuroscience research and to inform the mechanisms and treatment of brain injury and disease. Before launching large-scale primate studies, the method needs to be further characterized and adapted for use in the primate brain. We assessed the safety and efficiency of two viral vector systems (lentivirus and adeno-associated virus), two human promoters (human synapsin (hSyn) and human thymocyte-1 (hThy-1)) and three excitatory and inhibitory mammalian codon-optimized opsins (channelrhodopsin-2, enhanced Natronomonas pharaonis halorhodopsin and the step-function opsin), which we characterized electrophysiologically, histologically and behaviorally in rhesus monkeys (Macaca mulatta). We also introduced a new device for measuring in vivo fluorescence over time, allowing minimally invasive assessment of construct expression in the intact brain. We present a set of optogenetic tools designed for optogenetic experiments in the non-human primate brain.	\N	\N
21291294	We have assessed gastroduodenal, endoscopical and histopathological findings in a series of patients with microscopic colitis (MC). We studied 75 patients with MC, 27 with collagenous colitis (CC) and 48 with lymphocytic colitis (LC), and 60 controls. Data of endoscopical findings were collected and biopsies were assessed. Helicobacter pylori infection rate was 15% in MC and 28% in the controls (p = 0.088). Age at diagnosis of MC was higher in H. pylori positive than negative patients (63.4 ± 9.6 vs. 54.4 ± 13.1 years; p = 0.034). Gastric endoscopic erosions were more prevalent in CC than in LC (25.9% vs. 6.2%; p = 0.030) and associated with thick body glands and antral predominance of gastritis in H. pylori positive patients. Rates of focal gastritis (5.6% vs. 6.9%) and lymphocytic gastritis (5.6% vs. 10%) were similar in MC and controls. LC was associated with gastric epithelial lymphocytosis and lymphocytic gastritis. Fifteen patients (20%) had celiac disease. Unlike LC, CC is associated with endoscopic erosions, likely related with the high acid secretion capacity as indicated by the ample body glands and antral predominance of gastritis in H. pylori associated cases of CC. The presence of some divergent gastroduodenal features in LC and CC, and in comparison with those reported in inflammatory bowel disease (IBD), supports the concept that these two conditions differ not only from IBD but also from each other. The findings also suggest the presence of pathogenetic links between colorectal and gastroduodenal abnormalities.	\N	\N
21297177	Moderate chronic kidney disease (CKD) (defined by an estimated glomerular filtration rate of 30-60 ml/min) is associated with mild hypertriglyceridemia related to delayed catabolism of triglyceride-rich lipoprotein particles. Altered apolipoprotein C-III (apoC-III) metabolism may contribute to dyslipidemia in CKD. To further characterize the dyslipidemia of CKD, we investigated the kinetics of plasma apoC-III in 7 nonobese, nondiabetic, non-nephrotic CKD subjects and 7 age- and sex-matched healthy controls, using deuterated leucine ([5, 5, 5, ²H₃]leucine), gas chromatography-mass spectrometry, and multicompartmental modeling. Compared with controls, CKD subjects had higher concentrations of plasma and VLDL triglycerides and plasma and VLDL apoC-III (P < 0.05). The increased plasma apoC-III concentration was associated with a decreased apoC-III fractional catabolic rate (FCR) (1.21 ± 0.15 vs. 0.74 ± 0.12 pools/day, P = 0.03). There were no differences between apoC-III production rates of controls and those of CKD subjects. In CKD subjects, plasma apoC-III concentration was significantly and negatively correlated with apoC-III FCR (r = -0.749, P = 0.05) but not with apoC-III production rate. Plasma apoC-III concentration was positively correlated with plasma and VLDL triglycerides and VLDL apoB concentrations and negatively correlated with VLDL apoB FCR (P < 0.05 for all). ApoC-III FCR was negatively correlated with plasma and VLDL triglycerides and VLDL apoB concentration and positively correlated with VLDL apoB FCR (P < 0.05 for all). Altered plasma apoC-III metabolism is a feature of dyslipidemia in moderate CKD. Modification of apoC-III catabolism may be an important therapeutic target for reducing cardiovascular disease risk in moderate CKD.	\N	\N
21303529	Evidence indicates that supervised home exercises, combined or not with manual therapy, can be beneficial for patients with non-specific chronic neck pain (NCNP). The objective of the study is to investigate the efficacy of preventive spinal manipulative therapy (SMT) compared to a no treatment group in NCNP patients. Another objective is to assess the efficacy of SMT with and without a home exercise program. Ninety-eight patients underwent a short symptomatic phase of treatment before being randomly allocated to either an attention-group (n = 29), a SMT group (n = 36) or a SMT + exercise group (n = 33). The preventive phase of treatment, which lasted for 10 months, consisted of meeting with a chiropractor every two months to evaluate and discuss symptoms (attention-control group), 1 monthly SMT session (SMT group) or 1 monthly SMT session combined with a home exercise program (SMT + exercise group). The primary and secondary outcome measures were represented by scores on a 10-cm visual analog scale (VAS), active cervical ranges of motion (cROM), the neck disability index (NDI) and the Bournemouth questionnaire (BQ). Exploratory outcome measures were scored on the Fear-avoidance Behaviour Questionnaire (FABQ) and the SF-12 Questionnaire. Our results show that, in the preventive phase of the trial, all 3 groups showed primary and secondary outcomes scores similar to those obtain following the non-randomised, symptomatic phase. No group difference was observed for the primary, secondary and exploratory variables. Significant improvements in FABQ scores were noted in all groups during the preventive phase of the trial. However, no significant change in health related quality of life (HRQL) was associated with the preventive phase. This study hypothesised that participants in the combined intervention group would have less pain and disability and better function than participants from the 2 other groups during the preventive phase of the trial. This hypothesis was not supported by the study results. Lack of a treatment specific effect is discussed in relation to the placebo and patient provider interactions in manual therapies. Further research is needed to delineate the specific and non-specific effects of treatment modalities to prevent unnecessary disability and to minimise morbidity related to NCNP. Additional investigation is also required to identify the best strategies for secondary and tertiary prevention of NCNP. ClinicalTrials.gov: NCT00566930.	\N	\N
21305298	Spondyloarthritis (SpA) are diseases with increased gut inflammation. To search for (anti-Saccharomyces cerevisiae) ASCA IgA, ASCA IgG, and anti-endomysial antibodies (EmA-IgA) in a cohort of 70 patients with SpA, we found 18.6% (13/70) positive for IgA-ASCA in the SpA group and 3/57 (5.2%) in the control group (P = 0.031). ASCA IgG and EmA-IgA were found at the same frequency in SpA and controls. No relationship of ASCA IgA positivity could be established with disease activity (measured by ESR, C-reactive protein, and BASDAI), presence of uveitis, or peripheral arthritis neither with functional status measured by BASFI. SpA patients present an increase in the IgA-ASCA positivity without any relationship to disease activity, functional index, clinical profile or the presence of HLA-B27. There is no evidence of higher prevalence of EmA-IgA in SpA patients in the studied sample.	\N	\N
21307778	Vitamin D deficiency is a global health problem that has various adverse consequences. Vitamin D is mainly synthesized in the skin by sunlight (UV light) irradiation; therefore, vitamin D status is influenced by geographic locations, seasonal changes, and skin pigmentations. The kidney is involved in the biosynthesis of 1,25-dihydroxyvitamin D and the reuptake of filtered 25-hydroxyvitamin D from the proximal tubules, thus, vitamin D deficiency is highly prevalent in patients with kidney disease who have renal insufficiency. There is a growing body of epidemiological and clinical evidence in the literature that links vitamin D deficiency to cardiovascular disease. The discovery of the vitamin D hormone functioning as an endocrine inhibitor of the renin-angiotensin system provides an explanation for this association. This review will discuss the mechanism underlying the connection between vitamin D and cardiovascular disease and its physiological and therapeutic implications.	\N	\N
21312278	Abnormal repetitive behaviors have been reported in Parkinson's disease (PD) during dopamine replacement therapy (DRT) and associated with individual predisposing features, including impulsivity. However, impulsivity and compulsive symptoms have never been explored in PD patients before initiation of DRT. We previously reported a 20% of impulse control disorders (ICD) in an Italian cohort. 103 consecutive newly diagnosed drug-naïve PD patients (means: age = 60.5 ± 9.2 years; duration = 15.4 ± 15.3 months) were screened for compulsive sexual behavior, compulsive buying, intermittent explosive disorder (Minnesota Impulsive Disorders Interview, MIDI), and pathological gambling (South Oaks Gambling Screen, SOGS). Barratt Impulsiveness Scale (BIS-11) and Maudsley Obsessional-Compulsive Questionnaire (MOCQ/R) assessed impulsivity, obsessive-compulsive symptoms, respectively. Depression (GDS-15) and general cognitive status were additionally assessed. We also compared ICDs frequency with our healthy controls. 17.5% of PD patients screened positive for at least one ICD at MIDI (17/103) and SOGS (1/103), though none had a disorder based on DSM-IV criteria. These frequencies were similar to healthy controls. There was a trend toward higher scores in BIS-11 attentive-impulsivity subscale (15.2 ± 4.8 vs. 18.7 ± 4.9; P = 0.007) and in MOCQ/R-Doubting subscale (0.67 ± 1.1 vs. 1.5 ± 1.2; P = 0.007) in PD with ICD. We also observed a positive correlation between GDS-15 and BIS-11. Similar to our healthy control population, we found a significant proportion of early PD patients positive for ICDs before starting treatment. We also found a relationship between impulsivity and depression. A detailed behavioral assessment before starting dopaminergic therapy is recommended.	\N	\N
21316322	The role of oxidative stress in patients with chronic kidney disease (CKD) as a potential marker of morbidity and mortality remains poorly evaluated. The aim of the present study aims was thus: to determine plasma levels of malondialdehyde (MDA), end product of lipid peroxidation in patients at different CKD stages (predialysis and dialysis); to evaluate the association between plasma MDA levels and vascular disease or overall and cardiovascular mortality. Plasma MDA levels evaluated by HPLC, pulse wave velocity, aortic calcification score were evaluated in 94 CKD patients (67±13 years, 54% males, 29% at CKD stages 2-3, 32% at stages 4-5, 39% at stage 5D) prospectively followed for mortality. We observed that the plasma MDA levels were increased in patient with CKD and augmented progressively with CKD stages. However, we did not find any independent association between plasma levels of MDA and pulse wave velocity, aortic calcification score, or overall and cardiovascular mortality. Our results suggest that plasma MDA is not a useful biomarker in CKD patients.	\N	\N
21317510	Many studies document racial variation, gender differences, and socioeconomic status (SES) patterning in cardiovascular disease (CVD) risk factors but few studies have investigated heterogeneity in SES differences by race/ethnicity or gender. Using data from the Multi-Ethnic Study of Atherosclerosis (N=6,814) and stratified regression models, we investigated race/ethnic differences in the SES patterning of diabetes, hypertension, smoking, and body mass index (BMI). Inverse socioeconomic gradients in hypertension, diabetes, smoking, and BMI were observed in White and Black women but associations were weaker or absent in Hispanic and Chinese women (except in the case of diabetes for Hispanic women). Even greater heterogeneity in social patterning of risk factors was observed in men. In White men all four risk factors were inversely associated with socioeconomic position, although often associations were only present or were stronger for education than for income. The inverse socioeconomic patterning was much less consistent in men of other races/ethnic groups, and higher SES was associated with higher BMI in non-White men. These findings have implications for understanding the causes of social patterning, for the analysis of SES adjusted race/ethnic differences, and for the targeting of interventions.	\N	\N
21327566	A synergistic effect of alcohol and hypertension has been suggested to increase the risk for stroke. However, the contribution of alcohol-induced hypertension to stroke morbidity and mortality may be greater than observed, because the effects of different drinking patterns have not been separately investigated. Alcohol-induced transient peaks in systolic blood pressure may predispose to stroke. Recent studies have measured time trends of blood pressure elevations in relation to alcohol consumption. They found a significant morning surge in blood pressure, which was related to alcohol intake in a dose-dependent manner and was independent of smoking. Men with a severe form of hypertension showed a 12-fold increased risk for cardiovascular disease mortality associated with heavy binge drinking. Binge drinking is a significant risk factor for stroke. Hypertensive patients should be warned about the risks of alcohol and urged to avoid binge drinking because of an increased risk for all subtypes of stroke.	\N	\N
21329838	We sought to study whether patients with right ventricular failure (RVF) secondary to chronic thromboembolic pulmonary hypertension (CTEPH) have reduced left ventricular (LV) mass, and whether LV mass reduction is caused by atrophy. The LV in patients with CTEPH is underfilled (unloaded). LV unloading may cause atrophic remodeling that is associated with diastolic and systolic dysfunction. We studied LV mass using cardiac magnetic resonance imaging (MRI) in 36 consecutive CTEPH patients (before/after pulmonary endarterectomy [PEA]) and 11 healthy volunteers selected to match age and sex of patients. We studied whether LV atrophy is present in monocrotaline (MCT)-injected rats with RVF or controls by measuring myocyte dimensions and performing in situ hybridization. At baseline, CTEPH patients with RVF had significantly lower LV free wall mass indexes than patients without RVF (35 ± 6 g/m(2) vs. 44 ± 7 g/m(2), p = 0.007) or volunteers (42 ± 6 g/m(2), p = 0.006). After PEA, LV free wall mass index increased (from 38 ± 6 g/m(2) to 44 ± 9 g/m(2), p = 0.001), as right ventricular (RV) ejection fraction improved (from 31 ± 8% to 56 ± 12%, p < 0.001). Compared with controls, rats with RVF had reduced LV free wall mass and smaller LV free wall myocytes. Expression of atrial natriuretic peptide was higher, whereas that of α-myosin heavy chain and sarcoplasmic reticulum calcium ATPase-2 were lower in RVF than in controls, both in RV and LV. RVF in patients with CTEPH is associated with reversible reduction in LV free wall mass. In a rat model of RVF, myocyte shrinkage due to atrophic remodeling contributed to reduction in LV free wall mass.	\N	\N
21332905	• To describe a multicentre experience with preoperative platinum-based chemotherapy before radical nephroureterectomy (RNU) in patients with upper tract urothelial carcinoma (UTUC) with loco-regional nodal metastases. • We identified 313 patients from the UTUC Collaboration (over 1200 patients), who underwent RNU with concomitant retroperitoneal lymph node dissection between 1990 and 2007 and met the inclusion criteria for one of three groups. • Group 1 comprised patients who received chemotherapy before RNU because of biopsy-proven loco-regional nodal metastases. • Group 2 consisted of patients who underwent primary RNU and were found to have metastatic nodal disease on final pathological review (node-positive). • Group 3 comprised a comparative cohort of patients treated with primary RNU for invasive or locally advanced (pT2/pT4) node-negative (N0) UTUC. • Groups 1, 2 and 3 included 18, 120 and 175 patients, respectively. The 5-year disease-free survival rates were 49%, 30% and 64%, whereas the 5-year cancer-specific survival rates were 44%, 36% and 69% in groups 1, 2 and 3, respectively. • In group 1, on final pathological evaluation, nine patients were pN0, six patients were pT0 and five patients had pT0N0 disease. Kaplan-Meier survival analyses showed similar recurrence and survival rates in group 1 compared with group 3 (P= 0.14 and P= 0.06, respectively). • Meanwhile, group 2 had significantly lower disease-free and cancer-specific survival rates compared with group 3 (P < 0.001 and P < 0.001, respectively) and compared with group 1 (P= 0.04 and P= 0.06, respectively). • Preoperative chemotherapy followed by aggressive surgical consolidation may yield favourable oncological outcomes in patients with UTUC with loco-regional nodal metastases. • These data support further evaluation of neoadjuvant systemic therapy in patients at risk for locally advanced UTUC.	\N	\N
21342667	In Belgium, the 7-valent pneumococcal conjugate vaccine (PCV7) was introduced into the national schedule in 2007. The early impact of PCV7 vaccination on paediatric invasive disease was estimated by comparing pre- and post-vaccination incidence from national surveillance. In children <2 year-olds, vaccine-serotype incidence declined by 96% but non-vaccine-types increased 2-3-fold. Overall invasive disease decreased by 23-46%, depending on adjustment for under-reporting and pre-vaccine trends. Non-vaccine-types 1 and 19A had increased before PCV7 use, suggesting the contribution of other factors. Estimation of PCV7 impact comparing pre- and post-vaccination data should adjust for pre-vaccine trends, and serotype dynamics need further exploration.	\N	\N
21349334	The intestinal microbiota is an ecosystem formed by a variety of ecological niches, made of several bacterial species and a very large amount of strains. The microbiota is in close contact with the intestinal mucosa or epithelial interface which is, after the respiratory area, the largest surface of the body, occupying approximately 250-400 m(2). The physiological activities of the microbiota are manifold and are just being unraveled. Based on the observations of the multiple roles played by the microbiota in health and disease, the notion of modifying it with appropriate formulations, i.e. probiotics, is being tested in several settings. This review summarizes the current knowledge on probiotics and discusses both limitations and acquired evidence to support their use in preventive and therapeutic medicine.	\N	\N
21350933	This study used data mining techniques to investigate disease forms in various administrative areas and to analyze the differences among various administrative areas in order to further draw up a disease distribution map. It is hoped that may help formulate future public health strategies and to allocate medical resources more appropriately. The major disease forms for residents under the age of 60 were hypertension, hyperglycemia and hyperlipidemia. In regard to the neighboring areas, three neighboring areas, A1, A3, and B9, shared the same disease problems with A4, A5, and B3, while two mountain-area cities, B7 and C10, experienced higher instances of liver function impairment. In terms of the clustering phenomenon among municipally graded administrative areas, the major health problems in Grade A cities were hypertension, hyperglycemia, and hyperlipidemia. The health problems such as liver function impairment and renal dysfunction were more frequently observed in Grade B and Grade C cities.	\N	\N
21352090	Autologous chondrocyte implantation (ACI) is considered a promising choice for the treatment of cartilage defects. However, the application of ACI to osteoarthritic patients is, in general, contraindicated. The purpose of this study is to evaluate the efficiency of three-dimensionally structured ACI (3D-ACI; CaReS) in a rat model of knee osteoarthritis (OA). OA-like degenerative changes in the articular cartilage were created by transecting the anterior cruciate ligament (ACLT) in athymic nude rats. Two weeks later, CaReS was transplanted at the cartilage injury sites created by micro-drilling in the patella groove (Chondrocyte-implanted (CI) group: CaReS collagen with human chondrocytes; Collagen group: CaReS collagen without cells; and Sham group: sham operation; n = 15/group). Reverse Transcription Polymerase Chain Reaction (RT-PCR) analysis demonstrated the expression of human-specific type 2 collagen and Sry-type high-mobility-group box 9 (SOX9) in the CI group-not in the other groups-throughout the study period. Double immunohistochemistry for human-specific type 2 collagen and human leukocyte antigen-abacavir (HLA-ABC) at week 4 showed positive staining in the CI group only. Macroscopic assessment showed better repair at the cartilage defect sites in the CI group, compared to the other groups. Histological assessment with toluidine blue staining showed that the thickness of the articular cartilage and semi-quantitative histological scores were higher in the CI group than in the other groups up to week 20. We demonstrate, for the first time, that 3D-ACI is effective in repairing cartilage defects in a rat model of ACLT-induced OA.	\N	\N
21354253	Molecular rotors are a form of fluorescent intramolecular charge-transfer complexes that can undergo intramolecular twisting motion upon photoexcitation. Twisted-state formation leads to non-radiative relaxation that competes with fluorescence emission. In bulk solutions, these molecules exhibit a viscosity-dependent quantum yield. On the molecular scale, the fluorescence emission is a function of the local free volume, which in turn is related to the local micro-viscosity. Membrane viscosity, and the inverse; fluidity, are characteristic terms used to describe the ease of movement withing the membrane. Often, changes in membrane viscosity govern intracellular processes and are indicative of a disease state. Molecular rotors have been used to investigate viscosity changes in liposomes and cells, but accuracy is affected by local concentration gradients and sample optical properties. We have developed self-calibrating ratiometric molecular rotors to overcome this challenge and integrated the new molecules into a DLPC liposome model exposed to the membrane-fluidizing agent propanol. We show that the ratiometric emission intensity linearly decreases with the propanol exposure and that the ratiometric intensity is widely independent of the total liposome concentration. Conversely, dye concentration inside liposomes influences the sensitivity of the system. We suggest that the new self-calibrating dyes can be used for real-time viscosity sensing in liposome systems with the advantages of lifetime measurements, but with low-cost steady-state instrumentation.	\N	\N
21357888	This review is the summary of a workshop on the role of distal airways in chronic obstructive pulmonary disease (COPD), which took place in 2009 in Vence, France. The evidence showing inflammation and remodelling in distal airways and the possible involvement of these in the pathobiology, physiology, clinical manifestations and natural history of COPD were examined. The usefulness and limitations of physiological tests and imaging techniques for assessing distal airways abnormalities were evaluated. Ex vivo studies in isolated lungs and invasive measurements of airway resistance in living individuals have revealed that distal airways represent the main site of airflow limitation in COPD. Structural changes in small conducting airways, including increased wall thickness and obstruction by muco-inflammatory exudates, and emphysema (resulting in premature airway closure), were important determinants of airflow limitation. Infiltration of small conducting airways by phagocytes (macrophages and neutrophils), dendritic cells and T and B lymphocytes increased with airflow limitation. Distal airways abnormalities were associated with patient-related outcomes (e.g. dyspnoea and reduced health-related quality of life) and with the natural history of the disease, as reflected by lung function decline and mortality. These data provide a clear rationale for targeting distal airways in COPD.	\N	\N
21360500	In addition to inducing a self-limited myopathy, statin use is associated with an immune-mediated necrotizing myopathy (IMNM), with autoantibodies that recognize ∼200-kd and ∼100-kd autoantigens. The purpose of this study was to identify these molecules to help clarify the disease mechanism and facilitate diagnosis. The effect of statin treatment on autoantigen expression was addressed by immunoprecipitation using sera from patients. The identity of the ∼100-kd autoantigen was confirmed by immunoprecipitation of in vitro-translated 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) protein. HMGCR expression in muscle was analyzed by immunofluorescence. A cohort of myopathy patients was screened for anti-HMGCR autoantibodies by enzyme-linked immunosorbent assay and genotyped for the rs4149056 C allele, a predictor of self-limited statin myopathy. Statin exposure induced expression of the ∼200-kd/∼100-kd autoantigens in cultured cells. HMGCR was identified as the ∼100-kd autoantigen. Competition experiments demonstrated no distinct autoantibodies recognizing the ∼200-kd protein. In muscle biopsy tissues from anti-HMGCR-positive patients, HMGCR expression was up-regulated in cells expressing neural cell adhesion molecule, a marker of muscle regeneration. Anti-HMGCR autoantibodies were found in 45 of 750 patients presenting to the Johns Hopkins Myositis Center (6%). Among patients ages 50 years and older, 92.3% had taken statins. The prevalence of the rs4149056 C allele was not increased in patients with anti-HMGCR. Statins up-regulate the expression of HMGCR, the major target of autoantibodies in statin-associated IMNM. Regenerating muscle cells express high levels of HMGCR, which may sustain the immune response even after statins are discontinued. These studies demonstrate a mechanistic link between an environmental trigger and the development of sustained autoimmunity. Detection of anti-HMGCR autoantibodies may facilitate diagnosis and direct therapy.	\N	\N
21362127	Type 3 von Willebrand disease (VWD) is an autosomal recessive bleeding disorder, characterized by virtually undetectable plasma von Willebrand factor (VWF) and consequently reduced plasma factor VIII levels. Genetic mutations responsible for type 3 VWD are very heterogeneous, scattered throughout the VWF gene and show high variability among different populations. Twenty-five severe VWD patients were studied by direct sequencing of the 51 coding exons of the VWF gene. The total number of VWD type 3 families in Hungary is 24, of which 23 were investigated. Fifteen novel mutations were identified in 31 alleles, five being nonsense mutations (p.Q1238X, p.Q1898X, p.Q1931X, p.S2505X and p.S2568X), four small deletions and insertions resulting in frame shifts (c.1992insC, c.3622delT, c.5315insGA and c.7333delG), one a large partial deletion (delExon1-3) of the 5'-region, four candidate missense mutations (p.C35R, p.R81G, p.C295S, p.C623T) and one a candidate splice site mutation (c.1730-10C>A). Six previously described mutations were detected in 17 alleles, including the repeatedly found c.2435delC, p.R1659X and p.R1853X. Only one patient developed alloantibodies to VWF, carrying a homozygous c.3622delT. We report the genetic background of the entire Hungarian type 3 VWD population. A large novel deletion, most probably due to a founder effect, seems to be unique to Hungarian type 3 VWD patients with high allele frequency. In contrast to previous reports, none of the five patients homozygous for the large partial deletion developed inhibitors to VWF. This discrepancy raises the possibility of selection bias in some of the reports.	\N	\N
21363991	Hemorrhagic fever with renal syndrome (HFRS) is an important public health problem in Shandong Province, China. In this study, we combined ecologic niche modeling with geographic information systems (GIS) and remote sensing techniques to identify the risk factors and affected areas of hantavirus infections in rodent hosts. Land cover and elevation were found to be closely associated with the presence of hantavirus-infected rodent hosts. The averaged area under the receiver operating characteristic curve was 0.864, implying good performance. The predicted risk maps based on the model were validated both by the hantavirus-infected rodents' distribution and HFRS human case localities with a good fit. These findings have the applications for targeting control and prevention efforts.	\N	\N
21397153	Epidermolysis bullosa acquisita (EBA) is the rarest of the autoimmune bullous diseases (AIBD). It is defined as an AIBD secondary to production of antibodies directed against type VII collagen and then binding to anchoring fibrils in the basal membrane zone (BMZ) of the skin and the Malpighian mucosa. To evaluate risk factors, different clinical forms and diagnostic methods, and the efficacy of treatments. The articles were identified by a search of PubMed and Embase from the initial creation of these databases through to March 2009. We selected generalised reviews and meta-analyses, cases involving unusual and/or serious clinical presentations, studies of immunological tests and homogeneous retrospective series regarding therapy. Of the 206 articles analysed, only two were of an adequate level of proof, with four of intermediate level, and all the others of only low level. EBA affects all age groups (from newborn infants to the very elderly) with a slight predominance in female subjects. Diagnosis must be considered in subjects with black skin of African origin. A drug-induced origin of the disease was reported in 11% of cases of IgA-EBA. Classical EBA (30 to 50% of cases), resembles epidermolysis bullosa hereditaria (EBH), with fragile skin, non-inflammatory bullae, dystrophic scars and milia. Numerous atypical and misleading forms exist. Evocative signs are the presence of mucosal lesions and/or scars. The severity of EBA is determined by the extent of cutaneous lesions, and ophthalmological, ENT and/or oesophageal involvement. Crohn's disease is associated in 25% of cases of EBA. Unequivocal diagnosis is provided by direct immunoelectron microscopy (IEM). Therapeutic efficacy has been reported for dapsone, sulphapyridine and colchicine in milder forms, and for cyclosporine, mycophenolate mofetil, rituximab, intravenous immunoglobulins and extracorporeal photochemotherapy in resistant and severe forms. A number of authors have reported inefficacy of systemic corticosteroids, even in high-dose regimens, with the development of corticosteroid dependence in certain cases. In the absence of any therapeutic trials, it is difficult to select optimal treatment; however, the benefit/risk ratio of systemic corticosteroid treatment is unfavourable.	\N	\N
21397734	In this paper we introduce a new technical development of branching processes that can potentially model spread of epidemics by including various stages of infection. In fact, we present an epidemic model that the disease spreads from an individual to another one in such a way that the ability of individual u to infect a susceptible individual depends only on how long u has been infected. For analysis of this model, we introduce a new and special model of the Crump-Mode-Jagers branching processes in discrete time and obtain some of its fundamental properties.	\N	\N
21404106	To confirm the efficacy and toxicity of Erlotinib in combination with Gemcitabine and Capecitabine when used as a first-line therapy in metastatic/recurrent pancreatic cancer (PC). Locally advanced PC was excluded. Erlotinib was given at a dose of 100 mg daily from D1 to D28. 1000 mg/m(2) of gemcitabine was given on D1,8,15 and 1660 mg/m(2)/day of capecitabine was given from D1 to 21, repeated every 4 weeks. Response was assessed every 8 weeks. A total of 47 patients were enrolled. Response rate and disease control rate was 32.6% (95% CI, 18.6-46.6%) and 83.7% (95% CI, 72.7-94.7%) respectively. The PFS was 6.5 months (95% CI, 3.4-9.7) and OS was 12.0 months (95% CI, 8.6-15.9). The Gr 3/4 toxicities were: neutropenia (6.8%), thrombocytopenia (3.2%), anemia (1.6%). nausea (1.6%), vomiting (1.6%), anorexia (5.3%), rash (2.4%). The EGFR expression was associated with shorter OS and ERCC2 expression was associated with longer PFS and OS. PFS and OS were not different according to K-RAS mutation or polymorphism of RRM1 and CDA. Erlotinib, gemcitabine and capecitabine combination showed promising efficacy and good tolerability in metastatic PC. This efficacy was observed irrespective of K-RAS mutation, and EGFR expression was poor prognostic factor for OS.	\N	\N
21415164	Activation of lipid metabolism is an early event in carcinogenesis and a central hallmark of many cancers. However, the precise molecular composition of lipids in tumors remains generally poorly characterized. The aim of the present study was to analyze the global lipid profiles of breast cancer, integrate the results to protein expression, and validate the findings by functional experiments. Comprehensive lipidomics was conducted in 267 human breast tissues using ultraperformance liquid chromatography/ mass spectrometry. The products of de novo fatty acid synthesis incorporated into membrane phospholipids, such as palmitate-containing phosphatidylcholines, were increased in tumors as compared with normal breast tissues. These lipids were associated with cancer progression and patient survival, as their concentration was highest in estrogen receptor-negative and grade 3 tumors. In silico transcriptomics database was utilized in investigating the expression of lipid metabolism related genes in breast cancer, and on the basis of these results, the expression of specific proteins was studied by immunohistochemistry. Immunohistochemical analyses showed that several genes regulating lipid metabolism were highly expressed in clinical breast cancer samples and supported also the lipidomics results. Gene silencing experiments with seven genes [ACACA (acetyl-CoA carboxylase α), ELOVL1 (elongation of very long chain fatty acid-like 1), FASN (fatty acid synthase), INSIG1 (insulin-induced gene 1), SCAP (sterol regulatory element-binding protein cleavage-activating protein), SCD (stearoyl-CoA desaturase), and THRSP (thyroid hormone-responsive protein)] indicated that silencing of multiple lipid metabolism-regulating genes reduced the lipidomic profiles and viability of the breast cancer cells. Taken together, our results imply that phospholipids may have diagnostic potential as well as that modulation of their metabolism may provide therapeutic opportunities in breast cancer treatment.	\N	\N
21418090	To investigate associations between fasting plasma glucose level and the prevalence of acquired colour vision impairment in type 2 diabetes patients without diabetic retinopathy. Participants in this cross-sectional study of male officials aged 20-60 yr in the Japanese Self Defence Force, underwent colour vision testing, ophthalmic examination, a standardized interview and examination of venous blood samples. Ishihara plates, a Lanthony 15-hue desaturated panel and Standard Pseudoisochromatic Plates Part 2 were used to examine colour vision. The Farnsworth-Munsell 100-hue test was performed to define acquired colour vision impairment. Cardiovascular disease risk factors were determined from serum blood samples, physical records and an interview. We performed logistic regression analysis adjusted for age, diagnosed hypertension, dyslipidaemia, cataract, glaucoma, being overweight, smoking status and alcohol intake. Crude and adjusted odds ratios were calculated for three glucose levels, which included normal fasting glucose, impaired fasting glucose and diabetes. Out of a total of 1042 men enrolled, 872 were eligible for the study, and 31 were diagnosed with acquired colour vision impairment. As compared with the subjects with normal fasting glucose (< 5.6 mmol/l), the crude odds ratio for acquired colour vision impairment was 0.93 (95% CI 0.32-2.74) for the subjects with impaired fasting glucose (5.6-6.9 mmol/l) and 8.07 (95% CI 2.48-26.22) for the patients with type 2 diabetes. The multiple-adjusted odds ratios were 0.77 (95% CI 0.25-2.34) for the subjects with impaired fasting glucose and 5.89 (95% CI 1.55-22.40) for the patients with type 2 diabetes. Our findings suggest that there is a dramatically increased prevalence of acquired colour vision impairment in type 2 diabetes patients without diabetic retinopathy which might be attributable to another pathogenesis associated with diabetic retinopathy.	\N	\N
21421095	Appendectomy remains one of the most common emergency surgical procedures encountered throughout the United States. With improvements in diagnostic techniques, the efficiency of diagnosis has increased over the years. However, the entity of negative appendectomies still poses a dilemma because these are associated with unnecessary risks and costs to both patients and institutions. This study was conducted to show current statistics and trends in negative appendectomy rates in the United States. A retrospective analysis was conducted using data from the National Inpatient Sample from 1998 to 2007. Adult patients (>18 y) having undergone appendectomies were identified by the appropriate International Classification of Diseases 9th revision codes. Patients with incidental appendectomy and those with appendiceal pathologies, also identified by relevant International Classification of Diseases 9th revision codes, were excluded. The remaining patients represent those who underwent an appendectomy without appendiceal disease. The patients then were stratified according to sex, women were classified further into younger (18-45 y) and older (>45 y) based on child-bearing age. The primary diagnoses subsequently were categorized by sex to identify the most common conditions mistaken for appendiceal disease in the 2 groups. Between 1998 and 2007, there were 475,651 cases of appendectomy that were isolated. Of these, 56,252 were negative appendectomies (11.83%). There was a consistent decrease in the negative appendectomy rates from 14.7% in 1998 to 8.47% in 2007. Women accounted for 71.6% of cases of negative appendectomy, and men accounted for 28.4%. The mortality rate was 1.07%, men were associated with a higher rate of mortality (1.93% vs .74%; P < .001). Ovarian cyst was the most common diagnosis mistaken for appendicitis in younger women, whereas malignant disease of the ovary was the most common condition mistaken for appendiceal disease in women ages 45 and older. The most common misdiagnosis in men was diverticulitis of the colon. There has been a consistent decline in the rates of negative appendectomy. This trend may be attributed to better diagnostics. Gynecologic conditions involving the ovary are the most common to be misdiagnosed as appendiceal disease in women.	\N	\N
21422948	This study was designed to characterize the energy metabolism in the patients with acute-on-chronic liver failure (ACLF). Protein-energy malnutrition usually occurs in the patients with chronic liver disease and is exacerbated during the progression of liver failure. Unfortunately, there is limited study to fully elucidate the energy metabolism in the patients with ACLF. A retrospective cohort was designed with a total of 282 patients (100 patients with ACLF, 100 with liver cirrhosis, and 82 with chronic hepatitis B). Resting energy expenditure and the oxidation rates of glucose, lipid, and protein were assessed by indirect heat measurement using the critical care monitor and desktop analysis system, nutritive metabolic investigation system. Survival rate was estimated with the Kaplan-Meier method. There was no significant difference in resting energy expenditure among the patients with ACLF, the liver cirrhosis, and the chronic hepatitis (1402.05±480.07 kcal/d in patients with ACLF, 1274.27±316.36 kcal/d in patients with liver cirrhosis, and 1396.77±384.80 kcal/d in patients with chronic hepatitis). Respiratory quotient (RQ) was significantly lower in the patients with ACLF than those in the liver cirrhosis and the chronic hepatitis B (P=0.000). In patients with ACLF, RQ of the nonsurvival group was significantly lower than the survival group (P=0.000). It is identified from receiver operating characteristic curve analysis that a RQ cutoff value of 0.83 (area under the receiver operating characteristic curve, 0.760) is favorable to predict good prognosis in patients with liver failure, which has a sensitivity of 73.68%, a specificity of 74.42%, and positive predictive value of 79.2% and negative predictive value of 68.1%. In patients with ACLF, RQ was significantly lower in the nonsurvival group than the survival group, thus suggesting that RQ may be used as an indicator of prognosis of liver failure.	\N	\N
21426326	To investigate for the first time the natural history and long-term evolution of "familial cortical tremor, myoclonus, and epilepsy." We evaluated the clinical, electrophysiologic, and treatment data of 14 patients from three families linked to 2p11.1-q12.2. A simplified scale was used to score myoclonus severity. Electroencephalography (EEG) studies were reviewed for the evaluation of background activity, paroxysmal abnormalities, and photoparoxysmal response. Data were organized for age groups. Correlation and logistic regression analysis were performed. Patients' mean age was 47.8 ± 22.0 years (range 20-86 years). Mean age at disease onset was 20.2 ± 7.8 years (range 11-40 years); mean follow-up duration was 14.0 ± 5.8 years (range 7-28 years). Evaluation at different age groups revealed a gradual, progressive worsening of the myoclonus in 10 patients (71.4%). Two subjects aged >80 years showed myoclonus interfering with autonomous walking. Myoclonus severity was correlated with disease duration (p<0.001) and patients' age (p=0.001). Six patients (42.8%) experienced seizures, usually between the second and sixth decades of life. Evaluation of EEG long-term evolution revealed progressive slowing of background activity in parallel with the gradual worsening of myoclonus. In contrast, paroxysmal activity and photosensitivity were particularly evident during the intermediate phases of the disease. In addition, psychiatric and neuropsychological dysfunction occurred in more than one third of the patients. We provide data for a slight age-dependent progression and the presence of neuropsychiatric and neuropsychological dysfunction in this unique syndrome, for which the definition of familial or autosomal dominant cortical tremor, myoclonus, and epilepsy (FCTME/ADCME) seems to be, therefore, more appropriate.	\N	\N
21429534	Familial combined hyperlipidemia (FCH) is a genetic model of atherogenic dyslipidemia with insulin resistance and early coronary disease. Our objective was to evaluate the presence of carotid alterations as a marker of systemic atherosclerosis in subjects with FCH and assess the effect of 80 mg of atorvastatin per day in carotid plaque thickness after 2 years. 100 non diabetic subjects with FCH in primary prevention were consecutively included. Clinical and biochemical parameters and carotid ultrasonography were performed. Subjects with carotid plaque started treatment with 80 mg of atorvastatin per day for 2 years. 29% of subjects had carotid plaques. We did not find significant differences in any of the parameters between subjects with presence or absence of carotid plaques. Twenty subjects with carotid plaques accepted/agreed to participate in the interventional study. Two years follow-up showed a significant reduction in LDLc (30%) and carotid plaque thickness (10%). Carotid ultrasonography is useful to detect subclinical atherosclerosis in high risk cardiovascular patients such as subjects with FCH. Treatment with high doses of atorvastatin induces the regression of carotid plaque thickness after 2 years follow-up. Our results suggest that intensive treatment with atorvastatin could be useful to reduce the development of cardiovascular disease in this group of patients.	\N	\N
21430371	The aim of this study was to evaluate the impact of clinical variables and biologic features on response rate (RR), overall survival (OS) and progression-free survival (PFS) in 111 patients with de novo diffuse large B cell lymphoma (DLBCL). Fifty-three patients were treated with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) and 58 patients were treated with R-CHOP (rituximab + CHOP). The variables predictive of RR in the CHOP group were B symptoms, age, clinical stage, bone marrow involvement, bulky disease, International Prognostic Index (IPI) and Bcl-2; in the R-CHOP group, these variables were bulky disease, bone marrow involvement, IPI and Ki67 expression >80%. Multivariate analysis showed that in patients treated with CHOP, the independent prognostic factors associated with PFS were age, bulky disease, IPI and Bcl-2 and those associated with OS were performance status, clinical stage, IPI and bone marrow involvement. In contrast, in patients treated with R-CHOP, the variable shown by multivariate analysis to be an independent prognostic factor associated with PFS was bulky disease, whereas Ki67 expression >80% was associated with OS and PFS. Our data show that a high Ki67 expression and bulky disease could represent possible predictive factors of poor prognosis, which would help to identify a high-risk subgroup of newly diagnosed DLBCL.	\N	\N
21437774	The enormous abundance of lipid molecules in the central nervous system (CNS) suggests that their role is not limited to be structural and energetic components of cells. Over the last decades, some lipids in the CNS have been identified as intracellular signalers, while others are known to act as neuromodulators of neurotransmission through binding to specific receptors. Neurotransmitters of lipidic nature, currently known as neurolipids, are synthesized during the metabolism of phospholipid precursors present in cell membranes. Therefore, the anatomical identification of each of the different lipid species in human CNS by imaging mass spectrometry (IMS), in association with other biochemical techniques with spatial resolution, can increase our knowledge on the precise metabolic routes that synthesize these neurolipids and their localization. The present study shows the lipid distribution obtained by MALDI-TOF IMS in human frontal cortex, hippocampus, and striatal area, together with functional autoradiography of cannabinoid and LPA receptors. The combined application of these methods to postmortem human brain samples may be envisioned as critical to further understand neurological diseases, in general, and particularly, the neurodegeneration that accompanies Alzheimer's disease.	\N	\N
21438696	To test the hypothesis of a significant association between resting heart rate (RHR) and coronary artery calcium (CAC). This is a cross-sectional study of a subset of women enrolled in the estrogen-alone clinical trial of the Women's Health Initiative (WHI). We used a longitudinal study that enrolled 998 postmenopausal women with a history of hysterectomy between the ages of 50 and 59 at enrollment at 40 different clinical centers. RHR was measured at enrollment and throughout the study, and CAC was determined approximately 7 years after the baseline clinic visit. The mean (standard deviation [SD]) age was 55 (2.8) years. With adjustment for age and ethnicity, a 10-unit increment in RHR was significantly associated with CAC (SD 1.18, 95% confidence interval [CI] 1.01-1.38), but this was no longer significant after adjustment for body mass index (BMI), income, education, dyslipidemia, diabetes, smoking, and hypertension (SD 1.06, 95% CI 0.90-1.25). In a fully adjusted multivariable model, however, there was a significant interaction (p=0.03) between baseline RHR and systolic blood pressure (SBP) for the presence of any CAC. Compared to women with an RHR < 80 beats per minute (BPM) and an SBP < 140 mm Hg, those who had an RHR ≥ 80 BPM and an SBP ≥ 140 mm Hg had 2.66-fold higher odds (1.08-6.57) for the presence of any CAC. Compared to those with normal BP and RHR, postmenopausal, hysterectomized women with an elevated SBP and RHR have a significantly higher odds for the presence of calcified coronary artery disease.	\N	\N
21438811	Hepatic steatosis, considered the first step in the pathophysiologic continuum of non-alcoholic fatty liver disease, is estimated to afflict 30% of the US population and over 75% of patients with Type 2 diabetes. Given the expected rise in the prevalence of obesity and Type 2 diabetes in the following decades, hepatic steatosis will, if not already, become an epidemic. The consequences of hepatic steatosis are numerous, and range from progression to chronic liver disease, with its associated morbidity and mortality, to worsening insulin resistance and Type 2 diabetes, as well as being an independent contributor to cardiovascular disease. All such consequences are more likely to occur in patients with Type 2 diabetes who are already at high risk of cardiovascular events. In this article we review the evidence behind the available therapeutic options for hepatic steatosis, and identify challenges and unmet needs in the field.	\N	\N
21439159	The influence of respiratory infections on asthma has not been fully understood. Acute viral and bacterial infections often lead to exacerbations. Less is known about the role of chronic infections, particularly with atypical pathogens. The aim of this study was to evaluate the impact of Chlamydophila pneumoniae and Mycoplasma pneumoniae infections on the control and severity of asthma. Spirometry, skin-prick tests as well as measurement of immunoglobulin G (IgG), IgM, and IgA against C. pneumoniae and M. pneumoniae (ELISA) were performed in 95 patients with persistent asthma and 58 healthy controls. Additionally, in the selected group of asthmatic patients, presence of C. pneumoniae and M. pneumoniae genetic material was tested in induced sputum (polymerase chain reaction [PCR]). IgA against C. pneumoniae was found in 42 (44.2%) asthmatic patients and 17 (29.3%) controls (p < 0.05). It was found more often in the group with uncontrolled asthma (p = 0.001) as well as in nonatopic asthmatic patients (p < 0.05). IgG was detected in 58 asthmatic patients (61%) and 21 (36.2%) controls, more often in cases of uncontrolled (p < 0.05) and nonatopic asthma patients (p < 0.05). Such correlations were not found in relation to M. pneumoniae infections. C. pneumoniae was detected by means of PCR in respiratory secretions of eight asthmatic patients (40%), and M. pneumoniae was detected in two asthmatic patients (10%). In conclusion, C. pneumoniae infections are more frequent in asthmatic patients compared with healthy individuals and in nonatopic asthmatic patients compared to atopic patients. Chronic infection is associated with poor control of asthma.	\N	\N
21443521	The inherited disorders of hemoglobin synthesis are the most common monogenic disorders worldwide. They include thalassemias, hemoglobin variants, and hereditary persistence of fetal hemoglobin. β-thalassemia is the most common monogenic disorder in India. Clinical manifestations of β-thalassemia are extremely variable in severity. The reasons for this heterogeneity are not very well understood. Previous studies have shown that the genetic variants that modulate HbF levels have a very strong impact on ameliorating the clinical phenotype. In the present study, 5570 blood samples from suspected cases were analyzed using HPLC, amplification refractory mutation system-PCR and reverse dot blot techniques. Of 5570 individuals, we found 676 cases of β-thalassemia disease. Molecular analysis revealed the presence of different β-thalassemia mutations in the population under study. Patients with β-thalassemia were classified into mild, moderate, and severe according to severity score based on Hb level, age of onset, age at which patients received their first blood transfusion, degree of growth retardation and splenectomy. Patients with β-thalassemia were analyzed for zinc finger and homeoboxes 2 (ZHX2) G779A polymorphism, and the association between ZHX2 gene polymorphism and severity of β-thalassemia was evaluated. We did not find a significant difference in genotypic and allelic frequency of ZHX2 gene between mild and moderate, mild and severe, and moderate and severe cases. There was no significant difference in high and low percentage of HbF in GG, GA, and AA bearing individuals showing that ZHX2 gene variant has no role in ameliorating the severity of β-thalassemia major in the South Indian population from Andhra Pradesh.	\N	\N
21458394	Encapsulating peritoneal sclerosis (EPS) is a rare but life-threatening complication of peritoneal sclerosis (PD). In 2000, the International Society for Peritoneal Dialysis outlined diagnostic guidelines and a clinical definition of EPS. Over the intervening years, new evidence was published and several centers became more experienced managing patients with EPS. Although, further networking was initiated (European EPS Working Group), evidence regarding therapy and diagnosis of EPS is still lacking. Multicenter trials are needed to establish evidence regarding the management of EPS. Risk factors for EPS are identified and patients at risk should be monitored closely. In case of emerging signs of EPS, patients should be referred to an EPS-center before initiation of therapy. Morphology and immunohistochemistry will play a central role in the near future. Nowadays, most pathologists are not sophisticated in the pathology of peritoneal biopsies. Clear histological criteria are warranted. For the outcome of the patient, it is crucial that an EPS experienced surgeon conducts surgery.	\N	\N
21463281	Dravet syndrome (DS) is an epileptic encephalopathy related mainly to mutations in the SCN1A gene, encoding for neuronal sodium channels. Patients with DS have a high risk of sudden unexpected death in epilepsy (SUDEP). In this study we investigated whether patients with DS present abnormalities in electrical and autonomic cardiac function. To this aim we assessed ventricular repolarization and heart rate variability (HRV) on standard electrocardiography (ECG) and on 24-h ECG Holter monitoring, respectively, in 20 patients affected by DS (6.8 ± 4 years, 11 female). As age- and sex-matched control groups, we also studied 20 patients with other epileptic syndromes receiving antiepileptic drugs (ES/AED, 6.0 ± 5 years, 12 female), 20 patients with other epileptic syndromes without treatment (ES/no-AED, 6.7 ± 4 years, 10 female), and 20 healthy children (HC, 7.2 ± 5 years, 11 females). Data analysis showed that patients with DS had depressed HRV variables compared to both ES patients (ES/AED and ES/no-AED) and HC control group, whereas no significant differences in HRV variables were found between ES patients (with and without treatment) and HC. There was no significant difference between patients with DS and all the other control groups in RR intervals, QT, and QTc interval analysis. In conclusion, DS patients display an imbalance of cardiac autonomic function toward a relative predominance of adrenergic tone compared to both healthy children and patients with other forms of epilepsy, independent of antiepileptic therapy. Follow-up studies should clarify the clinical significance of this autonomic impairment and whether HRV analysis can be helpful in predicting the risk of sudden death in patients with DS.	\N	\N
21463368	Oral lichen planus (OLP) is generally accepted as a chronic and T-cell-mediated autoimmune disease, whose immunopathogenesis may involve antigen presentation, T-cell activation and migration as well as, possibly, tumor necrosis factor-alpha (TNF-α)-induced keratinocytes apoptosis. However, present treatment options for OLP are far from being satisfactory. Recent advances in understanding the pathogenesis of OLP, progress in biologics, and the success of biologic therapies in OLP indicate that biologic agents are facing expanding indications in OLP. In this review, we mainly discuss the role of T cells in the pathogenesis of OLP and several biologic therapies that directly and/or indirectly target T cells to treat OLP.	\N	\N
21467169	Purpose. To compare the properties of the visual field index (VFI) to those of mean deviation (MD) in patients with glaucoma. Methods. MD and VFI were calculated in data obtained from an ongoing longitudinal study in which patients with glaucoma (N = 109, 204 eyes) were observed for 9.8 years (median, 21 tests) with static automated perimetry. MD and VFI were compared in one test of each eye, and a subset of 30 tests were selected to compare the VFI with the judgments of eight experts who judged the percentage of the remaining visual field. In series of tests obtained over time, rates of change, statistical significance, evidence of nonlinearity, and variability were compared between both indices. Results. In single tests, MD and VFI were closely related (r = 0.88, P < 0.001). The relationship between both indices appeared linear, except in visual fields with MDs better than -5.0 dB where 29 (22%) of 129 eyes exhibited a ceiling effect (VFI = 100%). Based on this relationship, the predicted VFIs for visual fields with MDs of -5, -10, and -15 dB were 91%, 76%, and 60%, respectively. The percentage of remaining visual field suggested by the VFI exceeded the range of the experts' subjective judgments in 16 (53%) of 30 eyes. In series of tests obtained over time, rates of change with the two indices were closely related (r = 0.79, P < 0.001), and statistically significant reductions over time (P < 0.05) occurred in a similar number of eyes (92 [45%] with MD, and 87 [43%] with VFI). Of the 105 eyes with statistically significant (P < 0.05) negative trend in either MD or VFI, 74 (70%) showed such trends with both indices (κ = 0.69). The variability of MD and VFI increased with damage, and there was no evidence that change over time was more linear with VFI than with MD. Conclusions. The VFI provides a simple and understandable metric of visual field damage, but its estimates of remaining visual field were more optimistic than those of the experts. Rates of change over time with both indices were closely related, but the reliance of the VFI on pattern deviation probability maps caused a ceiling effect that may have reduced its sensitivity to change in eyes with early damage. In this group of patients there was no evidence to suggest that the VFI is either superior or inferior to the MD as a summary measure of visual field damage.	\N	\N
21468585	Basic transcription element-binding protein 2 (BTEB2) is a regulator of the proliferation and phenotypic changes of vascular smooth muscle cells (SMCs). The aim of the present study was to determine whether or not BTEB2 knockdown inhibits balloon injury-induced neointimal hyperplasia attributed to the proliferation and phenotypic changes of vascular SMCs. We found that the knockdown of BTEB2 with antisense oligonucleotides (Ad-As-BTEB2) significantly reduced the intima/media ratio compared to uninjured arteries and vessels treated with Ad-LacZ. Knockdown of BTEB2 suppresses the proliferation of cultured vascular SMCs, concurrent with the down-regulation of proliferating cell nuclear antigen, angiotensin II type 1 receptor and platelet-derived growth factor BB. In addition, BTEB2 knockdown caused the up-regulation of the differentiation marker smooth muscle α-actin and down-regulation of the dedifferentiation marker embryonic smooth muscle myosin heavy chain. The present study provides direct evidence that BTEB2 plays a critical role in balloon injury-induced neointimal hyperplasia, which is closely linked to vascular SMC proliferation and phenotypic modulation. This study highlights the fact that BTEB2 may be a potential target for the prevention of restenosis after vascular intervention.	\N	\N
21473920	Diffusion imaging of post mortem brains has great potential both as a reference for brain specimens that undergo sectioning, and as a link between in vivo diffusion studies and "gold standard" histology/dissection. While there is a relatively mature literature on post mortem diffusion imaging of animals, human brains have proven more challenging due to their incompatibility with high-performance scanners. This study presents a method for post mortem diffusion imaging of whole, human brains using a clinical 3-Tesla scanner with a 3D segmented EPI spin-echo sequence. Results in eleven brains at 0.94 × 0.94 × 0.94 mm resolution are presented, and in a single brain at 0.73 × 0.73 × 0.73 mm resolution. Region-of-interest analysis of diffusion tensor parameters indicate that these properties are altered compared to in vivo (reduced diffusivity and anisotropy), with significant dependence on post mortem interval (time from death to fixation). Despite these alterations, diffusion tractography of several major tracts is successfully demonstrated at both resolutions. We also report novel findings of cortical anisotropy and partial volume effects.	\N	\N
21474147	Total proctocolectomy with ileal pouch-anal anastomosis (IPAA) is the gold standard surgical treatment for chronic ulcerative colitis. More recently, this procedure is being performed laparoscopically assisted. Postoperatively, small bowel obstruction (SBO) is one of the more common associated complications. However, it is unknown whether the addition of a laparoscopic approach has changed this risk. This study aims to assess and compare the incidence of SBOs after both open and laparoscopic restorative proctocolectomy. All subjects who underwent restorative proctocolectomy from 1998-2008 were identified from a prospective Colorectal Surgery Database. Medical records were reviewed for all cases of SBO, confirmed by a combination of clinical symptoms and radiologic evidence. Comparisons were made between laparoscopic and open approaches. The incidence of SBO was also subdivided into pre-ileostomy takedown, early post-ileostomy takedown (30 d post), and late post-ileostomy takedown (30 d to 1 y post). Several potential risk factors were also evaluated. Statistical analysis was performed utilizing Fisher's exact (for incidence) or t-tests (for means). Significance was defined as P < 0.05 A total of 290 open cases and 100 laparoscopic cases were identified during this time period. The overall incidence of SBO at 1 y post-ileostomy takedown was 14% (n = 42) in the open group and 16% (n = 16) laparoscopic (P = NS). In the pre-ileostomy takedown period the incidence of SBO was 7% (n = 21) open and 13% (n = 13) laparoscopic (P = NS). While in the post-takedown period, the early incidence was 4% (n = 12) open and 1% (n = 1) laparoscopic and late incidence was 3% (n = 9) open and 2% (n = 2) laparoscopic (P = NS). Factors associated with an increased risk of SBO include coronary artery disease, prior appendectomy and W and J pouch configurations. The burden of postoperative small bowel obstruction after restorative proctocolectomy is not changed with a laparoscopic approach. Most cases occur in the early postoperative period, especially prior to ileostomy reversal.	\N	\N
21475985	To investigate the nationwide prevalence of hepatitis E virus (HEV) infection and to characterize HEV genomes among Japanese wild boars (Sus scrofa leucomystax), 578 boars captured in 25 prefectures from 2003 to 2010 were studied. Anti-HEV IgG was detected in 8.1%, and HEV RNA in 3.3% of boars. Among the 19 boar HEV isolates obtained from infected boars, 14 isolates (74%) were classified as genotype 3, 4 isolates (21%) as genotype 4, and the remaining isolate (wbJOY_06) was distantly related to all known HEV isolates of genotypes 1-4, differing by 18.4-25.0% and 18.0-24.3% within the 412-nucleotide sequence of ORF1 and ORF2, respectively. A genotype 4 boar HEV isolate (wbJGF_08-1) obtained herein shared 98.6% identity over the entire genome with a human HEV isolate obtained from a patient who developed acute hepatitis after consuming undercooked wild boar meat, suggesting that wild boars are also reservoirs for genotype 4 HEV in humans.	\N	\N
21476292	The performance of a latex agglutination test (Mediace TPLA) in the detection of anti-treponemal antibody was evaluated in comparison with chemical luminescence tests (LumipulsII-N and Architect TPAb) in 346 cases. Anti-treponemal antibody was further determined by immunochromatography and immunoblotting tests and additionally evaluated by a serological test for syphilis with lipoidal antigens. The total concordance rate between the latex agglutination test and chemical luminescence tests ranged from 96% to 97%: the positive concordance rate ranged from 96% to 97%, and the negative concordance rate, from 97% to 98%. The latex agglutination test showed two false positive cases, and each chemical luminescence test showed two false positive cases, respectively. In eight cases, only the latex agglutination test showed negative results; all specimens contained anti-treponemal antibodies. However, none of these was considered to be a false positive and each was treated as syphilis based on the results of confirmatory analysis with immunochromatography and immunoblotting tests and a serological test for syphilis. The discordant results in the latex agglutination test and chemical luminescence tests may be caused by the different antigenisity of each test. With detailed analysis of those sera treated as syphilis, each specimen was found to contain various antibodies against syphilitic antigens, suggesting that there was a different specificity of native and recombinant antigens. Based on the present results for the comparison between the latex agglutination test and chemical luminescence tests, it was considered that further investigation is necessary to clarify the anti-treponemal antibody profile of syphilis at the disease stage.	\N	\N
21477408	Ideally putative disease-modifying therapies for Alzheimer's disease (AD) should be tested in patients who have minimal morbidity. Current barriers to such trials in early disease include the lack of disease-specific early biomarkers, insensitivity of quantitative cognitive outcome measures, and expensive trial designs requiring large sample sizes and long duration. This paper describes principles and progress towards a novel trial design that overcomes these problems, utilizing wide-scale cognitive performance screening to define pre-trial cognitive decline trajectories which can serve as trial outcome measures to assess AD disease-modifying efficacy. Theoretical principles important for the detection of intra-individual cognitive decline and a practical example are described. Serial evaluations of community-based volunteers demonstrate how a screening tool method to detect subtle cognitive decline can predict in vivo amyloid pathology as a trigger for etiological evaluation. Trajectories of decline appear consistent over at least two years, suggesting they could be used as a trial inclusion criterion and ameliorable outcome measure together with other AD biomarkers. Informative trial durations could be 6-12 months, or extend to incorporate staggered random withdrawal or start designs, with as few as 20 individuals per treatment arm. This trial methodology offers significant advantages over current AD trial designs, including treatment at earlier stages of disease, shorter trial duration, obviation of informed consent difficulties, smaller sample sizes, reduced cost and--given adequate screening programs--sufficient subjects for multiple simultaneous trials. Importantly, it allows the rapid evaluation of putative treatments that may only be efficacious in pre-dementia states.	\N	\N
21478119	The impact of drug-eluting stents (DES) has not been extensively investigated in patients with moderate to severe renal dysfunction, as these patients are consistently excluded from randomised studies. We sought to assess prospectively the effectiveness and safety of the new-generation DES in patients with moderate chronic kidney disease (CKD) and an isolated de novo lesion in the proximal segment of the left anterior descending artery (pLAD). We evaluated 400 consecutive patients with a pLAD lesion. There were 96 patients with moderate CKD (estimated glomerular filtration rate 59 ml/min/1.73 m2) and 304 without CKD. Major adverse cardiac events (MACE) were defined as death, non-fatal myocardial infarction and target lesion revascularisation (TLR). Clinical or telephone follow up was performed. There was a significantly higher incidence of mortality in patients with CKD (n=4) as compared with non-CKD (n=2) (4.16% versus 0.65%, respectively, p=0.03). The rate of non-fatal myocardial infarction was similar in the 2 cohorts (p=0.59), as was the TLR rate (p=0.99). Overall, there were no significant differences regarding MACE between the 2 groups of patients (p=0.19) during the 13.62 ± 6.22 month follow-up period. The rate of angiographic stent thrombosis was 2.08% in the CKD group versus 0.98% in the non-CKD group (p=0.59). New generation DES implantation in patients with CKD and a pLAD lesion is effective and safe, with rates of TLR and stent thrombosis comparable to those in patients with normal renal function. However, the higher mortality in patients with CKD needs further evaluation.	\N	\N
21481900	Non-Hodgkin lymphomas are common cancers that can develop in the upper aero-digestive tract. We describe a case of a large B-cell palatine lymphoma with spontaneous clinical regression. A 58-year-old female patient presented with a sub-mucosal lesion of the hard palate. CT scan and magnetic resonance imaging revealed a lesion invading the right posterior palatine canal. At the second consultation, 15 days after performing the biopsy, the lesion had disappeared. PET scan proved the absence of lesion. Lymph node biopsy supported the diagnosis of large B-cell lymphoma. Large B-cell lymphoma of the hard palate is a rare disease. Only 27 cases have been described in the international literature. The anatomopathological analysis is often difficult to perform. The final diagnosis is often made by immunochemistry. The usual treatment is R-CHOP chemotherapy (cyclophosphamide, adriamycin, vincristine, prednisone combined to rituximab) with a 5-year survival rate at 55%.	\N	\N
21484828	Anterior interosseous nerve syndrome (AINS) has not been widely recognized as a possible complication following peripheral catheterization. Herein we present a retrospective review of patients with AINS over the last 5 years. Six cases were identified, 4 associated with catheterization. AINS may be a rare complication of catheterization. Magnetic resonance imaging (MRI) may serve as an adjunct diagnostic modality to conventional electromyography (EMG) and nerve conduction studies, especially in patients who are intolerant of pain.	\N	\N
21485204	This paper presents a novel matching method of vessels in 3D reconstruction of heart vessel. The directed binary tree was used to describe the topological structure of heart vessel tree's skeleton. Based on topological property and epipolar property, the branch-points and end-points of each branch level could be automatically matched along the direction of blood stream. Thereupon it is easy to couple the corresponding vessels segments of two angiograms projected in different directions. The 3D heart vessel tree was successfully reconstructed from clinic coronary angiograms, which validates the presented method.	\N	\N
21489314	The standard treatment for patients with advanced transitional cell carcinoma of the bladder is platin based chemotherapy. Only approximately 50% of the patients respond to chemotherapy. Therefore, molecular predictive markers for identification of chemotherapy sensitive subgroups of patients are highly needed. We selected the transcription factor TFAP2α from a previously identified gene expression signature for chemotherapy response. TFAP2α expression and localization was assessed by immunohistochemistry using a tissue microarray (TMA) containing 282 bladder cancer tumors from patients with locally advanced (pT2-T4(b) and N(1-3)) or metastatic (M(1)) disease. All patients had received cisplatin containing chemotherapy. Furthermore, QPCR analysis of three TFAP2α isoforms was performed on tumor specimens of advanced muscle invasive bladder cancers (T2-4). Using the bladder cell lines T24 and SW780 the relation of TFAP2α and cisplatin and gemcitabine sensitivity as well as cell proliferation was examined using siRNA directed TFAP2α knockdown. TFAP2α protein expression was analyzed on a TMA with cores from 282 advanced bladder cancer tumors from patients treated with cisplatin based combinational chemotherapy. TFAP2α was identified as a strong independent predictive marker for a good response and survival after cisplatin-containing chemotherapy in patients with advanced bladder cancer. Strong TFAP2α nuclear and cytoplasmic staining predicted good response to chemotherapy in patients with lymph node metastasis, whereas weak TFAP2α nuclear staining predicted good response in patients without lymph node metastasis. In vitro studies showed that siRNA mediated knockdown of TFAP2α increased the proliferation of SW780 cells and rendered the cells less sensitive to cisplatin and gemcitabine. In contrast to that T24 bladder cells with mutated p53 showed to be more drug sensitive upon TFAP2α depletion. High levels of nuclear and cytoplasmic TFAP2α protein were a predictor of increased overall survival and progression free survival in patients with advanced bladder cancer treated with cisplatin based chemotherapy. TFAP2α knockdown increased the proliferation of the SW780 bladder cells and reduced cisplatin and gemcitabine induced cell death. The inverse effect was observed in the TP53 mutated T24 cell line where TFAP2α silencing augmented cisplatin and gemcitabine sensitivity and did not stimulate proliferation.	\N	\N
21493631	Data on right ventricle (RV) regional function in adults with interatrial shunt are scarce. The aim of the study was to assess the regional RV deformation in the population of adults with uncorrected atrial left-to-right shunt and to establish a potential relationship between its magnitude and RV regional deformation. We studied 40 adults (30F/10M; mean age 39.2 years) with atrial septal defect (ASD) [average pulmonary-to-systemic blood flow ratio (Qp/Qs) 2.1 ± 0.7]. Standard echocardiographic evaluation was completed with right ventricular dimensions, parameters of its global [tricuspid annular plane systolic excursion (TAPSE), fractional area change, myocardial performance index], and regional [strain/strain rate (ε/SR)] function. Among echocardiographic indices describing RV global function, only TAPSE was increased when compared with healthy subjects. No differences in RV deformation data (ε/SR) between ASD patients and control group were found. Non-linear relationship between the differing Qp/Qs and maximal ε in the mid-segments of the RV free wall was observed. In patients with moderate shunt, maximal ε values were higher when compared with the values obtained in mild and large shunts. Regional RV deformation (ε/SR) does not differ significantly in the group of patients with various degrees of the left-to-right shunts when compared with healthy subjects. However, a non-linear correlation between Qp/Qs and ε could be observed. The affected region of the RV wall is the mid-segment and the highest values of ε were recorded in patients with moderate left-to-right shunts.	\N	\N
21493742	The risk of a posttransplant recurrence of secondary glomerulonephritis (GN) is quite variable. Histologic recurrence is frequent in lupus nephritis, but the lesions are rarely severe and usually do not impair the long-term graft outcome. Patients with Henoch-Schonlein nephritis have graft survival similar to that of other renal diseases, although recurrent Henoch-Schonlein nephritis with extensive crescents has a poor prognosis. Amyloid light-chain amyloidosis recurs frequently in renal allografts but it rarely causes graft failure. Amyloidosis secondary to chronic inflammation may also recur, but this is extremely rare in patients with Behcet's disease or in those with familial Mediterranean fever, when the latter are treated with colchicine. Double organ transplantation (liver/kidney; heart/kidney), chemotherapy, and autologous stem cell transplantation may be considered in particular cases of amyloidosis, such as hereditary amyloidosis or multiple myeloma. There is little experience with renal transplantation in light-chain deposition disease, fibrillary/immunotactoid GN, or mixed cryoglobulinemic nephritis but successful cases have been reported. Diabetic nephropathy often recurs but usually only after many years. Recurrence in patients with small vessel vasculitis is unpredictable but can cause graft failure. However, in spite of recurrence, patient and graft survival rates are similar in patients with small vessel vasculitis compared with those with other renal diseases. Many secondary forms of GN no longer represent a potential contraindication to renal transplantation. The main issues in transplantation of patients with secondary GN are the infectious, cardiovascular, or hepatic complications associated with the original disease or its treatment.	\N	\N
21496186	Certainty is seen as the 'Holy Grail' of science, despite the fact that all science is based in doubt, and that good scientists always leave a door open for an alternative explanation of their findings. Certainty also is a human desire providing comfort and surety. How can these two notions coexist? The way we perceive is the way we see and understand. Perception, however, is not objective; the way we 'know' what the sensory input we receive means arises from matching it against stored images of prior experiences, or put differently, the way we perceive the world depends on successfully predicting our own sensory status. Only large mismatches create new awareness resulting in new learning. At large we are prisoners of our own making, and awareness of the boundaries of our understanding will help to expand our horizon. The four papers of this edition attempt to expand the boundaries of 'common certainty' in terms of statistical interpretation, management of individual patients, disease management and health policy.	\N	\N
21498295	Patients suffering from hereditary hyperlipidemia have a high risk for premature cardiovascular disease and death as a consequence of accelerated atherosclerosis. To prospectively and intra-individually compare image quality and detectability of stenoses in contrast enhanced whole-body MRA (WBMRA) at 1.5 and 3 Tesla (T) in patients with hereditary hyperlipidemia. Twenty-seven patients with hereditary hyperlipidemia received a 1.5 and 3 T gadopentetate dimeglumine contrast-enhanced WBMRA. Twenty-three defined arterial segments were analyzed regarding depiction of target vessels and image quality according to a 5-point-scale ('not evaluable' to 'excellent'). Wilcoxon matched pair test was performed for comparison. Forty-three defined arterial segments were analyzed for the degree of stenosis (0%, 1-49%, 50-99% and 100%) as well as vessel alterations such as aneurysms. Chi-square test was performed for comparison. 1.5 T and 3 T scans yielded WBMRA with diagnostic quality in all patients. In seven of 23 arterial segments (30.4%) image quality was rated significantly higher at 3 T, whereas there was no significant difference in the remaining 16 segments between WBMRA at 1.5 T and 3 T. All relevant stenoses (n = 5), occlusions (n = 6), and aneurysms (n = 3) were evaluated similarly at both field strengths. WBMRA can be performed at 1.5 T and 3 T with diagnostic image quality. Image quality was significantly higher at 3 T than at 1.5 T in only 30.4% of the arterial segments. In order to effectively take advantage of the higher field strength, further optimization of sequence parameters and injection protocols for WBMRA at 3 T is necessary.	\N	\N
21503392	The rate of transient dilatation can be determined by exercise testing or pharmacological stress test. It is unknown whether the type of stress has an impact on average transient dilatation index values. To compare average transient dilation index values in 99mTc-sestamibi scintigraphy in patients undergoing treadmill stress test, versus dipyridamole stress test. The secondary purpose was to evaluate the impact on the average index value by demographic characteristics, risk factors for coronary artery disease and severity of ischemia. The cross-sectional study included 200 patients between 40 and 70 years old, with or without risk factors for ischemic heart disease, with or without a previous diagnosis of ischemic heart disease. The separation between groups was sequential. The software 4D-MSPECT calculated the transient dilatation index and provided a scoring system for perfusion analysis. The average transient dilation index value of the group undergoing exercise stress test was 1.06 (±0.23). For the group undergoing the dipyridamole stress test, it was 1.10 (±0.22); (p = 0.200). There was no association between the type of stress and the average transient dilatation index values. An association was found between the average index values and age only for those patients from the exercise test group (p = 0.009). The results of our study demonstrate that the transient dilation index does not differ when patients undergo exercise stress test on a treadmill or pharmacological stress by dipyridamole.	\N	\N
21506835	Rapid and reliable detection and identification of coccidian oocysts are essential for animal health and foodborne disease outbreak investigations. Traditional microscopy and morphological techniques can identify large and unique oocysts, but they are often subjective and require parasitological expertise. The objective of this study was to develop a real-time quantitative PCR (qPCR) assay using melting curve analysis (MCA) to detect, differentiate, and identify DNA from coccidian species of animal health, zoonotic, and food safety concern. A universal coccidia primer cocktail was designed and employed to amplify DNA from Cryptosporidium parvum, Toxoplasma gondii, Cyclospora cayetanensis, and several species of Eimeria, Sarcocystis, and Isospora using qPCR with SYBR Green detection. MCA was performed following amplification, and melting temperatures (T(m)) were determined for each species based on multiple replicates. A standard curve was constructed from DNA of serial dilutions of T. gondii oocysts to estimate assay sensitivity. The qPCR assay consistently detected DNA from as few as 10 T. gondii oocysts. T(m) data analysis showed that C. cayetanensis, C. parvum, Cryptosporidium muris, T. gondii, Eimeria bovis, Eimeria acervulina, Isospora suis, and Sarcocystis cruzi could each be identified by unique melting curves and could be differentiated based on T(m). DNA of coccidian oocysts in fecal, food, or clinical diagnostic samples could be sensitively detected, reliably differentiated, and identified using qPCR with MCA. This assay may also be used to detect other life-cycle stages of coccidia in tissues, fluids, and other matrices. MCA studies on multiple isolates of each species will further validate the assay and support its application as a routine parasitology screening tool.	\N	\N
21507892	Manitoba-oculo-tricho-anal (MOTA) syndrome is a rare condition defined by eyelid colobomas, cryptophthalmos and anophthalmia/microphthalmia, an aberrant hairline, a bifid or broad nasal tip, and gastrointestinal anomalies such as omphalocele and anal stenosis. Autosomal recessive inheritance had been assumed because of consanguinity in the Oji-Cre population of Manitoba and reports of affected siblings, but no locus or cytogenetic aberration had previously been described. This study shows that MOTA syndrome is caused by mutations in FREM1, a gene previously mutated in bifid nose, renal agenesis, and anorectal malformations (BNAR) syndrome. MOTA syndrome and BNAR syndrome can therefore be considered as part of a phenotypic spectrum that is similar to, but distinct from and less severe than, Fraser syndrome. Re-examination of Frem1(bat/bat) mutant mice found new evidence that Frem1 is involved in anal and craniofacial development, with anal prolapse, eyelid colobomas, telecanthus, a shortened snout and reduced philtral height present in the mutant mice, similar to the human phenotype in MOTA syndrome. The milder phenotypes associated with FREM1 deficiency in humans (MOTA syndrome and BNAR syndrome) compared to that resulting from FRAS1 and FREM2 loss of function (Fraser syndrome) are also consistent with the less severe phenotypes resulting from Frem1 loss of function in mice. Together, Fraser, BNAR and MOTA syndromes constitute a clinically overlapping group of FRAS-FREM complex diseases.	\N	\N
21508333	c-Src is a non-receptor tyrosine kinase whose activity is induced by phosphorylation at Y418 and translocation from the cytoplasm to the cell membrane. Increased activity of c-Src has been associated with cell proliferation, matrix adhesion, motility, and apoptosis in tumors. Immunohistochemistry suggested that activated (pY(418))-Src activity is increased in cyst-lining autosomal dominant polycystic kidney disease (ADPKD) epithelial cells in human and mouse ADPKD. Western blot analysis showed that SKI-606 (Wyeth) is a specific inhibitor of pY(418)-Src without demonstrable effects on epidermal growth factor receptor or ErbB2 activity in renal epithelia. In vitro studies on mouse inner medullary collecting duct (mIMCD) cells and human ADPKD cyst-lining epithelial cells showed that SKI-606 inhibited epithelial cell proliferation over a 24-h time frame. In addition, SKI-606 treatment caused a striking statistically significant decrease in adhesion of mIMCD and human ADPKD to extracellular collagen matrix. Retained viability of unattached cells was consistent with a primary effect on epithelial cell anchorage dependence mediated by the loss of extracellular matrix (ECM)-attachment due to α(2)β(1)-integrin function. SKI-606-mediated attenuation of the human ADPKD hyperproliferative and hyper-ECM-adhesive epithelial cell phenotype in vitro was paralleled by retardation of the renal cystic phenotype of Pkd1 orthologous ADPKD heterozygous mice in vivo. This suggests that SKI-606 has dual effects on cystic epithelial cell proliferation and ECM adhesion and may have therapeutic potential for ADPKD patients.	\N	\N
21537035	To determine if time to diagnosis is associated with stage of disease at diagnosis or survival among women with symptomatic ovarian cancer. A representative sample of Australian women (n = 1,463) with ovarian cancer diagnosed between 2002 and 2005 who participated in a population-based case-control study were interviewed regarding the events leading to their diagnosis and were observed for mortality for 5 years. Of the 1,318 women (90%) who presented to a medical practitioner with symptoms, 55% presented within 1 month, 70% in less than 2 months, and 92% within 6 months of symptom onset. There were no significant differences in the time from symptom onset to first medical practitioner consultation (P = .19) or symptom onset to diagnosis (P = .64) among women with borderline, early (International Federation of Gynecology and Obstetrics [FIGO] stages I to II) or late (FIGO stages III to IV) disease. There was also no association between time to diagnosis and survival; adjusted hazard ratio for long delay (> 12 months from symptom onset to diagnosis) versus short delay (≤ 1 month) was 0.94 (95% CI, 0.68 to 1.30). Women who had asymptomatic cancers diagnosed incidentally (n = 145) were younger and were more likely to have borderline or stage I disease compared with women who had symptomatic ovarian cancer. The results of this study suggest that, once ovarian cancer is symptomatic, reducing the time to diagnosis would not greatly alter stage of disease at diagnosis or survival.	\N	\N
21542809	Endometriosis-associated infertility results in reduced ovarian response, fewer oocytes available for fertilization, compromised oocyte quality and higher miscarriage rates. A consistent proportion of women with endometriosis require in vitro fertilization. We sought to clarify the impact of deep infiltrating pelvic disease on antral follicle count and ovarian response to follicle-stimulating hormone (FSH) stimulation in patients with severe endometriosis. Retrospective cohort study. University hospital. Patients with severe endometriosis (stages III-IV; n=51) were divided into two groups regarding localization of endometriosis during surgical staging: ovarian (n=27) and both ovarian and deep infiltrating disease (n=24). A total of 73 long-protocol ovulation induction cycles with recombinant FSH for an intracytoplasmic sperm injection program were given. On day 3 of the cycle, measurements of FSH and luteinizing hormone and an ultrasound evaluation of antral follicle count were performed. Number of oocytes collected at ovum pick up, number of mature oocytes, number of embryos transferred and clinical pregnancy rate. Ovarian reserve in terms of antral follicle count was damaged in both groups but, if adjusted for age, it was significantly lower in the ovarian and pelvic infiltrating group compared with patients having only ovarian endometriosis. Pelvic deep infiltrating disease significantly impacted on the number of oocytes collected at pick up when adjusted for age. Deep infiltrating pelvic disease can negatively affect ovarian reserve in terms of antral follicle count and number of oocytes retrieved. Mechanisms underlying this phenomenon need to be elucidated.	\N	\N
21545837	The proteasome is an enzyme complex responsible for targeted intracellular proteolysis. Alterations in proteasome-mediated protein clearance have been implicated in the pathogenesis of aging, Alzheimer's disease (AD) and Parkinson's disease (PD). In such diseases, proteasome inhibition may contribute to formation of abnormal protein aggregates, which in turn activate intracellular unfolded protein responses that cause oxidative stress and apoptosis. In this study, we investigated the protective effect of Insulin-like Growth Factor-I (IGF-1) for neural SH-SY5Y cells treated with the proteasomal inhibitor, Epoxomicin. In SH-SY5Y cells, Epoxomicin treatment results in accumulation of intracellular ubiquitinated proteins and cytochrome c release from damaged mitochondria, leading to cell death, in Epoxomicin time- and dose-dependent manner. In cells treated with small amounts of IGF-1, the same dosages of Epoxomicin reduced both mitochondrial damage (cytochrome c release) and reduced caspase-3 activation and PARP cleavage, both of which are markers of apoptosis. Notably, however, IGF-1-treated SH-SY5Y cells still contained ubiquitinated protein aggregates. This result indicates that IGF-1 blocks the downstream apoptotic consequences of Epoxomicin treatment leading to decreased proteasome function. Clues as to the mechanism for this protective effect come from (a) increased AKT phosphorylation observed in IGF-1-protected cells, vs. cells exposed to Epoxomicin without IGF-1, and (b) reduction of IGF-1 protection by pretreatment of the cells with LY294002 (an inhibitor of PI3-kinase). Together these findings suggest that activation of PI3/AKT pathways by IGF-1 is involved in IGF-1 neuroprotection against apoptosis following proteasome inhibition.	\N	\N
21547907	Intraductal papillary mucinous neoplasm (IPMN) consists of four epithelial subtypes. Of those, pancreatobiliary and oncocytic types are recently recognized and relatively uncommon, and usually exhibit high-grade dysplasia. The biological properties and molecular characteristics of these two types have not been well documented. The few molecular studies of the oncocytic type showed absence of KRAS mutations commonly seen in the other subtypes, raising the possibility that the oncocytic type is distinct from the other subtypes. Thus, we examined clinicopathological features and molecular alterations of the two subtypes. The study cohort consisted of 12 pancreatobiliary and 18 oncocytic IPMN cases. KRAS, BRAF, and PIK3CA mutations and TP53, SMAD4, and β-catenin expression were analysed, and the results of molecular and clinicopathological profiles were compared between the two subtypes. KRAS mutations were identified in the oncocytic type, but less frequently than the pancreatobiliary type (17% versus 58%, p = 0.048). BRAF mutation was found in a single oncocytic tumour, and no PIK3CA mutations were seen in any of the study cohort. TP53 overexpression was less frequent in the oncocytic type than in the pancreatobiliary type (11% versus 58%, p = 0.013). Invasive components were present in 50% of the oncocytic and 92% of the pancreatobiliary types, with lymph node metastasis more frequently seen in the latter, corresponding to better outcomes in the former (5-year survival rates: 93% versus 32%, p = 0.014). Our demonstration of KRAS and BRAF mutations in the oncocytic-type IPMN supports a role for the activation of the RAS-MAPK pathway in this tumour type. However, the less frequent TP53 overexpression associated with the significantly lower rates of invasion and nodal disease in the oncocytic type correlates with better outcomes compared to the pancreatobiliary type.	\N	\N
21565878	Excessive dynamic airway collapse (EDAC) refers to abnormal and exaggerated bulging of the posterior wall within the airway lumen during exhalation. This condition is pathological if the reduced airway lumen is <50% of the normal. It is a relatively new disease entity that is recognised more easily now with the increased use of multi-detector row CT. EDAC is often asymptomatic and diagnosed incidentally. Although the term excessive dynamic airway collapse is often used interchangeably with tracheobronchomalacia, both entities represent morphologically and physiologically distinct processes. Considering the confusion between the two entities, the prevalence of stand-alone EDAC remains unclear. The prevalence of tracheobronchomalacia and EDAC depends upon the patient population, associated comorbidities and underlying aetiologies, diagnostic tools used and criteria used to define the airway collapse. This review defines EDAC and describes its pathophysiology, precipitating factors, associated symptoms and potential treatments.	\N	\N
21571478	To determine the accuracy of magnetic resonance spectroscopy (MRS), perfusion MR imaging (MRP), or volume modeling in distinguishing tumor progression from radiation injury following radiotherapy for brain metastasis. Twenty-six patients with 33 intra-axial metastatic lesions who underwent MRS (n=41) with or without MRP (n=32) after cranial irradiation were retrospectively studied. The final diagnosis was based on histopathology (n=4) or magnetic resonance imaging (MRI) follow-up with clinical correlation (n=29). Cho/Cr (choline/creatinine), Cho/NAA (choline/N-acetylaspartate), Cho/nCho (choline/contralateral normal brain choline) ratios were retrospectively calculated for the multi-voxel MRS. Relative cerebral blood volume (rCBV), relative peak height (rPH) and percentage of signal-intensity recovery (PSR) were also retrospectively derived for the MRPs. Tumor volumes were determined using manual segmentation method and analyzed using different volume progression modeling. Different ratios or models were tested and plotted on the receiver operating characteristic curve (ROC), with their performances quantified as area under the ROC curve (AUC). MRI follow-up time was calculated from the date of initial radiotherapy until the last MRI or the last MRI before surgical diagnosis. Median MRI follow-up was 16 months (range: 2-33). Thirty percent of lesions (n=10) were determined to be radiation injury; 70% (n=23) were determined to be tumor progression. For the MRS, Cho/nCho had the best performance (AUC of 0.612), and Cho/nCho >1.2 had 33% sensitivity and 100% specificity in predicting tumor progression. For the MRP, rCBV had the best performance (AUC of 0.802), and rCBV >2 had 56% sensitivity and 100% specificity. The best volume model was percent increase (AUC of 0.891); 65% tumor volume increase had 100% sensitivity and 80% specificity. Cho/nCho of MRS, rCBV of MRP, and percent increase of MRI volume modeling provide the best discrimination of intra-axial metastatic tumor progression from radiation injury for their respective modalities. Cho/nCho and rCBV appear to have high specificities but low sensitivities. In contrast, percent volume increase of 65% can be a highly sensitive and moderately specific predictor for tumor progression after radiotherapy. Future incorporation of 65% volume increase as a pretest selection criterion may compensate for the low sensitivities of MRS and MRP.	\N	\N
21572511	The epidemiology of Chagas disease, until recently confined to areas of continental Latin America, has undergone considerable changes in recent decades due to migration to other parts of the world, including Spain. We studied the prevalence of Chagas disease in Latin American patients treated at a health center in Barcelona and evaluated its clinical phase. We make some recommendations for screening for the disease. We performed an observational, cross-sectional prevalence study by means of an immunochromatographic test screening of all continental Latin American patients over the age of 14 years visiting the health centre from October 2007 to October 2009. The diagnosis was confirmed by serological methods: conventional in-house ELISA (cELISA), a commercial kit (rELISA) and ELISA using T cruzi lysate (Ortho-Clinical Diagnostics) (oELISA). Of 766 patients studied, 22 were diagnosed with T. cruzi infection, showing a prevalence of 2.87% (95% CI, 1.6-4.12%). Of the infected patients, 45.45% men and 54.55% women, 21 were from Bolivia, showing a prevalence in the Bolivian subgroup (n=127) of 16.53% (95% CI, 9.6-23.39%). ALL THE INFECTED PATIENTS WERE IN A CHRONIC PHASE OF CHAGAS DISEASE: 81% with the indeterminate form, 9.5% with the cardiac form and 9.5% with the cardiodigestive form. All patients infected with T. cruzi had heard of Chagas disease in their country of origin, 82% knew someone affected, and 77% had a significant history of living in adobe houses in rural areas. We found a high prevalence of T. cruzi infection in immigrants from Bolivia. Detection of T. cruzi-infected persons by screening programs in non-endemic countries would control non-vectorial transmission and would benefit the persons affected, public health and national health systems.	\N	\N
21575881	Mesalazine remains the first line treatment for the induction and the maintenance of remission in mild to moderate ulcerative colitis (UC). Its efficacy as a maintenance treatment after a first flare treated with corticosteroids has not been specifically studied. The aims of our work were to study a cohort of UC patients treated with mesalazine after a course of oral systemic corticosteroids and to identify predictive factors of relapse and of colectomy. We studied retrospectively a cohort of 143 UC patients, who never received immunosuppressive drugs, and treated for the first time with oral corticosteroids for a flare. Among patients responding to corticosteroids, we studied the group treated by mesalazine after the flare. Fifty% (n=52) achieved a complete clinical remission with steroid weaning. In this group, 67% (n=35) received oral mesalazine. Seventy-five % of patients treated by mesalazine relapsed (median 29 months, range: 1-156). Fourteen % required a colectomy (median 11 months, range: 1-24). Kaplan Meier curve showed a relapse rate and a colectomy rate over one year of 26% and 11% respectively. In multivariate analysis, male gender and short duration of disease were predictive factors of the time-to-relapse. No factor was predictive of time-to-colectomy. Maintenance efficacy of mesalazine over one year after a first course of corticosteroids for a disease flare is reasonably high. The longer-term relapse rate becomes higher in male patients with a short disease duration. An immunosuppressive treatment could be discussed in case of further relapse despite improved medication-adherence. Medication-adherence should first be assessed and promoted. An immunosuppressive treatment could be discussed in case of further relapse despite improved medication-adherence.	\N	\N
21576904	Mutations in IRAK4 have been associated with recurrent Gram-positive infections in children. Given the central role of IRAK4 in innate immunity signaling, we hypothesized that common genetic variants of IRAK4 may be associated with prevalence of Gram-positive infection in critically ill adults. Haplotype clade tag single nucleotide polymorphisms (SNPs) of the IRAK4 gene were selected and genotyped in a cohort of 1,029 critically ill patients with systemic inflammatory response syndrome (SIRS). We found that a haplotype clade tagged by the A allele of the htSNP G29429A (Ala428Thr) was associated with increased relative risk of Gram-positive infection at admission to ICU (RR = 1.2, p < 0.05). Furthermore, the 29429A allele was associated with decreased lymphoblastoid cell response to CpG (as measured by IL-6 production) (raw values ± 95% CI 40.3 ± 32.3 vs. 85.8 ± 29.4 pg/ml; log-transformed values ± 95% CI 1.13 ± 0.37 vs. 1.55 ± 0.18, p < 0.04). We also found that IRAK4-deficient fibroblasts transfected with an IRAK4 expression plasmid containing the 29429A allele produced less IL-6 in response to lipopolysaccharide (p = 0.07). Our data suggest that the IRAK4 haplotype clade marked by 29429A (428Thr) alters susceptibility to Gram-positive bacteria, by decreasing cellular response to TLR ligands.	\N	\N
21585286	β-site APP-cleaving enzyme (BACE1) cleaves the wild type (WT) β-site very slowly (k(cat)/K(m): 46.6 m(-1) s(-1)). Therefore we searched for additional β-secretases and identified three cathepsins that split the WT β-site much faster. Human cathepsin S cleaves the WT β-site (k(cat)/K(m): 54 700 m(-1) s(-1)) 1170-fold faster than BACE1 and cathepsins B and L are 440- and 74-fold faster than BACE1, respectively. These cathepsins split two bonds flanking the WT β-site (K-MD-A), where the K-M bond (85%) is cleaved more efficiently than the D-A bond (15%). Cleavage at the major K-M bond yields Aβ (amyloid β-peptide) extended by N-terminal Met that should be removed to generate Aβ initiated by Asp1. The activity of cytosol and microsomal aminopeptidases on relevant peptides revealed rapid removal of N-terminal Met but not N-terminal Asp. Brain aminopeptidases showed similar specificity. Thus, aminopeptidases would convert Aβ extended by Met into regular Aβ (Asp1) found in amyloid plaques. Earlier studies indicate that Aβ is likely produced in the endosome and lysosome system where cathepsins S, B and L are localized and cysteine cathepsin inhibitors reduce the level of Aβ in cells and animals. Taken together, cathepsins S, B and L deserve further evaluation as therapeutic targets to develop disease modifying drugs to treat Alzheimer's disease.	\N	\N
21596857	Femoral and lumbar bone mineral densities (BMDs) were measured in 159 adults enrolled in the Leucémies de l'Enfant et de l'Adolescent program, a French prospective multicentric cohort of childhood leukemia survivors. BMDs were expressed as Z-scores, and multivariate linear regression analyses were used to construct association models with potential risk factors. Mean age at evaluation and follow-up was 23 and 14.7 years, respectively. In the whole cohort, mean femoral Z-score was -0.19 ± 0.08. Two factors were associated with lower femoral BMD transplantation (-0.49 ± 0.15 vs -0.04 ± 0.10 in the chemotherapy group; P = .006) and female sex (-0.34 ± 0.10 vs -0.03 ± 0.13; P = .03). Among patients who received a transplant, the only significant risk factor was hypogonadism (-0.88 ± 0.16 vs -0.10 ± 0.23; P = .04). A slight reduction in lumbar BMD (mean Z-score, -0.37 ± 0.08) was detected in the whole cohort without difference between the transplantation and chemotherapy groups. Among patients who received a transplant, younger age at transplantation was correlated with a low lumbar BMD (P = .03). We conclude that adults who had received only chemotherapy for childhood leukemia have a slight reduction in their lumbar BMD and a normal femoral BMD. Patients who received a transplant with gonadal deficiency have a reduced femoral BMD which might increase the fracture risk later in life.	\N	\N
21601991	Cardiovascular disease (CVD) is a major cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE). Due to either infection or disease activity, elevated levels of inflammatory markers and up-regulation of the autoimmune process can contribute to the development of atherosclerosis in SLE patients. Periodontal diseases are among the most prevalent chronic infections in humans and are characterized by pathogen-induced oral inflammatory disease affecting the supporting tissues of teeth. Several cytokines capable of inducing systemic effects are produced during the course of this infection. The presence of these cytokines can be verified by changes in the levels of C-reactive protein (CRP). Periodontal disease is a well-known risk factor for atherosclerosis. The potential for beneficial prevention of CVD events through the use of periodontal treatment has been previously recommended. This review reinforces the hypothesis that periodontal infection could be a risk factor for CVD in patients diagnosed with SLE, and suggests that by reducing the progression of this oral infection, levels of inflammatory markers common to both diseases (SLE and periodontal disease) would likely decrease.	\N	\N
21603646	Miniature pigs are useful model animals for humans because they have similar anatomy and digestive physiology to humans and are easy to breed and handle. In this study, whole blood microarray analyses were conducted to evaluate variations of correlation among individuals and ages using specific pathogen-free (SPF) Clawn miniature pigs. Whole blood RNA is easy to handle compared to isolated white blood cell RNA and can be used for health and disease monitoring and animal control. In addition, whole blood is a heterogeneous mixture of subpopulation cells. Once a great change occurs in composition and expressing condition of subpopulations, their associated change will be reflected on whole blood RNA. From 12 to 30 weeks of age, fractions of lymphocytes, monocytes, neutrophils, eosinophils, and basophils in white blood cells showed insignificant differences with age as a result of ANOVA analysis. This study attempted to identify characteristics of age-related gene expression by taking into account the change in the number of expressed genes by age and similarities of gene expression intensity between individuals. As a result, the number of expressed genes was less in fetal stage and infancy period but increased with age, reaching a steady state of gene expression after 20 weeks of age. Variation in gene expression intensity within the same age was great in fetal stage and infancy period, but converged with age. The variation between 20 and 30 weeks of age was comparable to that among 30 weeks individuals. These results indicate that uniformity of laboratory animals is expected for miniature pigs after 20 weeks of age. Furthermore, a possibility was shown that whole blood RNA analysis is applicable to evaluation of physiological state.	\N	\N
21607722	It has been only 5 years since the identification of TDP-43 as the major protein component of the ubiquitinated inclusions in FTLD-U. At that time, there were approximately a dozen papers about TDP-43; today, a "TDP-43" search reveals almost 600 papers. It is now clear that the majority of FTLD cases containing tau- and alpha-synuclein-negative, ubiquitin-positive inclusions (FTLD-U) are FTLD-TDP. The spectrum of TDP-43 proteinopathies includes FTLD-TDP with or without ALS, with or without mutations in GRN, VCP, or TARDBP, with or without chromosome 9p linkage, and sporadic and non-SOD1 familial ALS with or without FTLD-TDP. There are four sub-types of FTLD-TDP, and these correlate with specific clinical and genetic profiles. Sub-types are determined by the presence, predominance, and distribution of the various TDP-43 immunopositive insoluble aggregates-neuronal cytoplasmic inclusions, neuronal intranuclear inclusions, and dystrophic neurites. In this paper, FTLD-TDP pathologic sub-types will be described, and examples of each sub-type will be shown, and implications for future research will be discussed.	\N	\N
21609376	Differentiating between benign and malignant causes of obstructive jaundice can be challenging, even with the advanced imaging and endoscopic techniques currently available. In patients with obstructive jaundice, the predictive accuracy of bilirubin levels at presentation was examined in order to determine whether such data could be used to differentiate between malignant and benign disease. A total of 1,026 patients with obstructive jaundice were identified. Patients were divided into benign and malignant groups. The benign patients were subgrouped into those with choledocholithiasis and those with inflammatory strictures of the biliary tree. Bilirubin levels at presentation and other demographic data were obtained from case records. Area under the curve (AUC) values for bilirubin as a predictor of malignancy were highly significant for all benign presentations and for those with benign biliary strictures (AUC: 0.8 for both groups; P < 0.001). A bilirubin level > 100 µmol/l was determined to provide the optimum sensitivity and specificity for malignancy in all patients and in those without choledocholithiasis (71.9% and 86.9%, 71.9% and 88.0%, respectively). The application of a bilirubin level > 250 µmol/l achieved specificities of 97.1% and 98.0% in each subgroup of patients, respectively. In patients with obstructive jaundice, bilirubin levels in isolation represent an important tool for discriminating between benign and malignant underlying causes.	\N	\N
21621489	The aim of this study is to develop a standardized LC-MS/MS method for accurate measurement of desmosine (DES) and isodesmosine (IDS) in all body fluids as biomarkers for in vivo degradation of matrix tissue elastin in man and animals. A reproducible three-step analytical procedure: (1) sample hydrolysis in 6N HCl, (2) SPE by a CF1 cartridge with addition of acetylated pyridinoline as internal standard (IS), and (3) LC/MSMS analysis by SRM monitoring of transition ions; DES or IDS (m/z 526-481+397) and IS (m/z 471-128) was developed. The method achieves accurate measurements of DES/IDS in accessible body fluids (i.e. urine, plasma, and sputum). LOQ of DES/IDS in body fluids is 0.1 ng/ml. The % recoveries and reproducibility from urine, plasma, and sputum samples are above 99 ± 8% (n = 3), 94 ± 9% (n = 3) and 87 ± 11% (n = 3), with imprecision 8%, 9% and 10%, respectively. The proposed method was applied to measure DES/IDS in body fluids of patients with chronic obstructive pulmonary disease (COPD) and healthy controls. Total DES/IDS in sputum and plasma is increased over normal controls along with the free DES/IDS in urine in patients. DES/IDS can be used to study the course of COPD and the response to therapy. This practical and reliable LC-MS/MS method is proposed as a standardized method to measure DES and IDS in body fluids. This method can have wide application for investigating diseases which involve elastic tissue degradation.	\N	\N
21626540	The Movement Disorder Society (MDS) developed out of a merger with two short-lived organizations, the Movement Disorder Society, primarily organized to develop a journal for the subspecialty, and the International Society of Motor Disturbances, primarily organized to develop international congresses. The formal merger of the Movement Disorder Society and the International Society of Motor Disturbances into the Movement Disorder Society took place at the 2nd International Congress of Movement Disorders in Munich, Germany, in June 1992. Whereas the journal, Movement Disorders, and the annual International Congress of Parkinson's Disease and Movement Disorders remain the anchors of the society, the goals now include the development of regional symposia, regional sections, Web-based educational programs, and outreach efforts to include young investigators, wide international membership, and inclusion of non-neurologists, including basic scientists, neurosurgeons, and nonphysician health professionals. Movement Disorders has a continuingly growing subscribership and rising impact factor.	\N	\N
21630606	Renal biopsy is the definitive diagnostic test in patients with renal parenchymal disease. Renal biopsy registry is an important tool which can provide valuable data concerning early and correct epidemiological description and clinical correlations of renal diseases. Records of 326 adult renal biopsies performed at our hospital from January 1991 till the end of December 2006 were retrospectively examined. Overall, secondary glomerular diseases (SGD) were predominant (39.9%), followed by primary glomerular diseases (PGD) (30.4%), vascular diseases (13.2%) and TIN (6.7%). Total sclerosis of the kidney did not allow histopathological diagnosis in 5.8% of all biopsied kidneys. Focal and Segmental Glomerular Sclerosis (FSGS), IgA Nephropathy (IgAGN) and Minimal Change Disease (MCD) and Membranous Glomerulopathy (MGN) were the most common PGD, altogether representing 75.7% of all PGD. FSGS was the most frequent (30.3%), followed by IgAGN (21.2%), MCD (19.1%) and MGN in 15.1%. Vasculitis, HIVAN, diabetic nephropathy and amyloidosis were the most common SGD, altogether representing 90% of all SGD. Immune Mediated Glomerulonephritis (IMGN) were the most frequent (32.3%), followed by HIVAN (16.9%), diabetic nephropathy (14.6%) and amyloidosis (10%). Nephroangiosclerosis (benign and malignant nephroangiosclerosis) was the most frequent vascular nephropathy responsible for 79% of all vascular diseases. Thrombotic microangiopathy was seen in 9.3% and atherothrombotic disease in 7% of all vascular diseases. Concerning tubular diseases, chronic TIN accounted for 63.6% of all tubular diseases, followed by light chain-cast nephropathy (22.7%) and acute TIN (13.6%). Because of lack of material, 3.4% of all biopsies could not be analyzed. These data demonstrate that the distribution of biopsy-proved renal diseases in a Belgian population of the Brussels area is strongly influenced by the indications of renal biopsy. Harmonization of these indications might reflect with more accuracy the actual incidence of different nephropathies in a given population. Nation and worldwide renal biopsy registers are important to follow patterns of renal diseases in different populations. This information is important not only for health organizations in order to plan health budget but also for helping clinicians to provide a better care to patients.	\N	\N
21641369	Although very late stent thrombosis occurs several years after implantation of sirolimus-eluting stent (SES), the morphologic changes of the stent beyond 2 years have not yet been systematically studied in living patients. The late vascular response to SES was therefore evaluated by serial angioscopic studies at 2 and 5 years after stent implantation. A total of 17 patients with 17 SES underwent a repeated angioscopy procedure at 2 and 5 years. Neointimal stent coverage (NSC) was classified as follows: grade 0, presence of uncovered struts; grade 1, visible struts through a thin neointima; or grade 2, complete neointimal coverage without visible struts. For each patient, the minimum and maximum NSC grade and the existence of in-stent thrombus were recorded. The minimum and maximum NSC grade did not increase between the 2 and 5 years (0.59 ± 0.51 vs 0.88 ± 0.70, P = .17, and 1.82 ± 0.39 vs 1.94 ± 0.24, P = .30, respectively). The prevalence of patients with uncovered struts did not significantly decrease from 2 to 5 years (41% vs 29%, P = .49). During the follow-up period, 3 of 6 thrombi disappeared, whereas new thrombus formation was found in 3 patients without any clinical symptoms. In-stent thrombus did not decrease (35% vs 35%, P > .99). The current serial angioscopic study suggests that incomplete NSC and the prevalence of latent thrombus within the SES segments did not decrease from 2 to 5 years. The risk of stent thrombosis related to incomplete healing of SES may continue for an extended period.	\N	\N
21645024	Retinol-binding protein 4 (RBP4), produced by adipocytes and hepatocytes, contributes to an unfavourable lipid profile and insulin resistance, which can contribute to the development of coronary artery disease (CAD). Recently, several studies have shown that epicardial adipose tissue (EAT) differs from subcutaneous adipose tissue (SAT) and plays a role on the physiopathology of CAD because of its proximity to the coronary arteries. We aimed to study the expression and secretion levels of RBP4 in both fat tissues and explore its possible association with CAD. Fifty-eight patients undergoing heart surgery were included in the study. We analysed RBP4 mRNA expression by real-time PCR, protein expression by Western blot and immunohistochemistry, and secretion of EAT and SAT explants from CAD and non-CAD patients by Enzyme Immunoassay. Retinol-binding protein 4 is expressed at similar levels in EAT and SAT, mainly from adipocytes. Protein levels were higher in EAT from CAD than non-CAD patients (0·63 ± 0·09 arbitrary units (a.u).; n = 10) vs (0·41 ± 0·04 a.u.; n = 13, P = 0·039). In contrast, GLUT4 mRNA levels were lower in EAT from CAD than non-CAD patients (6·55 ± 0·16 a.u.; n = 13) vs (7·21 ± 0·18 a.u.; n = 14, P = 0·012). We also found differential expression in SAT between samples from CAD and non-CAD patients [(6·63 ± 0·16 a.u.; n = 14) vs (7·21 ± 0·14 a.u.; n = 14, P = 0·009)]. Besides, EAT releases higher RBP4 levels than SAT after 3, 6, 24 and 48 h of culture. These levels were independent of CAD but significantly higher in diabetic than nondiabetic patients. Retinol-binding protein 4 levels behave differently in EAT and SAT with respect to CAD. However, both adipose tissues have lower GLUT4 levels in patients with CAD. These findings suggest a differential regulation of RBP4 production in EAT and SAT that may be influenced by local factors.	\N	\N
21647871	In this phase 1 trial, the authors evaluated sunitinib combined with radiation therapy (RT) for the treatment of primary or metastatic central nervous system (CNS) malignancies. Eligible patients had CNS malignancies that required a (minimum) 2-week course of RT. Sunitinib (37.5 mg) was administered daily for the duration of RT with optional treatment extension of 1 month. Urine was collected at 3 time points for correlative biomarker studies. The primary endpoint was acute toxicity defined according to Common Toxicity Criteria version 3. Fifteen patients were enrolled (12 with CNS metastasis and 3 with primary tumors). RT doses ranged from 14 Gray (Gy) to 70 Gy (1.8-3.5 Gy per fraction). Acute toxicities included hematologic, nausea, hyperglycemia, fatigue, hypocalcemia, and diarrhea. Six patients (40%) developed grade ≤ 2 toxicities. Grade 3 toxicities occurred in 7 patients (47%) and included hematologic toxicity, fatigue, deep vein thrombosis, dysphasia, hyperglycemia, and hyponatremia. No grade 3 through 5 hypertensive events or intracerebral hemorrhages occurred. Two grade 5 adverse events attributed to disease progression occurred. The median follow-up was 34.2 months. Two patients (13%) achieved a partial response, 9 patients (60%) had stable disease, and 2 patients (13%) patients had progressive disease. The 6-month progression-free survival rate for patients who had brain metastasis was 58%. Grade 3 hematologic toxicity was correlated with greater changes in vascular endothelial growth factor levels changes between baseline and the completion of RT. Continuous 37.5-mg sunitinib combined with RT in patients who had CNS malignancies yielded acceptable toxicities and adverse events. The current results indicated that changes in urine vascular endothelial growth factor levels are associated with hematologic toxicity, and this association should be analyzed in a larger cohort. The feasibility, safety, and early response results warrant a phase 2 trial.	\N	\N
21653298	US estimates of the Clostridium difficile infection (CDI) burden have utilized International Classification of Disease, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis codes. Whether ICD-9-CM code rank order affects CDI prevalence estimates is important because the National Hospital Discharge Survey (NHDS) and the Nationwide Inpatient Sample (NIS) have varying limits on the number of ICD-9-CM codes collected. ICD-9-CM codes for CDI (008.45), C. difficile toxin assay results, and dates of admission and discharge were collected from electronic hospital databases for adult patients admitted to 4 hospitals in the United States from July 2000 through June 2006. CDI prevalence per 1000 discharges was calculated and compared for NHDS and NIS limits and toxin assay results from the same hospitals. CDI prevalence estimates were compared using the χ(2) test, and the test of equality was used to compare slopes. CDI prevalence measured by NIS criteria was significantly higher than that measured using NHDS criteria (10.7 cases per 1000 discharges versus 9.4 cases per 1000 discharges; P<.001) in the 4 hospitals. CDI prevalence measured by toxin assay results was 9.4 cases per 1000 discharges (P=.57 versus NHDS). However, the CDI prevalence increased more rapidly over time when measured according to the NHDS criteria than when measured according to toxin assay results (β=1.09 versus 0.84; P=.008). Compared with the NHDS definition, the NIS definition captured 12% more CDI cases and reported significantly higher CDI rates. Rates calculated using toxin assay results were not different from rates calculated using NHDS criteria, but CDI prevalence appeared to increase more rapidly when measured by NHDS criteria than when measured by toxin assay results.	\N	\N
21659502	Despite high vaccination coverage rates, there has been a gradual increase in reported pertussis cases. Although whooping cough affects all ages, young infants continue to suffer the greatest pertussis disease burden. Adolescents and adults are the primary source of infection for young babies. In this paper, we report two cases involving the likely transmission of pertussis from mothers to infants in Tunisia.	\N	\N
21665106	Radiating leg pain is a common symptom presenting in manual therapy practices. Although this symptom has been reported as a complication of endometriosis, its prevalence and characteristics have not been studied. We surveyed members of a national endometriosis support group with endometriosis using a self-administered, mailed questionnaire. The main outcome measures were the prevalence and characteristics of leg pain. Of 94 respondents, leg pain was reported by 48 women (51%), and was bilateral in 59% of these symptomatic women. The likelihood of experiencing leg pain was related to weight gain since age 18, age, and height. The most common treatments tried included exercise, over-the-counter medications, and massage therapy, all with variable results. These data support leg pain as a prevalent complication of endometriosis, and that the disease may affect multiple peripheral nerves. Manual therapists should remain aware to this possible etiology for radiating pain.	\N	\N
21674011	Intestinal luminal microbiota likely contribute to the etiology of necrotizing enterocolitis (NEC), a common disease in preterm infants. Microbiota development, a cascade of initial colonization events leading to the establishment of a diverse commensal microbiota, can now be studied in preterm infants using powerful molecular tools. Starting with the first stool and continuing until discharge, weekly stool specimens were collected prospectively from infants with gestational ages ≤32 completed weeks or birth weights≤1250 g. High throughput 16S rRNA sequencing was used to compare the diversity of microbiota and the prevalence of specific bacterial signatures in nine NEC infants and in nine matched controls. After removal of short and low quality reads we retained a total of 110,021 sequences. Microbiota composition differed in the matched samples collected 1 week but not <72 hours prior to NEC diagnosis. We detected a bloom (34% increase) of Proteobacteria and a decrease (32%) in Firmicutes in NEC cases between the 1 week and <72 hour samples. No significant change was identified in the controls. At both time points, molecular signatures were identified that were increased in NEC cases. One of the bacterial signatures detected more frequently in NEC cases (p<0.01) matched closest to γ-Proteobacteria. Although this sequence grouped to the well-studied Enterobacteriaceae family, it did not match any sequence in Genbank by more than 97%. Our observations suggest that abnormal patterns of microbiota and potentially a novel pathogen contribute to the etiology of NEC.	\N	\N
21674889	Awareness of the clinical importance of second-line chemotherapy for incurable gastric cancer has been increasing. To assess the clinical validity of the new concept that second-line chemotherapy following predetermined cycles of first-line chemotherapy would improve survival, we conducted a phase II study. Patients with pathologically proven incurable gastric adenocarcinoma and adequate organ functions were enrolled. S-1 or S-1 plus cisplatin was administered as first-line chemotherapy. The number of cycles of S-1-based chemotherapy was determined to be three as a maximum unless there was disease progression. The treatment was followed by weekly administration of paclitaxel. The primary endpoint was overall survival and the secondary endpoints were progression-free survival and safety. Thirty-seven patients were eligible for enrollment. Twenty-eight patients (76%) underwent the second-line chemotherapy with paclitaxel after completion of S-1-based chemotherapy or disease progression. Treatment-related grade 3 or 4 toxicity was noted in 14 patients during S-1-based chemotherapy, and in 6 patients during paclitaxel treatment. The median survival time was 455 days and the median progression-free survival was 229 days. Sequential set chemotherapy with three cycles of S-1-based chemotherapy followed by weekly paclitaxel is feasible. The survival results are equivalent to those of other current regimens using S-1.	\N	\N
21681643	Long-term central venous catheter (CVC) implantation has become more affordable in Taiwan since 1995. Surgical removal of the catheter may be the essential treatment for catheter-related bloodstream infections (CRBSI). The aim of this study was to evaluate the clinical features and microbial isolates in pediatric cancer patients with removal of CVC for CRBSI. The records of positive blood culture from hospitalized pediatric oncology patients between 1995 and 2004 were reviewed. One hundred and forty-three patients implanted with a long-term CVC were further identified. Seventeen catheters in 16 patients developed catheter-related bacteremia that needed catheter removal. The rate of catheter removal was 11.9%. The median device life was 7.7 months. Six catheters were removed within 3 months of insertion. Nine of the 17 catheters were removed from patient younger than 2 years. Eight infections occurred during severe neutropenia, and 6 patients had refractory or relapsed underlying disease. The cultural isolates were Gram-negative bacilli in 7, Gram-positive in 5, fungi in 5, and atypical mycobacterium in 1. The frequency of catheter removal for infection control was significantly higher in the first 5 years (1994-1999) compared to the last 5 years (2000-2004) (30.9 vs. 4.0%, p = 2.3 × 10(-4)). Factors such as microbiological isolates, age of infection, the status of malignancy, and neutropenia are related to catheter outcome. The reduction in patients with positive cultures needing removal of the catheters can be related to improved nursing care and more aggressive antibiotic therapy.	\N	\N
21685330	Lymphatic metastasis constitutes a critical route of disease dissemination, which limits the prognosis of patients with pancreatic ductal adenocarcinoma (PDAC). As lymphangiogenesis has been implicated in stimulation of lymphatic metastasis by vascular endothelial growth factor-C (VEGF-C) and VEGF-D, we studied the effect of the angioregulatory growth factor angiopoietin-2 (Ang-2) on PDAC progression. Ang-2 was found to be expressed in transformed cells of human PDAC specimens, with corresponding Tie-2 receptors present on blood and lymphatic endothelium. In vitro in PDAC cells, Ang-2 was subject to autocrine/paracrine TGF-β stimulation (2-fold induction, P=0.0106) acting on the -61- to +476-bp element of the human Ang-2 promoter. In turn, Ang-2 regulated the expression of genes involved in cell motility and tumor suppression. Orthotopic PDAC xenografts with forced expression of Ang-2, but not Ang-1, displayed increased blood and lymphatic vessel density, and an enhanced rate of lymphatic metastasis (6.7- to 9.1-fold, P<0.01), which was prevented by sequestration of Ang-2 via coexpression of soluble Tie-2. Notably, elevated circulating Ang-2 in patients with PDAC correlated with the extent of lymphatic metastasis. Furthermore, median survival was reduced from 28.4 to 7.7 mo in patients with circulating Ang-2 ≥ 75th percentile (P=0.0005). These findings indicate that Ang-2 participates in the control of lymphatic metastasis, constitutes a noninvasive prognostic biomarker, and may provide an accessible therapeutic target in PDAC.	\N	\N
21689845	To describe the number of urethral dilations, urethrotomies, and urethroplasties performed on men with a diagnosis of urethral stricture disease seeking care in the Veterans Affairs (VA) health care system in southern California and southern Nevada over a 5-year period. To date, few health services research studies have evaluated patterns of care for urethral stricture disease using national datasets. We analyzed stricture treatment for male veterans with an ICD-9 diagnosis code for urethral stricture in the National Patient Care Database (NPCD). Encounters for urethral stricture procedures performed were identified based on the presence of Physicians Current Procedural Terminology Coding System (4th edition, CPT-4) codes for treatments performed during the fiscal years 2002-2006. A total of 1457 men carried a diagnosis of urethral stricture disease during the index time period. Of these, 333 men (23%) underwent 431 procedures. Of the 216 men who underwent urethral dilations, 170 (79%) underwent only 1 procedure and 26 (12%) underwent 2 procedures. Of the 79 men who underwent urethrotomy, 76 (96%) underwent 1 procedure. Sixteen men (5%) underwent a urethroplasty, 8 of whom underwent a perineal urethrostomy. The vast majority of men treated for stricture disease underwent only 1 such procedure over a 5-year time period. Further research is required to investigate whether this is a quality-of-care issue or patients refusing intervention. It is possible that some patients may be temporized for a significant period with dilation/urethrotomy, whereas those with rapid recurrence require early urethroplasty.	\N	\N
21690452	Laparoscopy is increasingly used in colon and rectal procedures. However, little is known regarding the incidence of venous thromboembolism (VTE) in laparoscopic colorectal (LC) compared with that in open colorectal (OC) procedures. We aimed to compare the incidences and to highlight the risk factors of developing VTE after LC and OC surgery. Analysis of the Nationwide Inpatient Sample data from 2002 through 2006. National database. Patients who underwent elective LC and OC surgery from 2002 through 2006. Incidence of VTE during initial hospitalization after LC and OC surgery; VTE classified by surgical site, pathology type, and at-risk patient population. Over a 60-month period, 149,304 patients underwent LC or OC resection. Overall, the incidence of VTE was significantly higher in OC cases (2036 of 141,456 [1.44%]) compared with the incidence in LC cases (65 of 7848 [0.83%]) (P < .001). When stratified according to pathologic condition and surgical site, the overall rate of VTE was highest in patients with inflammatory bowel disease and in those undergoing rectal resections. Patients who underwent OC surgery were almost twice as likely to develop VTE compared with patients who underwent LC surgery. We also identified malignancy, obesity, and congestive heart failure as statistically significant (P < .05) risk factors for VTE in OC and LC surgery. On the basis of data from a large clinical data set, the incidence of perioperative VTE is lower after LC than after OC surgery. These findings may help colorectal surgeons use appropriate VTE prophylaxis for patients undergoing colorectal procedures.	\N	\N
21699733	Itch sensation is one of the major sensory experiences of human and animals. Recent studies have proposed that gastrin releasing peptide (GRP) is a key neurotransmitter for itch in spinal cord. However, no direct evidence is available to indicate that GRP actually mediate responses between primary afferent fibers and dorsal horn neurons. Here we performed integrative neurobiological experiments to test this question. We found that a small population of rat dorsal horn neurons responded to GRP application with increases in calcium signaling. Whole-cell patch-clamp recordings revealed that a part of superficial dorsal horn neurons responded to GRP application with the increase of action potential firing in adult rats and mice, and these dorsal horn neurons received exclusively primary afferent C-fiber inputs. On the other hands, few A(δ) inputs receiving cells were found to be GRP positive. Finally, we found that evoked sensory responses between primary afferent C fibers and GRP positive superficial dorsal horn neurons are mediated by glutamate but not GRP. CNQX, a blocker of AMPA and kainate (KA) receptors, completely inhibited evoked EPSCs, including in those Fos-GFP positive dorsal horn cells activated by itching. Our findings provide the direct evidence that glutamate is the principal excitatory transmitter between C fibers and GRP positive dorsal horn neurons. Our results will help to understand the neuronal mechanism of itch and aid future treatment for patients with pruritic disease.	\N	\N
21699956	The NMDA glutamate hypofunction model of schizophrenia is based in part upon acute effects of NMDA receptor blockade in humans and rodents. Several laboratories have reported glutamate system abnormalities following prenatal exposure to immune challenge, a known environmental risk factor for schizophrenia. Here we report indices of NMDA glutamate receptor hypofunction following prenatal immune activation, as well as the effects of treatment during periadolescence with the atypical antipsychotic medications risperidone and paliperidone. Pregnant Sprague-Dawley rats were injected with polyinosinic:polycytidylic acid (poly I:C) or saline on gestational day 14. Male offspring were treated orally via drinking water with vehicle, risperidone (0.01mg/kg/day), or paliperidone (0.01mg/kg/day) between postnatal days 35 and 56 (periadolescence) and extracellular glutamate levels in the prefrontal cortex were determined by microdialysis at PD 56. Consistent with decreased NMDA receptor function, MK-801-induced increases in extracellular glutamate concentration were markedly blunted following prenatal immune activation. Further suggesting NMDA receptor hypofunction, prefrontal cortex basal extracellular glutamate was significantly elevated (p<0.05) in offspring of poly I:C treated dams. Pretreatment with low dose paliperidone or risperidone (0.01mg/kg/day postnatal days 35-56) normalized prefrontal cortical basal extracellular glutamate (p<0.05 vs. poly I:C vehicle-treatment). Pretreatment with paliperidone and risperidone also prevented the acute MK-801-induced increase in extracellular glutamate. These observations demonstrate decreased NMDA receptor function and elevated extracellular glutamate, two key features of the NMDA glutamate receptor hypofunction model of schizophrenia, during periadolescence following prenatal immune activation. Treatment with the atypical antipsychotic medications paliperidone and risperidone normalized basal extracellular glutamate. Demonstration of glutamatergic abnormalities consistent with the NMDA glutamate receptor hypofunction model of schizophrenia as an early developmental consequence of prenatal immune action provides a model to identify novel early interventions targeting glutamatergic systems which play an important role in both positive and negative symptoms of schizophrenia.	\N	\N
21700931	Caloric restriction (CR) confers cardioprotection against ischemia/reperfusion injury. However, the exact mechanism(s) underlying CR-induced cardioprotection remain(s) unknown. Recent evidence indicates that Sirtuins, NAD(+)-dependent deacetylases, regulate various favorable aspects of the CR response. Thus, we hypothesized that deacetylation of specific mitochondrial proteins during CR preserves mitochondrial function and attenuates production of reactive oxygen species during ischemia/reperfusion. The objectives of the present study were (1) to investigate the effect of CR on mitochondrial function and mitochondrial proteome and (2) to investigate what molecular mechanisms mediate CR-induced cardioprotection. Male 26-week-old Fischer344 rats were randomly divided into ad libitum-fed and CR (40% reduction) groups for 6 months. No change was observed in basal mitochondrial function, but CR preserved postischemic mitochondrial respiration and attenuated postischemic mitochondrial H(2)O(2) production. CR decreased the level of acetylated mitochondrial proteins that were associated with enhanced Sirtuin activity in the mitochondrial fraction. We confirmed a significant decrease in the acetylated forms of NDUFS1 and cytochrome bc1 complex Rieske subunit in the CR heart. Low-dose resveratrol treatment mimicked the effect of CR on deacetylating them and attenuated reactive oxygen species production during anoxia/reoxygenation in cultured cardiomyocytes without changing the expression levels of manganese superoxide dismutase. Treatment with nicotinamide completely abrogated the effect of low-dose resveratrol. These results strongly suggest that CR primes mitochondria for stress resistance by deacetylating specific mitochondrial proteins of the electron transport chain. Targeted deacetylation of NDUFS1 and/or Rieske subunit might have potential as a novel therapeutic approach for cardioprotection against ischemia/reperfusion.	\N	\N
21703749	Few studies have focused on the full complement of cardiac arrest cases seen in hospital emergency departments (ED). The aims of our study were to describe cardiac arrest visits in the ED by using a nationally representative sample of U.S. adults. ED data from the 2001-2007 National Hospital Ambulatory Medical Care Survey (NHAMCS) were analyzed. Cardiac arrest visits were considered to be those with an International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code of 427.5 as the primary diagnosis. From 2001 to 2007, adults in the U.S. made an estimated 600,729,000 ED visits. Of those, 1,001,000 (0.17%) had a primary diagnosis of cardiac arrest. The majority of patients with such visits were dead on arrival or died in the ED (74.0%). The mean age for cardiac arrest visits was 66.7 years (95% confidence interval [CI], 64.6-68.8 years). Women had a lower rate of cardiac arrest visits than men (age-adjusted odds ratio [AOR], 0.6; 95% CI, 0.5-0.8), and the privately insured (AOR, 0.4; 95% CI, 0.2-0.7) and those with government insurance (AOR, 0.5; 95% CI, 0.3-0.9) had a lower proportion of cardiac arrest ED visits than uninsured persons. In addition, increasing age was a significant predictor of cardiac arrest visits. Cardiac arrest visits did not vary significantly by race, geographic region, or metropolitan statistical area. ED visits classified as cardiac arrest represent 1 in 600 visits and these visits differ by age, sex, payment source, and arrival time at the ED.	\N	\N
21704888	The safety of long-acting β2 agonists (LABA) for the treatment of persistent asthma remains a topic of ongoing debate. To evaluate the risk of serious asthma-related events among patients treated with formoterol, a meta-analysis of all Novartis-sponsored controlled clinical trials was conducted. Forty-five randomized, placebo- and active-controlled, parallel-group or crossover studies with formoterol were included. Background inhaled corticosteroid (ICS) use was permitted in all studies; however, in only 2 studies was ICS randomized as study medication. Sub-analyses of the pooled data were performed according to age (5-12; 13-18; >18 years), baseline ICS use, and lung function. Odds ratios (OR) and 95% confidence intervals (CIs) were calculated between formoterol (twice-daily), albuterol (salbutamol) 4 times per day (active control), and placebo. Patients were randomized to formoterol (n = 5,367), placebo (n = 2,026), and albuterol (n = 976). Two deaths were reported, 1 each in the formoterol (asthma exacerbation) and the placebo (hemorrhagic pancreatitis) groups. No statistically significant differences in serious asthma exacerbations were observed compared with placebo in adolescents and adults. In children, a higher frequency of hospitalizations was observed among patients treated with formoterol compared with placebo (OR 8.4; 95% CI: 1.1-65.3). A trend toward fewer exacerbations was observed among subjects reporting concomitant ICS use at baseline. This analysis supports current guideline recommendations for the use of LABAs only as add-on therapy to ICS.	\N	\N
21706339	The prostate gland is the most common site of neoplastic disorders in men. The pathogenesis of inflammatory cells, prostatic intraepithelial neoplasia (PIN) lesions, and prostate cancer is still under investigation. Inflammatory cells by producing free radicals are considered as major and universal contributors to cancerogenesis. PIN is regarded as a precursor lesion to prostate cancer or a marker signaling the vulnerability of the epithelium to neoplastic transformation [1]. Differentiation markers that are frequently changed in early invasive carcinoma are also changed in PIN lesions. In this study, prostate tissue samples obtained during surgical operation and classified as various disease states (inflammation, PIN lesions, and cancer) were examined. The samples were measured by means of microbeam synchrotron-radiation-induced X-ray emission (micro-SRIXE). Special attention was paid to examine the relationship between the earlier-mentioned disorders and changes in relative concentrations of S, K, Ca, Fe, Cu, and Zn. Applying the image-processing program ImageJ enabled us to select the areas of interest from two-dimensional maps of various prostate samples according to the histopathologist's evaluation. Detailed analysis of micro-SRIXE spectra based on multivariate methods shows significant differences between elemental concentrations in inflammatory cells, PIN lesions, and cancerous tissues, which confirms that this method can be used to distinguish various pathological states in prostate tissues. Information obtained in this way may provide better understanding of the biochemistry of unhealthy prostate tissues, thus opening the way to find new medicines/treatments to prevent or slow down some harmful intracellular processes.	\N	\N
21712520	Data have shown that preprocedural statin therapy reduces periprocedural myocardial infarction after percutaneous coronary intervention (PCI). However, whether preprocedural statins improve clinical outcomes in patients with stable coronary artery disease (CAD) has not been established. We aimed to evaluate the clinical effectiveness of preprocedural statin therapy in patients with stable CAD undergoing PCI. We conducted an observational study of 12 980 patients, age >65 years with stable CAD, who underwent PCI from December 1, 2003, to March 31, 2008. Using propensity score-matching analysis, 3098 unique matched pairs (6196 patients) who had similar likelihood of receiving preprocedural statins were identified. Additional analyses adjusting for postprocedural statins as a time-varying variable were performed. The main outcome measure was a composite of death or recurrent acute coronary syndrome. In the propensity-matched cohort, at 90 days, the primary outcome of death and acute coronary syndrome occurred in 5.6% in the preprocedural statin group as compared with 7.4% in the no-pretreatment group (P=0.005). Improved clinical outcomes associated with preprocedural statins were still observed at 2 years (16.7% versus 19.3%, P=0.007). The effectiveness of preprocedural statins was most pronounced at 90 days after PCI (adjusted hazard ratio, 0.80; 95% confidence interval, 0.65 to 0.98) but was no longer significant at 1 year (adjusted hazard ratio, 0.92; 95% confidence interval, 0.79 to 1.07) after accounting for postprocedural statin therapy. Preprocedural statin therapy was associated with significant reduction in the risk of death or recurrent acute coronary syndrome in stable CAD patients after PCI. These findings support the routine use of preprocedural statins for suitable candidates.	\N	\N
21722500	To describe the MRI features of gout tophi in the soft-tissues or joints of the limbs by low-field extremity-dedicated MRI. Nine consecutive patients, 8M/1W, affected by chronic tophaceous gout were studied. Mean patients' age was 71.3±11.5 years, mean disease duration 98.1±44.9 months, and mean serum uric acid concentration 9.2±2.8 mg/L. Diagnosis was based on the ACR classification criteria for gout, and by identification of MSU crystals in the tophi and synovial fluid. Conventional radiograms and MRI with an extremity-dedicated system were obtained of the joint areas involved by tophi. At T1 weighted MRI images, all tophi showed a homogeneous intermediate signal intensity, similar to that of muscle. Conversely, in T2 weighted images, a wide spectrum of signal intensity patterns was observed. The pattern of contrast enhancement was variable from intense homogeneous to peripheral and heterogeneous. Capsulo-ligamentous structures were often thickened and degenerated and, on occasion, could be recognised as inhomogeneous, hypointense ribbon-shaped elements in the context of the tophus. In only two cases, tendons were infiltrated by tophaceous matter. Bone marrow oedema (BME) and erosions were seen in 8 out of 10 bones adjacent to tophi. The MRI appearance of gout tophi using an extremity-dedicated machine is similar to that described in the literature using whole body machines. BME adjacent to the tophus was a frequent finding. This technique may occasionally help in the differential diagnosis of nodules and in the follow-up of the disease. It also represents a useful tool to investigate the pathogenesis of gout and to better understand its clinical progression.	\N	\N
21726837	Data are lacking on the efficacy and safety of a loading dose (LD) of clopidogrel in elderly patients with acute myocardial infarction (AMI). FAST-MI is a nationwide registry that was carried out over a 1-month period in 2005 and included consecutive patients with AMI admitted to intensive care units <48 hours from symptom onset in 223 participating centers. We assessed the impact of a clopidogrel LD (≥300 mg) compared to a conventional dose (<300 mg) on bleeding, need for blood transfusion, and 30-day and 12-month survivals in 791 elderly patients (≥75 years old, mean age 81 ± 4 years, 48% women, 35% with ST-segment elevation MI) included in this registry. Fifty-nine percent (466 patients) received a clopidogrel LD. Follow-up was >99% complete. Major bleeding and blood transfusions were not significantly different in patients who received a clopidogrel LD (3.2% vs 3.7%, p = 0.72; 5.4% vs 6.2%, p = 0.64, respectively). Early mortality was also not significantly different (10.1 vs 10.8, p = 0.76). Using multivariate analyses, clopidogrel LD did not significantly affect major bleeding or transfusion (odds ratio 1.03, 95% confidence interval 0.49 to 2.17, p = 0.94) and 12-month mortality (hazard ratio 1.00, 95% confidence interval 0.72 to 1.40, p = 0.98). In conclusion, the present data showed that in elderly patients admitted for AMI, use of a LD of clopidogrel compared to a conventional dose was not associated with increased in-hospital bleeding, need for transfusion, or mortality. Large-scale randomized trials are still needed to identify the optimal LD of clopidogrel for elderly patients admitted for AMI.	\N	\N
21727012	The lung is the most common site for extrahepatic metastasis from hepatocellular carcinoma (HCC). We previously reported in a series of 20 patients that pulmonary metastasectomy for HCC is feasible in selected patients. The objective of this study was to re-evaluate the long-term outcomes and prognostic factors with an additional 25 patients. We retrospectively analyzed the records of 45 consecutive patients who underwent pulmonary metastasectomy due to HCC at our institution between 1990 and 2010. Thirty-nine patients underwent hepatectomy or liver transplantation, whereas six patients underwent locoregional therapy for primary liver lesions. Twenty-seven patients died during a median 17.6-month follow-up period. The 2-year disease-free survival (DFS) was 19.5%. The 5-year overall survival (OS) was 40.9%. History of recurrence and serum des-gamma-carboxy prothrombin (DCP) level >40 mAU ml(-1) at initial pulmonary resection were unfavorably associated with OS in univariate analysis. Pulmonary metastasectomy for HCC in selected patients resulted in relatively good outcomes with regard to OS. History of recurrence and serum DCP levels were shown to be candidates of prognostic factors for OS.	\N	\N
21735745	A 42-year-old Japanese woman was referred to our university hospital due to progressive anemia and bilateral hilar lymphadenopathy with diffuse ground-glass attenuation on chest computed tomography in December 2009. She had suffered from exertional dyspnea and fatigue for several months. Laboratory findings on admission demonstrated leukocytosis (10,950/ul), elevation of C-reactive protein (4.7 mg/dl), IL-6 (19.9 pg/ml), IgG4 (567 mg/dl) and polyclonal hyper gamma-globulinemia. Chest computed tomography represented mediastinal and bilateral hilar lymphadenopathy with diffuse centrilobular fine nodules and intralobular septal thickening. Histopathological findings of the specimens obtained by thoracoscopic lung and mediastinal lymph node biopsies revealed massive infiltration of IgG4-positive plasma cells in lung tissue and lymph nodes. Pathological findings and high levels of C-reactive protein and interleukin-6 suggested a diagnosis of multicentric Castleman's disease (MCD). In addition, pathological findings of peribronchiolar infiltration of IgG4-positive plasma cells and lymphoid follicles with infiltration of IgG4-positive plasma cells with a high level of IgG4 were indicative of the complication of IgG4-related lung disease. Radiological and serological findings improved rapidly soon after the initiation of oral corticosteroid treatment. It was speculated that this case indicated the close relationship between MCD and IgG4-related lung disease.	\N	\N
21737965	Bartonella henselae is the causative agent of cat scratch disease (CSD) in humans. Cats are the main reservoir of this bacterium and may infect humans through scratches and bites. The purpose of this study was to determine the B. henselae seroprevalence in cats in Turkey. A total of 298 cats blood samples were collected from six different provinces of Turkey. Sera were tested for the presence of anti-B. henselae IgG antibodies by indirect fluorescent antibody test (IFA). The seroprevalence of B. henselae was 27.9% (83/298) for the cats examined in this study. The seroprevalence of cats by province was significantly higher in Bursa (41.3%), Adana (33.9%), Aydin (27.5%) and Burdur (32.3%) than in Kayseri (17.9%) and Istanbul (12.5%). Statistically significant differences were not observed between cat sexes and living conditions of cats. The results revealed that B. henselae is an important zoonotic pathogen in Turkey.	\N	\N
21751546	Intravenous immunoglobulin (IVIG) products are derived from plasma pools of thousands of healthy donors. These immunoglobulin concentrates contain large number of antibodies as well trace levels various other immunologically active molecules. Therapeutic Ig formulations contain intact IgG molecules, with variable amounts of monomeric and dimeric form existing in a dynamic equilibrium. Paradoxically, IgG can exert both pro-and anti-inflammatory activities, depending on its concentration. IVIG have been used for the treatment of primary immunodeficiency disorders for more than 25 years. IVIG products are also effective in the treatment of autoimmune and inflammatory disorders; however, the precise mechanism (s) of action is not known. Clinical and laboratory studies have documented various mechanisms of action of IVIG. The complex network of immunological reactions resulting from the infusion of IVIG includes changes in several cytokines, interactions with dendritic cells, T-and B-cell effects, macrophage effects, mediated by distinct Fc-gamma receptors. IVIG is also a recently recognized modifier of complement activation and injury. The complement--scavenging ability of Ig implies expansion of the use of IVIG to all disease in which generation of complement fragments plays a crucial role in pathogenesis. Recent studies showed that the anti-inflammatory activity of IVIG result from a minor population of the pooled IgG molecules that contains terminal a-2,6 sialic acid linkages on their Fc-linked glycans. This fully processed glycan is found in 1-3% of IgG in IVIG, which may explain the requirement for a high dose of IVIG. Recent data demonstrate, that the anti-inflammatory properties of IVIG can be recapitulated with fully recombinant preparation of appropriately sialylated IgG Fc fragments. This recombinant preparation had a 35 fold enhanced activity and potentially could be used at much lower doses than IVIG preparation in the treatment of autoimmune disorders.	\N	\N
21764110	The impact of diffusion-weighted imaging (DWI) and apparent diffusion coefficients (ADCs) of MR imaging on the evaluation of residual Uterine Cervical Carcinoma after Radiation Therapy, in addition to conventional MR images. Fourty-nine women presenting with a uterine cervical cancer were examined with 1.5 T MRI and DWI, 8 (4-20) weeks after treatment. Treatment response was determined based on the histopathological results after therapy and was classified as a complete response (CR) or residual disease (RD). Post-treatment DWI and ADC results were compared. Five (11%) and 44 (89%) patients were considered as having histologically-proven RD or a CR respectively. The mean ADC of cervical tissue for all patients was 1.74±0.324×10(-3) mm(2)/s and the SD was 1.94±1.11×10(-4). The mean ADC was 1.62±0.21×10(-3) mm(2)/s (SD=1.45×10(-4)) for the 5 patients with RD versus 1.76±0.33×10(-3) mm(2)/s (SD=1.99×10(-4)) for the 44 patients with a CR (p=0.09). Using 1.7×10(-3) mm(2)/s as a radiological cut-off value for the ADC, all patients classified as having histologically-proven RD had a mean ADC of ≤1.7×10(-3). In 12 (25%) cases, RD was suspected on T2-weighted MRI images alone. Eight of these cases were considered as false positives compared to the histological results. Their mean ADC was 1.98×10(-3) mm(2)/s and none of them had an ADC of <1.7×10(-3) mm(2)/s. Although our results were not statistically significant, ADC values could potentially be used to predict and monitor the response of uterine cervical cancer.	\N	\N
21769106	Strong and unidirectional associations exist between the severity of cardiovascular calcifications and mortality in patients with advanced chronic kidney disease. In the past 10 years, a wealth of experimental and clinical information has been published on the key pathophysiological events that contribute to the development and progression of vascular and soft-tissue calcifications. These processes involve a sensitive balance of calcification inhibition, induction and removal. The traditional view of regarding secondary hyperparathyroidism and elevated calcium × phosphate product as the pivotal risk factors for calcification has been challenged by data demonstrating a role for other, more subtle and complex pathomechanisms. These mechanisms include the loss of endogenous calcification inhibitors, deficient clearance of calcified debris, effects of vitamin K and vitamin D, and the action of calcification inducers as in osteogenic transdifferentiation. In this Review, we describe our current knowledge of the factors involved in the passive and active regulation of extraosseous calcification processes, with an assessment of their importance as targets for future diagnostic and therapeutic interventions.	\N	\N
21776811	Tumor characterization employing a voxel-wise analysis of image signal facilitates the determination of the spatial distribution of tumor attributes, and when employed for therapy response assessment offers the promise of greater sensitivity to change than conventional approaches. However, the accuracy of a voxel-wise analysis of change is limited by local registration uncertainties that can disrupt the spatiotemporal correspondence between assessed voxels. We present a method for assessing voxel correspondence strength using a multiresolution local histogram-based measure of image structure similarity. When employed in a longitudinal tumor imaging context, a voxel similarity measure must be robust to intensity variations that can arise from the image acquisition, treatment effects, or changes in underlying disease processes. Consequently, the local histogram-based similarity measure is evaluated for sensitivity to structural change and robustness to intensity variation and is compared against normalized mutual information and normalized cross-correlation. T1-weighted (T1W) magnetic resonance (MR) images of glioblastoma acquired as part of a longitudinal response assessment study are first rigidly registered, and then similarity between spatially corresponding voxels is evaluated using multiresolution local histograms. Region-based and nonuniform intensity changes of varying magnitude as well as deformations to image structure are applied individually and in combination to the test images. Statistical analysis is used to test for interaction effects between the applied perturbations and the value of the local histogram similarity function. Pair-wise voxel similarity maps are computed for pairs of longitudinal clinical MR image volumes and compared with observed patterns of change on conventional imaging. The simulations demonstrated that the local histogram measure was robust to intensity modulations applied to increasing region sizes and exhibited a strong negative correlation with the magnitude of local deformation. No statistically significant interaction effects were observed upon the value of the local histogram similarity function when deformation was applied in conjunction with a nonuniform intensity change. Pair-wise voxel similarity maps were consistent with image change observed on T1W MR imaging and revealed patterns of change not apparent in conventional image sequences. A measure of local histogram image structure similarity can be used to assess the strength of voxel to voxel correspondences independently of intensity nonuniformities. The metric can provide a local estimate of the limits of achievable correspondence underlying the registration and voxel-wise comparison of signal in longitudinal imaging used for assessing tumor response to treatment.	\N	\N
21779916	Metastatic pulmonary calcification can be caused by a number of diseases, most common being end-stage renal disease. Most of the patients are asymptomatic, and imaging with computed tomography is useful in making a diagnosis. Demonstration of pulmonary and chest wall vessel calcification is characteristic. We report a case of a 60-year-old patient with chronic renal failure on dialysis, presenting with gradual onset dyspnea, who showed metastatic pulmonary calcification on chest imaging.	\N	\N
21784472	Long-term ketamine abuse in humans causes significant lower urinary tract symptoms. However, the etiology of ketamine associated cystitis is still not clear. We created a mouse model of ketamine induced lower urinary tract dysfunction to explore the pathogenesis of this condition. Female C57BL/6 mice randomly distributed into control and ketamine groups received daily intraperitoneal injection of saline and ketamine (100 mg/kg), respectively. Cystometry was done in each group at 4, 8 and 16 weeks. After sacrifice the bladders were harvested for isometric muscle tension recording and immunohistochemical examination. After 8 weeks of treatment body weight growth was significantly decreased in ketamine treated mice. Cystometry revealed a significantly decreased intercontraction interval (mean±SEM 237±9 vs 360±20 seconds, p<0.001) and decreased bladder capacity (0.1±0.004 vs 0.13±0.006 ml, p<0.001) in ketamine vs saline injected mice. Increased adenosine triphosphate evoked detrusor contraction developed in the ketamine group. Immunohistochemical examination revealed increased P2X1 receptor expression in ketamine treated mouse bladders while M2 and M3 receptor expression was unchanged. At 8 weeks mice treated with ketamine showed increased voiding frequency and decreased bladder capacity, the same symptoms that develop in human ketamine abusers. Enhanced noncholinergic contractions and P2X1 receptor expression in the ketamine bladder indicate that dysregulation of purinergic neurotransmission may underlie detrusor overactivity in cases of ketamine induced bladder dysfunction.	\N	\N
21785215	Sinus node dysfunction (SND) is a major public health problem that is associated with sudden cardiac death and requires surgical implantation of artificial pacemakers. However, little is known about the molecular and cellular mechanisms that cause SND. Most SND occurs in the setting of heart failure and hypertension, conditions that are marked by elevated circulating angiotensin II (Ang II) and increased oxidant stress. Here, we show that oxidized calmodulin kinase II (ox-CaMKII) is a biomarker for SND in patients and dogs and a disease determinant in mice. In wild-type mice, Ang II infusion caused sinoatrial nodal (SAN) cell oxidation by activating NADPH oxidase, leading to increased ox-CaMKII, SAN cell apoptosis, and SND. p47-/- mice lacking functional NADPH oxidase and mice with myocardial or SAN-targeted CaMKII inhibition were highly resistant to SAN apoptosis and SND, suggesting that ox-CaMKII-triggered SAN cell death contributed to SND. We developed a computational model of the sinoatrial node that showed that a loss of SAN cells below a critical threshold caused SND by preventing normal impulse formation and propagation. These data provide novel molecular and mechanistic information to understand SND and suggest that targeted CaMKII inhibition may be useful for preventing SND in high-risk patients.	\N	\N
21791221	This manuscript provides a survey of research findings catered to the development of effective countermeasures against nerve agent poisoning over the past decade. New neuropathophysiological distinctive features as regards organophosphate (OP) intoxication are presented. Such leading neuropathophysiological features include recent data on nerve agent-induced neuropathology, related peripheral or central nervous system inflammation and subsequent angiogenesis process. Hence, leading countermeasures against OP exposure are down-listed in terms of pre-treatment, protection or decontamination and emergency treatments. The final chapter focuses on the description of the self-repair attempt encountered in lesioned rodent brains, up to 3months after soman poisoning. Indeed, an increased proliferation of neuronal progenitors was recently observed in injured brains of mice subjected to soman exposure. Subsequently, the latter experienced a neuronal regeneration in damaged brain regions such as the hippocampus and amygdala. The positive effect of a cytokine treatment on the neuronal regeneration and subsequent cognitive behavioral recovery are also discussed in this review. For the first time, brain cell therapy and neuronal regeneration are considered as a valuable contribution towards delayed treatment against OP intoxication. To date, efficient delayed treatment was lacking in the therapeutic resources administered to patients contaminated by nerve agents.	\N	\N
21797955	The outcome of HCC after transplantation (OLT) in children is not well known. Unfavorable features based on adult reports may lead to contraindicate OLT even in children. We reviewed a cohort of children with cirrhosis and HCC to evaluate their outcome after primary transplantation. We considered children with cirrhosis and HCC who had a primary OLT. We retrospectively recorded demographic, medical and surgical features, and MC as predictors of outcome. Among 456 children transplanted in the last 15 yr, 10 (2%), median age at diagnosis 1.8 yr (range 0.5-7.2), had HCC in biliary atresia (3), BSEP deficiency (3), tyrosinemia type 1 (2), complications of choledocal cyst and glycogen storage disease type IV (1 each). At HCC discovery, median AFP was 2322 ng/mL (3-35,000), high or rising in 9/10 patients. Six patients were outside the MC. Median time on the waiting list was 38 days (1-152). Two patients died from early complications of OLT. In the other eight patients, there was no tumor recurrence after a median follow-up of four yr. Children with cirrhosis may develop HCC at a very young age. The outcome appears excellent even outside MC. Primary liver transplantation is advisable for children with cirrhosis, HCC, and no extrahepatic disease.	\N	\N
21802018	The cost associated with asthma impairment in children with severe asthma has not been determined. To assess the asthma cost burden in children with severe or difficult-to-treat asthma based on asthma impairment. Children aged 6 to 12 years in The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens study with available data at baseline (n = 628), month 12 (n = 385), and month 24 (n = 280) corresponding to the National Heart, Lung, and Blood Institute asthma guidelines' impairment domain were included. Children were categorized as either very poorly controlled (VPC), not well controlled (NWC), or well controlled (WC) and assessed cross-sectionally and longitudinally. Mean total asthma costs based on direct (medication usage, unscheduled office visits, emergency department visits, hospitalizations) and indirect (school/work days lost) asthma costs were assessed. Mean annual total asthma costs were more than twice as high in the VPC group compared with NWC and WC groups (baseline: $7,846, $3,526, $3,766.44, respectively; month 12: $7,326, $2,959, $2,043, respectively; month 24: $8,879, $3,308, $1,861, respectively (all P < .001). Indirect costs accounted for approximately half the total asthma costs for VPC asthma patients at each time point. Significantly lower costs were observed for patients whose impairment status improved or temporarily improved from VPC after baseline. The economic burden of severe or difficult-to-treat asthma in children is associated with VPC asthma and improvement in asthma control and is associated with reducing cost. Further attention to patients with poorly controlled asthma, through better management strategies or more effective medications, may significantly reduce this burden of illness.	\N	\N
21803694	The use of experimental model systems has expedited the elucidation of pathogenetic mechanisms of renal developmental disease in humans and the identification of genes that orchestrate developmental programming during nephrogenesis. We conducted studies to evaluate the role of AHR polymorphisms in the disruption of renal developmental programming by benzo(a)pyrene (BaP). We used metanephric cultures of C57BL/6J (C57) mice expressing the Ahr(b-1) allele and B6.D2N-Ahr(d)/J (D2N) mice expressing a mutant allele deficient in ligand binding (Ahr(d)) to investigate molecular mechanisms of renal development. Deficits in fetal programming were evaluated in the offspring of pregnant mice treated with BaP during nephrogenesis. Hydrocarbon challenge of metanephri from C57 mice altered Wilms' tumor suppressor gene (Wt1) mRNA splice variant ratios and reduced mRNAs of the Wt1 transcriptional targets syndecan-1 (Sdc1) paired box gene 2 (Pax2), epidermal growth factor receptor (Egfr), and retinoic acid receptor, alpha (Rarα). These changes correlated with down-regulation of effectors of differentiation [secreted frizzled-related sequence protein 1 (Sfrp1), insulin-like growth factor 1 receptor (Igf1r), wingless-related MMTV-integration site 4 (Wnt4), Lim homeobox protein 1 (Lhx1), E-cadherin]. In contrast, metanephri from D2N mice were spared hydrocarbon-induced changes in Wt1 splice variant ratios and deficits of differentiation. We observed similar patterns of dysmorphogenesis and progressive loss of renal function at postnatal weeks 7 and 52 in the offspring of pregnant C57 but not D2N mice gavaged with 0.1 or 0.5 mg/kg BaP on gestation days 10-13. These findings support a functional link between AHR and WT1 in the regulation of renal morphogenesis and raise important questions about the contribution of human AHR polymorphisms to the fetal origins of adult-onset kidney disease.	\N	\N
21804097	Proper understanding of the roles of, and interactions between genetic, lifestyle, environmental and psycho-social factors in determining the risk of development and/or progression of chronic diseases requires access to very large high-quality databases. Because of the financial, technical and time burdens related to developing and maintaining very large studies, the scientific community is increasingly synthesizing data from multiple studies to construct large databases. However, the data items collected by individual studies must be inferentially equivalent to be meaningfully synthesized. The DataSchema and Harmonization Platform for Epidemiological Research (DataSHaPER; http://www.datashaper.org) was developed to enable the rigorous assessment of the inferential equivalence, i.e. the potential for harmonization, of selected information from individual studies. This article examines the value of using the DataSHaPER for retrospective harmonization of established studies. Using the DataSHaPER approach, the potential to generate 148 harmonized variables from the questionnaires and physical measures collected in 53 large population-based studies (6.9 million participants) was assessed. Variable and study characteristics that might influence the potential for data synthesis were also explored. Out of all assessment items evaluated (148 variables for each of the 53 studies), 38% could be harmonized. Certain characteristics of variables (i.e. relative importance, individual targeted, reference period) and of studies (i.e. observational units, data collection start date and mode of questionnaire administration) were associated with the potential for harmonization. For example, for variables deemed to be essential, 62% of assessment items paired could be harmonized. The current article shows that the DataSHaPER provides an effective and flexible approach for the retrospective harmonization of information across studies. To implement data synthesis, some additional scientific, ethico-legal and technical considerations must be addressed. The success of the DataSHaPER as a harmonization approach will depend on its continuing development and on the rigour and extent of its use. The DataSHaPER has the potential to take us closer to a truly collaborative epidemiology and offers the promise of enhanced research potential generated through synthesized databases.	\N	\N
21813382	Living donor liver transplantation (LDLT) has recently emerged as an effective therapeutic alternative for patients with end-stage liver disease. In the meantime, the health-related quality of life (HRQoL) of the donors is becoming better appreciated. Here we aimed to review the current literature and summarize the effects of liver donation on the long-term HRQoL of living donors. A literature search of PubMed using "donors", "living donor liver transplantation", "health-related quality of life", and "donation" was performed, and all the information was collected. The varied postoperative outcomes of liver donors are attributive to the different evaluation instruments used. On the whole, donors experienced good long-term physical and mental well-being with a few complaining of compromised quality of life due to mild symptoms or psychiatric problems. The psychosocial dimension has received increasing attention with the vocational, interpersonal and financial impact of liver donation on donors mostly studied. Generally, donors have a good HRQoL after LDLT. Nevertheless, to achieve an ideal donor outcome, further work is necessary to minimize the negative effects as well as to incorporate recent progress in regenerative medicine.	\N	\N
21824495	Sandfly fever (SF) is an arthropod-borne disease, which has not yet been reported from Ankara. In the summer of 2007, the disease started to be seen in our region, surprisingly causing severe clinical presentations. This report reviews the clinical and laboratory findings of patients with sandfly virus infection of disease outbreaks in 2008 and 2009. A retrospective single-centre descriptive study was performed. Clinically suspected cases were defined on the basis of epidemiologic history and clinical and laboratory findings. The sera samples of the suspected patients were sent to Germany for diagnostic assistance. 50 patients were included in the study. Fever, headache, photophobia, conjunctivitis, myalgia, arthralgia, nausea, abdominal pain and anorexia were common symptoms. Although the fever lasted only 3-6 days, complete recovery required up to 30 days. Leukopenia, thrombocytopenia and elevated serum aspartate-aminotransferase and alanine-aminotransferase levels were remarkable findings. The viral-load of Sandfly fever Turkey Virus (SFTV) was detected in the serum of acute patients ranged from 3.19×10(6) to 2.79×10(9) viral RNA molecules/ml. As a result we want to underline that the new type of sandfly virus causes a severe clinical picture with elevated liver enzymes and thrombocytopenia, to an extent not described before in the literature, which might be due to the elevated viral-load observed.	\N	\N
21832975	In the United States, approximately one in three new human immunodeficiency virus (HIV) infections are transmitted via heterosexual contact. To monitor HIV risk behaviors and HIV prevalence among heterosexuals and other populations, CDC surveys persons in selected metropolitan statistical areas (MSAs), using the National HIV Behavioral Surveillance System (NHBS). This report summarizes data collected from heterosexuals in 24 MSAs with a high prevalence of acquired immunodeficiency syndrome (AIDS) that participated in NHBS during 2006-2007. Of 14,837 heterosexuals aged 18-50 years who were interviewed and tested, 2.0% were HIV infected. HIV prevalence was higher among those with lower socioeconomic status (SES). For example, HIV prevalence was 2.8% among participants with less than a high school education compared with 1.2% among those with more than a high school education, 2.6% among participants who were unemployed compared with 1.0% among those who were employed, and 2.3% among participants with annual household incomes at or below the poverty level compared with 1.0% among those with incomes above the poverty level. This association between HIV prevalence and SES could not be attributed to factors commonly associated with HIV infection risk in heterosexuals, such as using crack cocaine, exchanging sex for things such as money or drugs, or being diagnosed with a sexually transmitted disease (STD). Based on the association observed between HIV prevalence and SES, HIV prevention activities targeted at heterosexuals in urban areas with high AIDS prevalence should be focused on those with lower SES.	\N	\N
21835304	A fundamental challenge in analyzing exome-sequence data is distinguishing pathogenic mutations from background polymorphisms. To address this problem in the context of a genetically heterogeneous disease, retinitis pigmentosa (RP), we devised a candidate-gene prioritization strategy called cis-regulatory mapping that utilizes ChIP-seq data for the photoreceptor transcription factor CRX to rank candidate genes. Exome sequencing combined with this approach identified a homozygous nonsense mutation in male germ cell-associated kinase (MAK) in the single affected member of a consanguineous Turkish family with RP. MAK encodes a cilium-associated mitogen-activated protein kinase whose function is conserved from the ciliated alga, Chlamydomonas reinhardtii, to humans. Mutations in MAK orthologs in mice and other model organisms result in abnormally long cilia and, in mice, rapid photoreceptor degeneration. Subsequent sequence analyses of additional individuals with RP identified five probands with missense mutations in MAK. Two of these mutations alter amino acids that are conserved in all known kinases, and an in vitro kinase assay indicates that these mutations result in a loss of kinase activity. Thus, kinase activity appears to be critical for MAK function in humans. This study highlights a previously underappreciated role for CRX as a direct transcriptional regulator of ciliary genes in photoreceptors. In addition, it demonstrates the effectiveness of CRX-based cis-regulatory mapping in prioritizing candidate genes from exome data and suggests that this strategy should be generally applicable to a range of retinal diseases.	\N	\N
21846442	Cardiac rhabdomyoma (CR) is the cardiac tumour most commonly diagnosed in utero. Eighty percent of CRs are associated with tuberous sclerosis (TS). TS is a rare multi-system disease, with autosomal dominant genetic transmission. If the parents of an affected child do not have features of TS, then either one parent is mosaic for the TS gene mutation or the affected child is the result of a de novo germline mutation. We present a case of a dizygotic twin pregnancy complicated by CRs in both fetuses at 24 weeks. Twin A died in utero at 28 weeks. Preterm labour and delivery of twin B occurred at 33 weeks. Twin B had multiple small CRs and a large apical CR. At six weeks after delivery, the CRs had disappeared or reduced in size. Regression in the third trimester or postnatally is the natural course of CRs. Molecular testing for TS identified two variants in the TSC2 gene. The parents were clinically unaffected; however, the father was subsequently found on an MRI of the head to have cortical tubers, and he was found to carry the pathogenic TSC2 mutation. Since dizygotic twin pregnancy is akin to two consecutive pregnancies, the etiology in our case is due to one parent having subclinical TS. To the best of our knowledge, this is the first such case to be reported.	\N	\N
21852013	We compared the intergenerational variations of the clinical phenotype between 30 patients affected with multiple autoimmune syndrome (MAS) and their affected first- and second-degree relatives. Mean age at onset was always significantly higher in the previous generation than in probands for all the considered diseases.	\N	\N
21852664	Observational studies have reported an association between metabolic syndrome (MetS) and microalbuminuria or proteinuria and chronic kidney disease (CKD) with varying risk estimates. We aimed to systematically review the association between MetS, its components, and development of microalbuminuria or proteinuria and CKD. DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS AND POPULATION: We searched MEDLINE (1966 to October 2010), SCOPUS, and the Web of Science for prospective cohort confidence interval (CI) studies that reported the development of microalbuminuria or proteinuria and/or CKD in participants with MetS. Risk estimates for eGFR <60 ml/min per 1.73 m(2) were extracted from individual studies and pooled using a random effects model. The results for proteinuria outcomes were not pooled because of the small number of studies. Eleven studies (n = 30,146) were included. MetS was significantly associated with the development of eGFR <60 ml/min per 1.73 m(2) (odds ratio, 1.55; 95% CI, 1.34, 1.80). The strength of this association seemed to increase as the number of components of MetS increased (trend P value = 0.02). In patients with MetS, the odds ratios (95% CI) for development of eGFR <60 ml/min per 1.73 m(2) for individual components of MetS were: elevated blood pressure 1.61 (1.29, 2.01), elevated triglycerides 1.27 (1.11, 1.46), low HDL cholesterol 1.23 (1.12, 1.36), abdominal obesity 1.19 (1.05, 1.34), and impaired fasting glucose 1.14 (1.03, 1.26). Three studies reported an increased risk for development of microalbuminuria or overt proteinuria with MetS. MetS and its components are associated with the development of eGFR <60 ml/min per 1.73 m(2) and microalbuminuria or overt proteinuria.	\N	\N
21855111	The EHF (Ets homologous factor) gene was previously shown to be overexpressed in ovarian/primary peritoneal serous carcinoma compared to malignant mesothelioma using gene expression arrays. The objective of this study was to validate this finding at the mRNA level in a larger series. We analyzed the diagnostic role of EHF in 98 ovarian serous carcinoma effusions, 23 malignant mesothelioma specimens (20 effusions, 3 surgical specimens), and 28 primary ovarian serous carcinomas using quantitative real-time polymerase chain reaction. Expression levels of EHF in ovarian carcinoma were additionally investigated for association with clinicopathologic parameters and survival. Quantitative real-time polymerase chain reaction analysis showed significantly higher expression of EHF mRNA in ovarian carcinoma effusions and in primary ovarian carcinoma compared to malignant mesothelioma effusions (P < .001 for both). EHF mRNA expression was additionally higher in primary ovarian carcinomas compared to effusions of this cancer (P < .001). In univariate analysis for all patients with effusions, higher EHF mRNA levels were associated with a trend for shorter progression-free survival (P = .066), which became significant in analysis of 45 patients with primary diagnosis pre-chemotherapy effusions (P = .01). In Cox multivariate analysis, EHF mRNA expression was an independent predictor of poor progression-free survival for all patients and patients with primary diagnosis pre-chemotherapy effusions (P = .033 and P = .009, respectively). EHF mRNA levels differentiate ovarian carcinoma from malignant mesothelioma and may thus be of diagnostic value in this setting. EHF may be a novel prognostic marker in ovarian carcinoma.	\N	\N
21872587	Decline in verbal fluency is the most consistent and persistent cognitive impairment documented after deep brain stimulation of the subthalamic nucleus in Parkinson's disease. The mechanisms of this deficit are unclear. We aimed to identify and characterise verbal fluency related processing within the subthalamic nucleus through analysis of local field potentials. Local field potentials were recorded from deep brain stimulation electrodes implanted in the subthalamic nuclei of 8 patients (16 sides) with Parkinson's disease, when patients were on medication. Patients performed phonemic and semantic verbal fluency tasks and a control word repetition task to control for the motor output involved in response generation. Significant increases in local field potential Power (p ≤ 0.05) were seen across a broad gamma frequency band (30-95 Hz) during both verbal fluency tasks, after controlling for motor output. Increases in gamma local field potential Power of +7.5% ± 2.3% (SEM) in the semantic fluency task and +6.9% ± 2.0% in the phonemic fluency task were derived when averaging across all electrode contact pairs. Gamma changes recorded from contacts lying in the left hemisphere (dominant in verbal fluency) correlated with average number of correct responses generated (r=0.81 p=0.015) and measures of 'switching' (r=0.79 p=0.020) particularly strongly in the semantic fluency task. Frequency specific power changes observed during task performance are consistent with involvement of the subthalamic nucleus in switching during verbal fluency. Antagonism of such task-related activity with high frequency stimulation of this nucleus may explain the impairments reported.	\N	\N
21876350	We proposed a new method to estimate dry weight (DW) using single frequency bioimpedance. We hypothesized that the change in whole body resistance at 50 kHz (R(50)) was proportional to the ultrafiltration volume (UFV) during a hemodialysis (HD) session. When the targeted resistance estimated in healthy subjects was reached, the patient achieved his/her DW. UFV and R(50) were monitored in 40 HD patients. Another 43 HD patients were stratified into 2 groups to validate this method. The change in whole body resistance was proportional to UFV in each of the 40 HD patients. In the DW(decrease) group, pre-dialysis systolic blood pressure (n = 29, 154.5 ± 22.8 vs. 146.9 ± 22.3, p < 0.05) and antihypertensive medicine (4.7 ± 3.6 vs. 3.3 ± 2.2, p < 0.05) decreased without adverse symptoms change. In the DW(increase) group, the number of adverse symptoms in 1 week (n = 14, 26 vs. 6, p < 0.05) decreased without a change in systolic blood pressure. This method may become a convenient and cheaper way to estimate DW in HD patients.	\N	\N
21884641	Breast cancer is a complex and heterogeneous disease. Gene expression profiling has contributed significantly to our understanding of this heterogeneity at a molecular level, refining taxonomy based on simple measures such as histological type, tumour grade, lymph node status and the presence of predictive markers like oestrogen receptor and human epidermal growth factor receptor 2 (HER2) to a more sophisticated classification comprising luminal A, luminal B, basal-like, HER2-positive and normal subgroups. In the laboratory, breast cancer is often modelled using established cell lines. In the present review we discuss some of the issues surrounding the use of breast cancer cell lines as experimental models, in light of these revised clinical classifications, and put forward suggestions for improving their use in translational breast cancer research.	\N	\N
21884662	Asthma is a frequent illness in young adults and is characterized by airway hyper responsiveness (AHR) and airway inflammation. Asthma is a complex disease and AHR as well as inflammation may be limited, although characteristic symptoms are present. The clinical experience in asthma treatment is that not all asthmatics have a satisfactory effect of the different drugs. Asthma has been found to develop from one disease to a multifaceted disease with numerous different possibilities. More research is needed in strategic asthma management in the search for tailored treatment strategy.	\N	\N
21889188	We report the sixth autopsy case of a patient with aceruloplasminemia. He was the younger brother of the first reported autopsy case of this disease. Among autopsy cases with aceruloplasminemia reported to date, he had the longest duration of neurologic disorders. The neuropathologic findings showed that the basal ganglia and dentate nuclei were most severely affected. The most striking finding in the present case was that marked iron deposition was evident in the cerebral cortex. Many enlarged or deformed astrocytes and globular structures, both of which were heavily iron loaded, were found in the cerebral cortex as well as in the basal ganglia. Pyramidal neurons in his cerebral cortex were fewer in number than observed in the previous reported cases. There was a negative correlation between the number of cortical pyramidal neurons and globular structures. The present case clearly indicates that the neuropathologic process in aceruloplasminemia extends beyond the basal ganglia to the cerebral cortex with time.	\N	\N
21889832	Higher radiation dose levels have been shown to be associated with improved tumor-control outcomes in localized prostate cancer (PCa) patients. Identify predictors of biochemical tumor control and distant metastases-free survival (DMFS) outcomes for patients with clinically localized PCa treated with conformal external-beam radiotherapy (RT) as well as present an updated nomogram predicting long-term biochemical tumor control after RT. This retrospective analysis comprised 2551 patients with clinical stages T1-T3 PCa. Median follow-up was 8 yr, extending >20 yr. Prescription doses ranged from 64.8 to 86.4 Gy. A total of 1249 patients (49%) were treated with neoadjuvant and concurrent androgen-deprivation therapy (ADT); median duration of ADT was 6 mo. A proportional hazards regression model predicting the probability of biochemical relapse and distant metastases after RT included pretreatment prostate-specific antigen (PSA) level, clinical stage, biopsy Gleason sum, ADT use, and radiation dose. A nomogram predicting the probability of biochemical relapse after RT was developed. Radiation dose was one of the important predictors of long-term biochemical tumor control. Dose levels < 70.2 Gy and 70.2-79.2 Gy were associated with 2.3- and 1.3-fold increased risks of PSA relapse compared with higher doses. Improved PSA relapse-free survival (PSA-RFS) outcomes with higher doses were observed for all risk groups. Use of ADT, especially for intermediate- and high-risk patients, was associated with significantly improved biochemical tumor-control outcomes. A nomogram predicting PSA-RFS was generated and was associated with a concordance index of 0.67. T stage, Gleason score, pretreatment PSA, ADT use, and higher radiation doses were also noted to be significant predictors of improved DMFS outcomes. Higher radiation dose levels were consistently associated with improved biochemical control outcomes and reduction in distant metastases. The use of short-course ADT in conjunction with RT improved long-term PSA-RFS and DMFS in intermediate- and high-risk patients; however, an overall survival advantage was not observed.	\N	\N
21890816	A multicentre cohort follow-up study of a large number of patients with gastric mucosa-associated lymphoid tissue (MALT) lymphoma was conducted to elucidate the long-term outcome of the disease after Helicobacter pylori eradication. 420 patients with gastric low-grade MALT lymphoma who had undergone successful H pylori eradication and been followed up for at least 3 years were registered from 21 participating institutes. Responders to treatment were defined as patients whose post-treatment biopsies showed complete histological response (ChR) or probable minimal residual disease (pMRD). Treatment failure was defined as the status of progressive disease or lymphoma relapse after ChR/pMRD. 323 patients (77%) responded to H pylori eradication. A logistic regression analysis showed that absence of H pylori, submucosal invasion determined by endoscopic ultrasonography and t(11;18)/API2-MALT1 were independent predictors of resistance to H pylori eradication. During the follow-up periods ranging from 3.0 to 14.6 years (mean 6.5 years, median 6.04 years), the disease relapsed in 10 of 323 responders (3.1%) while progressive disease was found in 27 of 97 non-responders (27%). Thus, 37 of 420 patients (8.8%) were regarded as treatment failures. Of these 37 patients, transformation into diffuse large B cell lymphoma occurred in nine patients. Among the non-responders and relapsed patients, 17 patients were subjected to a 'watch and wait' strategy while 90 patients underwent second-line treatments including radiotherapy (n=49), chemotherapy (n=26), surgical resection (n=6), chemoradiotherapy (n=5), antibiotic treatment (n=2), rituximab monotherapy (n=1) or endoscopic resection (n=1). Probabilities of freedom from treatment failure, overall survival and event-free survival after 10 years were 90%, 95% and 86%, respectively. Cox multivariate analysis revealed endoscopic non-superficial type to be an independent prognostic factor for adverse freedom from treatment failure, overall survival and event-free survival. The excellent long-term outcome of gastric MALT lymphoma after H pylori eradication was confirmed by this large-scale follow-up study.	\N	\N
21896508	The interaction between transcription factor (TF) and transcription factor binding site (TFBS) is essential for gene regulation. Mutation in either the TF or the TFBS may weaken their interaction and thus result in abnormalities. To maintain such vital interaction, a mutation in one of the interacting partners might be compensated by a corresponding mutation in its binding partner during the course of evolution. Confirming this co-evolutionary relationship will guide us in designing protein sequences to target a specific DNA sequence or in predicting TFBS for poorly studied proteins, or even correcting and rescuing disease mutations in clinical applications. Based on six, publicly available, experimentally validated TF-TFBS binding datasets for the basic Helix-Loop-Helix (bHLH) family, Homeo family, High-Mobility Group (HMG) family and Transient Receptor Potential channels (TRP) family, we showed that the evolutions of the TFs and their TFBSs are significantly correlated across eukaryotes. We further developed a mutual information-based method to identify co-evolved protein residues and DNA bases. This research sheds light on the dynamic relationship between TF and TFBS during their evolution. The same principle and strategy can be applied to co-evolutionary studies on protein-DNA interactions in other protein families. All the datasets, scripts and other related files have been made freely available at: http://jjwanglab.org/co-evo. junwen@uw.edu. Supplementary data are available at Bioinformatics online.	\N	\N
21904924	The distribution of complement component 4 (C4) gene copy number (GCN) has been validated in European populations. Meanwhile, C4 gene has been identified as a susceptibility gene for systemic lupus erythematosus (SLE). However, the association and the possible phenotype significance remain to be determined intensely in the Chinese population. This study was designed to validate the distribution of C4 GCNs in Chinese Han and the correlation between C4 GCNs and SLE using quantitative real-time polymerase chain reaction in 924 SLE patients and 1,007 controls. The results presented distribution of C4 GCNs in healthy populations and also showed that lower C4 GCN was a risk factor for SLE and higher C4 GCN was a protective factor against the disease susceptibility, which was similar to the report in the Caucasian population. Furthermore, we found the association between C4A GCN and disease subphenotypes of arthritis with SLE. We conclude that the association of C4 GCN with SLE was replicated in Chinese Han population, which highlighted the importance of C4 in SLE pathogenesis of diverse populations.	\N	\N
21912125	Women undergoing isolated coronary artery bypass graft (CABG) surgery have been previously shown to be at an independently increased risk for post-operative morbidity and mortality. However, there are considerably less data on whether this trend remains true in patients undergoing concomitant aortic valve replacement (AVR) and CABG surgery. The aim of our study was to investigate this pertinent issue. Data obtained between June 2001 and December 2009 by the Australasian Society of Cardiac and Thoracic Surgeons Cardiac Surgery Database Program were retrospectively analysed. Demographic, operative data and post-operative complications were compared between male and female patients using χ(2) and t tests. Long-term survival analysis was performed using Kaplan-Meier survival curves and the log-rank test. Independent risk factors for short- and long-term mortality were identified using binary logistic and Cox regression, respectively. Concomitant AVR and CABG surgery was undertaken in 2,563 patients; 31.8% were female. Female patients were older (mean age 76 vs. 73 years; p < 0.001) and presented more often with hypertension (p < 0.001) but less often with severely impaired ejection fraction (p < 0.001), peripheral vascular disease (p < 0.001) and triple vessel disease (p < 0.001). Women did not demonstrate an increased risk of 30-day mortality (4.8 vs. 3.3%) on univariate (p = 0.069) or multivariate (p = 0.236) analysis. Female gender was independently associated with post-operative myocardial infarction (p = 0.022) and red blood cell transfusion (p < 0.001). There was no difference in long-term survival between men and women on multivariate analysis (p = 0.413). Female gender is not associated with poorer short- or long-term outcomes after concomitant CABG and AVR surgery.	\N	\N
21913717	Hepatocellular carcinoma (HCC) is one of the leading causes of mortality from solid organ malignancy worldwide. Because of the complexity of proteins within liver cells and tissues, the discovery of therapeutic targets of HCC has been difficult. To investigate strategies for decreasing the complexity of tissue samples for detecting meaningful protein mediators of HCC, we employed subcellular fractionation combined with 1D-gel electrophoresis and liquid chromatography-tandem mass spectrometry analysis. Moreover, we utilized a statistical method, namely, the Power Law Global Error Model (PLGEM), to distinguish differentially expressed proteins in a duplicate proteomic data set. Mass spectrometric analysis identified 3045 proteins in nontumor and HCC from cytosolic, membrane, nuclear, and cytoskeletal fractions. The final lists of highly differentiated proteins from the targeted fractions were searched for potentially translocated proteins in HCC from soluble compartments to the nuclear or cytoskeletal compartments. This analysis refined our targets of interest to include 21 potential targets of HCC from these fractions. Furthermore, we validated the potential molecular targets of HCC, MATR3, LETM1, ILF2, and IQGAP2 by Western blotting, immunohistochemisty, and immunofluorescent microscopy. Here we demonstrate an efficient strategy of subcellular tissue proteomics toward molecular target discovery of one of the most complicated human disease, HCC.	\N	\N
21915990	Investigations of rare cell types in peripheral blood samples, such as tumor, fetal, and endothelial cells, represent an emerging field with several potentially valuable medical applications. Peripheral blood is a particularly attractive body fluid for the detection of rare cells as its collection is minimally invasive and can be repeated throughout the course of the disease. Because the number of rare cells in mononuclear cells can be very low (1 in 10 million), a large number of cells must be quickly screened, which places demanding requirements on the screening technology. While enrichment technology has shown promise in managing metastatic disease, enrichment can cause distortions of cell morphology that limit pathological identification, and the enrichment targeting adds additional constraints that can affect sensitivity. Here, we describe a new approach for detecting rare leukemia cells that does not require prior enrichment. We have developed an immunocytochemical assay for identification of leukemia cells spiked in peripheral blood samples, and a high-speed scanning instrument with high numerical aperture and wide field of view to efficiently locate these cells in large sample sizes. A multiplex immunoassay with four biomarkers was used to uniquely identify the rare cells from leukocytes and labeling artifacts. The cytometer preserves the cell morphology and accurately locates labeled rare cells for subsequent high resolution imaging. The sensitivity and specificity of the approach show promise for detection of a low number of leukemia cells in blood (1 in 10 million nucleated cells). The method enables rapid location of rare circulating cells (25 M cells/min), no specific enrichment step, and excellent imaging of cellular morphology with multiple immunofluorescent markers. The cell imaging is comparable to other imaging approaches such as laser scan cytometry and image flow cytometry, but the cell analysis rate is many orders of magnitude faster making this approach practical for detection of rare cells.	\N	\N
21916327	Serum dioxin studies of Vietnam (VN) veterans, military historical records of tactical herbicide use in Vietnam, and the compelling evidence of the photodegradation of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and other aspects of environmental fate and low bioavailability of TCDD are consistent with few, if any, ground troop veterans being exposed to Agent Orange. That conclusion, however, is contrary to the presumption by the Department of Veterans Affairs (DVA) that military service in Vietnam anytime from January 9, 1962 to May 7, 1975 is a proxy for exposure to Agent Orange. The DVA assumption is inconsistent with the scientific principles governing determinations of disease causation. The DVA has nonetheless awarded Agent Orange-related benefits and compensation to an increasing number of VN veterans based on the presumption of exposure and the published findings of the Institute of Medicine that there is sufficient evidence of a "statistical association" (a less stringent standard than "causal relationship") between exposure to tactical herbicides or TCDD and 15 different human diseases. A fairer and more valid approach for VN veterans would have been to enact a program of "Vietnam experience" benefits for those seriously ill, rather than benefits based on the dubious premise of injuries caused by Agent Orange.	\N	\N
21917357	To know the relative weight of the diagnosis of detrusor overactivity (DO) in the Urodynamic Units of Spain and relate the prevalence of the overactive bladder (OB) syndrome. An epidemiological, descriptive, retrospective, multicenter, national study conducted according to registered data in 47 Urodynamic Units covering the Spanish geographic area in the different areas of health distributed among the regional communities. These data inform about the health care received by 35% of the Spanish population. Urodynamic diagnoses and related variables, recorded during 2007 and 2008, were collected. A mean of 346.45 (SD=304.03) and 349.72 (SD=296.49) urodynamics studies per care unit were performed in women during 2007 and 2008, respectively and 181.20 (SD=212.71) and 195.68 (SD=257.58) in men. The relative weight of the diagnosis of non-neurogenic DO in women per unit was 31.39% and 35.28%, in 2007 and 2008, and in men was 21.06% and 20.43%. The diagnostic capacity of DO was 19.28 new cases per 100,000 inhabitants/year. The diagnosis of non-neurogenic DO in the woman accounts for one third of all the urodynamic/year diagnoses and more than half of the diagnoses of DO. In men, DO accounts for 25% of the diagnoses, the most frequent one being that associated with benign prostatic hyperplasia, followed by that of neurogenic cause. Approximately half of the DO diagnoses in children correspond to non-neurogenic DO. The differences between the capacity of diagnosis of DO (ratio per 100,000 inhabitants) is far from many of the estimations of the prevalence of OB (relationship %). The doubt may exist about whether part of this quota is secondary and not-idiopathic, given the large difference between the frequency of OB and the capacity of diagnosis of DO.	\N	\N
21917441	Idiopathic pulmonary fibrosis (IPF) is a lethal lung disorder of unknown etiology. The disease is likely the result of complex interactions between genetic and environmental factors. Evidence suggests that certain environmental factors, such as cigarette smoking and metal dust exposures, or comorbidities like gastroesophageal reflux, and type 2 diabetes mellitus (DM2) may increase risk to develop IPF. Substantial uncertainty remains, however, regarding these and other putative risk factors for IPF. In this study we performed a case-control analysis including 100 patients with IPF and 263 controls matched for age sex and place of residence. We used a structured questionnaire to identify potential risk factors for IPF, including environmental and occupational exposures as well as the relevance of family history of pulmonary fibrosis. The multivariate analysis revealed that family history of pulmonary fibrosis [OR = 6.1, CI95% 2.3-15.9; p < 0.0001] was strongly associated with increased risk of IPF. Actually, 20% of the cases reported a parent or sibling with pulmonary fibrosis. Gastroesophageal reflux [OR = 2.9, CI: 1.3-6.6; p = 0.007], former cigarette smoking [OR = 2.5, CI: 1.4-4.6, p = 0.003], and past or current occupational exposure to dusts, smokes, gases or chemicals [OR = 2.8, CI: 1.5-5.5; p = 0.002] were also associated with the disease. Despite being a significant risk factor on univariate analysis DM2 was not significant in multivariate analysis. These findings indicate that family history of pulmonary fibrosis is a strong risk factor for IPF. Also, we confirmed that occupational exposures, gastroesophageal reflux and former smoking increase the risk for this disease.	\N	\N
21918487	Although the use of embryonic stem cells to treat disease has caused much controversy, one type of stem cell treatment has slowly and steadily shown promise but has not engendered negative ethical media attention: the use of umbilical stem cells. Umbilical cord blood (UCB) contains stem cells that have already successfully treated a variety of diseases, including leukemias, lymphomas, hemoglobinopathies, immunodeficiencies, and disorders of metabolism; ongoing research continues to explore additional diseases for potential treatment. Cord blood can be stored in private banks or public banks. Private cord blood banks save cord blood for use by the family only, at a cost. Public cord blood banks accept donations and the cord blood is then used for the general public and/or research. A review of the literature finds that public banking is the preferred recommendation over private unless there is a known family member with a disease that can currently be treated with cord blood. This article discusses cord blood banking options as well as the ethical issues and barriers facing both healthcare providers and patients when dealing with cord blood banking.	\N	\N
21924425	Recent genome-wide association studies (GWAS) have identified associations with myocardial infarction and coronary artery disease (CAD), but the mechanisms underlying these associations remain largely unclear. Carotid intima-media thickness (IMT) is a measure of early arterial remodeling and arteriosclerosis. Therefore, if CAD associated SNPs are also associated with carotid IMT; it suggests that they are acting via the early stages of the atherosclerotic process. In three large community based independent populations (CAPS, KORA and Young Finns) of European ancestry in which common carotid IMT had been measured (total 4961 individuals), we determined whether SNPs that have been associated with CAD in GWAS studies are also associated with carotid IMT. Associations with plaque were not examined. We identified 11 SNPs and one haplotype previously associated with CAD. None of these were associated with common carotid IMT. We found no evidence that SNPs associated with CAD on GWAS are also associated with carotid IMT. This suggests these genetic associations are not acting via early vessel remodeling or early arteriosclerosis.	\N	\N
21925097	The aim of this pilot study was to evaluate the feasibility of long-term subcutaneous application of low-dose IL-2 in children with malignancies at very high risk of relapse who underwent highly T cell and B cell depleted HLA-identical (MUD) or full haplotype mismatched related hematopoetic stem cell transplantation. We studied 11 patients with acute leukemias / myelodysplastic syndrome and juvenile myelomonocytic leukemia (active disease and/or second stem cell transplantation, n = 8; ≥CR 2, n = 2) and relapsed or progressive Ewing's sarcoma (n = 2) who received prophylactic IL-2 treatment for a high probability of disease recurrence after allo-HSCT. Toxicities from IL-2 were transient fever, fatigue and local inflammation. In one patient GvHD grade III with no clear association to IL-2 administration occurred. IL-2 administration was started at median day 57 (range 13-154) post-transplant for a mean duration of 28 days (range 15-250). IL-2 administration clearly increased NK cell activity. 3 of 11 patients (ALL, AML, multifocal Ewings sarcoma) survived with a follow-up of ten years. In conclusion, long-term low-dose IL-2 subcutaneous application is feasible in children due to a low side effect profile even after HLA mismatched transplantation and may be a strategy to prevent relapse in pediatric malignancies with extremely high risk of relapse.	\N	\N
21926372	Ryanodine receptor 1 (RyR1) is a Ca(2+) release channel located in the sarcoplasmic reticulum membrane of skeletal muscle. More than 200 variants in RyR1 have been identified in DNA from patients with malignant hyperthermia (MH) and congenital myopathies; only 30 have been sufficiently studied so as to be identified as MH-causative mutations. The Ala4894Thr RyR1 variant was found in a Japanese patient with susceptibility to MH, and the Ala4894Pro variant in a rare case of myopathy: congenital neuromuscular disease with uniform type 1 fiber (CNMDU1). We hypothesized that different Ala4894 variants of RyR1 cause different pathophysiological changes that are identifiable by having differing pharmacological sensitivities to RYR1 agonists. Expression vector with a mutation in RYR1 corresponding to the Ala4894Thr, Ala4894Pro, Ala4894Ser, or Ala 4894Gly variant of human RyR1 was transfected into human embryonic kidney 293 cells. At 72 hours after transfection, we determined the intracellular Ca(2+) changes induced by caffeine and 4-chloro-m-cresol (4CmC), in the presence or absence of dantrolene. Ala4894Thr-transfected cells and Ala4894Ser-transfected cells were more sensitive to caffeine than the wild type, and Ala4894Thr-transfected cells were also more sensitive to 4CmC than the wild type, whereas Ala4894Pro-transfected cells had no response to caffeine or 4CmC. Ala4894Gly-transfected cells were significantly less sensitive to caffeine than the wild type. In addition, the responses of Ala4894Thr-transfected cells and Ala4894Ser-transfected cells to caffeine were suppressed by dantrolene. We concluded that different Ala4894 variants of RyR1 lead to different agonist/antagonist sensitivities, which may predict differing RYR1 functionality during excitation-contraction coupling and sensitivity to MH. The hypersensitive Ala4894Thr-RyR1 is associated with MH and the poorly functional Ala4894Pro-RyR1 with CNMDU1.	\N	\N
21934067	The role of CRP as a regulator of inflammation is not fully understood. Structural rearrangement in CRP results in expression of potent proinflammatory actions. Proteolysis of CRP yields the C-terminal peptide Lys(201)-Pro-Gln-Leu-Trp-Pro(206). Here, we investigated the impact of this peptide on neutrophil interactions with endothelial cells and platelets, critical inflammatory events triggering acute coronary artery disease. CRP peptide 201-206 induced L-selectin shedding from human neutrophils and inhibited L-selectin-mediated neutrophil adhesion to TNF-α-activated HCAECs under nonstatic conditions. CRP peptide 201-206 also attenuated shear-induced up-regulation of platelet P-selectin expression, platelet capture of neutrophils, and subsequent homotypic neutrophil adhesion in human whole blood. Anti-CD32 but not anti-CD16 or anti-CD64 mAb effectively prevented the inhibitory actions of CRP peptide 201-206. Substitution of Lys(201), Gln(203), or Trp(205) with Ala in CRP peptide 201-206 resulted in loss of the biological activities, whereas peptides in which Pro(202), Leu(204), or Pro(206) was substituted with Ala retained biological activity. We identified amino acid residues involved in CRP peptide 201-206-FcγRII (CD32) interactions, which mediate potent antineutrophil and antiplatelet adhesion actions, and these findings open up new perspectives for limiting inflammation and thrombosis underlying coronary artery disease.	\N	\N
21935854	A 65-year-old woman presented with reduced general condition and dyspnoea that was progressive over the last months. Clinical findings revealed an exophthalmus on the right, xanthelasm and mild peripheral oedema. Previously, a pericardiocentesis had been performed due to a large pericardial effusion. A previous CT scan showed a mass attached to the pericardium extending through the atrio-ventricular groove and a thickened aorta. In addition, a retroperitoneal fibrosis and an occlusion of both Aa. iliacae internae were found. The ECG showed sinus rhythm. Laboratory findings demonstrated a microcytic anemia and a renal failure. Chest radiography showed a large cardiac silhouette, while the transthoracic echocardiography revealed a recurrent large pericardial effusion. A PET/CT scan of the chest and abdomen showed a tissue infiltration of the retroperitoneal structures, a mass surrounding the right coronary artery and the right orbita. Finally, a femur biopsy confirmed the diagnosis of Erdheim-Chester disease. With the diagnosis Erdheim-Chester disease we started a high dose immunsuppressive therapy using glucocorticoids and interferon-a. Tumour size slightly decreased during the following 2 months, however the patient developed a severe urosepsis and died from multiorgan failure. We report a case of an Erdheim-Chester disease with cardiovascular involvement primarily diagnosed due to a recurrent large pericardial effusion. In case of cardial tumors with interatrial septum or coronary artery involvement together with cerebral manifestations, an Erdheim-Chester disease should be taken into account.	\N	\N
21938677	Cyclosporine A is a potent immunosuppressant used to prevent organ transplant rejection and treat various autoimmune diseases. However, cyclosporine A can also induce gingival overgrowth, which is characterized by increased extracellular matrix due to an altered balance between collagen synthesis and degradation. This study proposed to verify whether trans-glutaminase 2, an enzyme thought to be responsible for the assembly and remodelling of extracellular matrix, plays any role in the pathogenesis of cyclosporine A-induced gingival overgrowth. Cyclosporine A-induced gingival overgrowths were collected from 21 liver transplant patients and case-controlled with 20 non-hyperplastic gingival biopsies from healthy patients who had previous periodontal treatment. In both groups, the presence and tissue distribution of transglutaminase 2 were determined by immunohistochemistry and analyzed in comparison with the tissue morphology and expression of lymphocyte-related antigens (CD3 and CD20) and a vessel-related marker (CD34). Transglutaminase 2 expression showed a significant increase (2.6-fold) in the stromal component of cyclosporine A-treated patients compared with controls (p<0.001), which suggested that transglutaminase 2 had a role in the pathogenesis of the disease. Further studies should investigate the therapeutic effect of anti-transglutaminase 2 drugs (putrescine or 1,4-diamino-butane) in these patients.	\N	\N
21946897	Genetic factors may play a role in fibrosis progression in patients with chronic hepatitis C (CHC). A cirrhosis risk score (CRS7) with seven single nucleotide polymorphisms was previously shown to correlate with cirrhosis in patients with CHC. This study aimed to assess the validity of CRS7 as a marker of fibrosis progression and cirrhosis and as a predictor of clinical outcomes in patients with CHC. A total of 938 patients (677 Caucasians, 165 African-Americans, and 96 Hispanic/Other) in the Hepatitis C Antiviral Long-term Treatment against Cirrhosis Trial were studied. CRS7 was categorized a priori as high risk (n=440), medium risk (n=310), or low risk (n=188). Patients were assessed for four possible outcomes: fibrosis progression, cirrhosis, clinical outcomes [decompensation or hepatocellular carcinoma (HCC)], or HCC alone. Twenty-nine percent (142/493) developed an increase in fibrosis score by greater than or equal to 2 points on follow-up biopsies, 58% had cirrhosis on one or more biopsies, 35% developed at least one clinical outcome, and 13% developed HCC. CRS7 (trend test) was associated with risk for fibrosis progression (P=0.04) with adjusted hazard ratio of 1.27 (95% confidence interval: 1.01-1.58) and with cirrhosis (P=0.05) with adjusted odds ratio of 1.19 (1.00-1.41). Rates of HCC and clinical outcomes were increased in patients with higher CRS7 scores, but were not statistically significant (P=0.12 clinical outcomes, and P=0.07 HCC). A single nucleotide polymorphism in AZIN1 was significantly associated with fibrosis progression. CRS7 was validated as a predictor of fibrosis progression and cirrhosis among Hepatitis C Antiviral Long-term Treatment against Cirrhosis patients, who all had advanced fibrosis. CRS7 was not predictive of clinical outcome.	\N	\N
21953291	Although tumor reduction via present-day prehepatectomy chemotherapy can render initially unresectable disease potentially resectable, little is known about the effects of such chemotherapy on liver metastases with known attachment to or invasion of major intrahepatic vessels. We histologically assessed the relationships of liver tumors to major intrahepatic vessels after chemotherapy. In 45 patients who underwent chemotherapy and hepatectomy with pretreatment images showing metastases attached to or invading major intrahepatic vessels, 77 metastases showed attachment to or invasion of 96 vessels. Using postchemotherapy imaging, 11 of 77 metastases (14.3%) appeared separated from 12 of 96 major hepatic vessels (12.5%). Among 83 vessels later examined pathologically, 29 showed direct invasion (35%) and 10 showed attachment (12%). Tumors involved another 9 vessels (11%) that were separated surgically from the tumor and preserved during hepatectomy. Tumor attachment that exceeded 25% of vessel circumferences via imaging after chemotherapy was a factor associated with pathological vascular invasion or attachment according to multivariate analysis (relative risk, 8.449; 95% confidence interval, 1.961-36.415; P = .0042). Liver metastasis attachment to or invasion of major intrahepatic vessels is difficult to eradicate even with otherwise effective chemotherapy.	\N	\N
21955617	Osteoarthritis (OA) is a degenerative joint disease characterized by progressive loss of articular cartilage, subchondral bone sclerosis, osteophyte formation, and synovial inflammation, causing substantial physical disability, impaired quality of life, and significant health care utilization. Traditionally, non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase (COX)-2 inhibitors, have been used to treat pain and inflammation in OA. Besides its anti-inflammatory properties, evidence is accumulating that celecoxib, one of the selective COX-2 inhibitors, has additional disease-modifying effects. Celecoxib was shown to affect all structures involved in OA pathogenesis: cartilage, bone, and synovium. As well as COX-2 inhibition, evidence indicates that celecoxib also modulates COX-2-independent signal transduction pathways. These findings raise the question of whether celecoxib, and potentially other coxibs, is more than just an anti-inflammatory and analgesic drug. Can celecoxib be considered a disease-modifying osteoarthritic drug? In this review, these direct effects of celecoxib on cartilage, bone, and synoviocytes in OA treatment are discussed.	\N	\N
21959310	We report 9 patients with pleural biopsies referred because of concern about infiltration of what appeared to be chest wall fat by pan-keratin-positive spindled cells, a finding that led to a consideration of desmoplastic mesothelioma. All patients showed pleural effusions/pleural thickening on computed tomographic scan. Pleural biopsy showed a greatly thickened and fibrotic paucicellular pleura with circular fat-like spaces and, sometimes, adjacent oblate spaces mostly deep in the fibrotic area. Indistinct, keratin-positive, spindle cells arranged parallel to the pleural surface coursed between these fat-like spaces. S-100 stains were negative around the fat-like spaces. Vimentin stains showed that the spaces did not have a cellular lining of any kind. Sometimes the spaces contained faintly hematoxyphilic material that was Alcian blue positive, and similar material was seen in the fibrotic stroma. Follow-up with periods ranging from 6 to 30 months revealed that 8 cases had stable disease on chest imaging or by clinical findings. One case had slowly progressive pleural thickening. These observations suggest that spaces resembling fat may be encountered in fibrotic pleurae and that horizontally oriented keratin-positive spindled cells between the fat-like spaces deep in the fibrotic portion of a thickened pleura represent a benign finding seen in some cases of organizing pleuritis/fibrothorax. The spaces themselves are probably artifacts derived from the biopsy procedure and/or cutting artifacts. In contrast, in true desmoplastic mesotheliomas there is downward, rather than horizontal, growth of keratin-positive spindled cells running between clearly definable fat cells.	\N	\N
21963153	Multimorbidity is increasing in frequency. It can be quantitatively measured and is a major correlate of high use of health services resources of all types, especially over time. The ACG System for characterizing multimorbidity is the only widely used method that is based on combinations of different TYPES of diagnoses over time, rather than the presence or absence of particular conditions or numbers of conditions. It incorporates administrative data (as from claims forms or medical records) on all types of encounters and is not limited to diagnoses captured during hospitalizations or other places of encounter. It can be employed in any one or combination of analytic models, and can incorporate medication use if desired. It is being used in clinical care, management of health services resources, in health services research to control for degree of morbidity, and in understanding morbidity patterns over time. In addition to its research uses, it is being employed in many countries in various applications as a policy to better understand health needs of populations and tailor health services resources to health needs.	\N	\N
21970661	Toxoplasma gondii is a major cause of chronic parasitic infection in the world. This protozoan can cause retino-choroiditis in newborns and in adults, both immunocompetent and immunodeficient. This disease tends to be recurrent and can lead to severe visual impairment. The authors review current knowledge on the role of parasite genetics in influencing susceptibility to ocular toxoplasmosis and on the immuno-pathogenesis of this disease.	\N	\N
21971930	The development of drug resistance represents a major complication in the effective treatment of breast cancer. Epigenetic therapy, through the use of histone deacetylase inhibitors (HDACi) or demethylation agents, is an emerging area of therapeutic targeting in a number of ontological entities, particularly in the setting of aggressive therapy-resistant disease. Using the well-described HDAC inhibitor trichostatin A (TSA) we demonstrate the suppression of in vitro clonogenicity in the previously described apoptosis-resistant MCF-7TN-R breast carcinoma cell line. Additionally, recent work has demonstrated that these agents can alter the expression profile of microRNA signatures in malignant cells. Using an unbiased microRNA microarray analysis, changes in miRNA expression of MCF-7TN-R cells treated with TSA for 24 h were analyzed. We observed significant up-regulation of 22 miRNAs and down-regulation of 10 miRNAs in response to TSA treatment. Our results demonstrate that the HDACi, TSA, exerts anticancer activity in the apoptosis-resistant MCF-7TN-R breast carcinoma cell line. This activity is correlated with TSA alteration of microRNA expression profiles indicative of a less aggressive phenotype.	\N	\N
21973247	Mortality level and cause of death trends are evaluated to chart the epidemiological transition in Fiji. IMPLICATIONS for current health policy are discussed. Published data for infant mortality rate (IMR), life expectancy (LE) and causes of death for 1940-2008 were assessed for quality, and compared with mortality indices generated from recent Ministry of Health death recording. Trends in credible mortality estimates are compared with trends in proportional mortality for cause of death. IMR declined from 60 deaths (per 1,000) in 1945 to below 20 by 2000. IMR for 2006-08 is estimated at 18-20 deaths per 1,000 live births. Excessive LE estimates arise by imputing from the IMR using inappropriate models. LE increased, but has been stable at 64 years for males and 69 years for females since the late 1980s and early 1990s respectively. Proportional mortality from diseases of the circulatory system has increased from around 20% in the 1960s to more than 45%. Extensive variation in published mortality estimates was indentified, including clearly incompatible ranges of IMR and LE. Mortality decline has stagnated. Relatively low IMR and proportional mortality trends suggest this is largely due to chronic diseases (especially cardiovascular) in adults. Reconciliation of mortality data in Fiji to reduce uncertainty is urgently needed. Fiji's health services and donor partners should place continued and increased emphasis on effective control strategies for cardiovascular disease.	\N	\N
21978795	Objective of this study was to evaluate the acute cardiovascular and respiratory effects of switching on the deep brain stimulation in the follow up of nine Parkinson's disease patients with subthalamic nucleus stimulation and six cluster headache patients with posterior hypothalamic area stimulation. Systolic and diastolic blood pressure, heart rate, and respiratory rate were monitored continuously during supine rest in both groups. Each patient was assessed in two conditions: resting supine with stimulator off and with stimulator on. In supine resting condition switching on the DBS induced no significant changes (p>0.05) in systolic and diastolic blood pressure as well as in heart rate and respiratory rate, in both groups of patients, either taking 1 min or 10 heartbeats as a sample for analysis. Switching on the DBS does not modify heart rate, blood pressure nor respiratory rate in both Parkinson and cluster headache patients under resting conditions.	\N	\N
21985741	Rarely, a patient presents to a surgeon for evaluation of an adrenal incidentaloma where the final pathology is primary malignancy. For primary adrenal lymphoma, fewer than 100 cases have been reported in the literature. We report a case of unilateral primary adrenal aggressive B cell lymphoma discovered incidentally in a 41-year-old female. Preoperative testing demonstrated the 6-cm mass to be biochemically silent. Subsequently, the patient underwent a laparoscopic adrenalectomy. Following pathologic diagnosis of B cell lymphoma, a metastatic workup was negative, and she underwent treatment with systemic chemotherapy. She is currently disease free 6 months postoperatively. Primary adrenal lymphoma should be considered in patients with unilateral adrenal incidentaloma. We believe that adherence to guidelines of resection of incidentalomas allowed for early surgical intervention and possible cure.	\N	\N
21986202	Parkinson's disease is a common neurodegenerative disorder characterized by α-synuclein (α-Syn)-containing Lewy body formation and selective loss of dopaminergic neurons in the substantia nigra. We have demonstrated the modulating effect of noopept, a novel proline-containing dipeptide drug with nootropic and neuroprotective properties, on α-Syn oligomerization and fibrillation by using thioflavin T fluorescence, far-UV CD, and atomic force microscopy techniques. Noopept does not bind to a sterically specific site in the α-Syn molecule as revealed by heteronuclear two-dimensional NMR analysis, but due to hydrophobic interactions with toxic amyloid oligomers, it prompts their rapid sequestration into larger fibrillar amyloid aggregates. Consequently, this process rescues the cytotoxic effect of amyloid oligomers on neuroblastoma SH-SY5Y cells as demonstrated by using cell viability assays and fluorescent staining of apoptotic and necrotic cells and by assessing the level of intracellular oxidative stress. The mitigating effect of noopept against amyloid oligomeric cytotoxicity may offer additional benefits to the already well-established therapeutic functions of this new pharmaceutical.	\N	\N
21987744	The filoviruses, Marburg virus and Ebola virus, cause severe hemorrhagic fever with a high mortality rate in humans and nonhuman primates. Among the most-promising filovirus vaccines under development is a system based on recombinant vesicular stomatitis virus (rVSV) that expresses a single filovirus glycoprotein (GP) in place of the VSV glycoprotein (G). Importantly, a single injection of blended rVSV-based filovirus vaccines was shown to completely protect nonhuman primates against Marburg virus and 3 different species of Ebola virus. These rVSV-based vaccines have also shown utility when administered as a postexposure treatment against filovirus infections, and a rVSV-based Ebola virus vaccine was recently used to treat a potential laboratory exposure. Here, we review the history of rVSV-based vaccines and pivotal animal studies showing their utility in combating Ebola and Marburg virus infections.	\N	\N
21994137	Proctitis is a common problem and is most frequently associated with inflammatory bowel diseases. However, the incidence of infectious proctitis appears to be rising, especially in men who have sex with men. This may be due to the rise of people participating in receptive anal sex as well as the increase in sexually transmitted infections. The most frequently reported pathogens include Neisseria gonorrhoeae, Chlamydia trachomatis, Treponema pallidum, and herpes simplex. Symptoms of infectious proctitis can include rectal blood and mucous discharge, anorectal pain, ulcers, and occasionally lymphadenopathy and fever. History and physical examination are crucial in establishing a diagnosis, supported by endoscopy, histology, serology, culture and PCR. Treatment with antibiotics or antivirals is usually initiated, either empirically or after establishing a diagnosis. Co-infections, HIV testing, and treatment of sexual partners should always be considered.	\N	\N
22002662	The destruction of blood-brain barrier (BBB) and blood-nerve barrier (BNB) has been considered to be a key step in the disease process of a number of neurological disorders including cerebral ischemia, Alzheimer's disease, multiple sclerosis, and diabetic neuropathy. Although glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) facilitate neuronal or axonal regeneration in the brain or peripheral nerves, their action in the BBB and BNB remains unclear. The purpose of the present study was to elucidate whether these neurotrophic factors secreted from the brain or peripheral nerve pericytes increase the barrier function of the BBB or BNB, using our newly established human brain microvascular endothelial cell (BMEC) line or peripheral nerve microvascular endothelial cell (PnMEC) line. GDNF increased the expression of claudin-5 and the transendothelial electrical resistance (TEER) of BMECs and PnMECs, whereas BDNF did not have this effect. Furthermore, we herein demonstrate that the GDNF secreted from the brain and peripheral nerve pericytes was one of the key molecules responsible for the up-regulation of claudin-5 expression and the TEER value in the BBB and BNB. These results indicate that the regulation of GDNF secreted from pericytes may therefore be a novel therapeutic strategy to modify the BBB or BNB functions and promote brain or peripheral nerve regeneration.	\N	\N
22010196	The eukaryotic cell is organized into membrane-covered compartments that are characterized by specific sets of proteins and biochemically distinct cellular processes. The appropriate subcellular localization of proteins is crucial because it provides the physiological context for their function. In this Commentary, we give a brief overview of the different mechanisms that are involved in protein trafficking and describe how aberrant localization of proteins contributes to the pathogenesis of many human diseases, such as metabolic, cardiovascular and neurodegenerative diseases, as well as cancer. Accordingly, modifying the disease-related subcellular mislocalization of proteins might be an attractive means of therapeutic intervention. In particular, cellular processes that link protein folding and cell signaling, as well as nuclear import and export, to the subcellular localization of proteins have been proposed as targets for therapeutic intervention. We discuss the concepts involved in the therapeutic restoration of disrupted physiological protein localization and therapeutic mislocalization as a strategy to inactivate disease-causing proteins.	\N	\N
22011558	Although moderate alcohol drinkers have lower rates of incident coronary artery disease than abstainers, much less is known about the health effects of different patterns of alcohol use in women with established coronary artery disease. In the Determinants of Myocardial Infarction Onset Study, 1,253 women hospitalized for acute myocardial infarction (MI) at 64 centers nationwide from 1989 to 1996 were followed for mortality through December 31, 2007. Of the women, 761 (61%) reported abstention in the year before their MIs, 280 (22%) reported consumption of <1 serving/week, 75 (6%) reported consumption of 1 to 3 servings/week, and 137 (11%) reported consumption of ≥3 servings/week. Using Cox proportional-hazards models, the associations between total weekly volume of consumption, drinking days per week, drinks per drinking day, and beverage type with 10-year mortality were investigated, adjusting for clinical and socioeconomic potential confounders. Compared with abstention, adjusted hazard ratios were 0.66 (95% confidence interval 0.50 to 0.86) for <1 serving/week, 0.65 (95% confidence interval 0.38 to 1.11) for 1 to 3 servings/week, and 0.65 (95% confidence interval 0.38 to 1.11) for ≥3 servings/week (p for trend = 0.008). No differences were found by beverage type, and generally inverse associations of drinking frequency and quantity with mortality were found. In conclusion, in women who survive MI, moderate drinking is associated with a decreased risk for mortality, with no clear differences on the basis of pattern or beverage type. These results suggest that women who survive MI need not abstain from alcohol, but any derived benefit would appear to occur well below currently recommended limits in alcohol consumption.	\N	\N
22015458	Cholangitis arising from biliary infection dominates the prognosis in Caroli's disease. To clarify the influences of bacterial infection on the biliary cystogenesis, in vivo and in vitro studies were performed using the polycystic kidney (PCK) rat as an animal model of Caroli's disease. Cholangitis became a frequent histological finding in aged PCK rats, and neovascularization around the bile ducts also increased in aged PCK rats. Immunohistochemistry revealed that expression of vascular endothelial growth factor (VEGF) was increased in PCK rat biliary epithelium. In vitro, PCK cholangiocytes overexpressed VEGF, and the supernatant of cultured PCK cholangiocytes significantly increased the proliferative activity, migration, and tube formation of cultured rat vascular endothelial cells. Stimulation with lipopolysaccharide (LPS) further induced VEGF expression in PCK cholangiocytes, which might be mediated by signaling pathways involving phosphatidylinositol 3-kinase (PI3K)-Akt and c-Jun N-terminal kinase (JNK). Both LPS and VEGF increased cell proliferative activity in PCK cholangiocytes, and siRNA against VEGF significantly reduced LPS-induced cell proliferation. Thus, LPS-induced overexpression of VEGF in the biliary epithelium may lead to hypervascularity around the bile ducts; concurrently, LPS and VEGF act as cell proliferation factors for cholangiocytes. Biliary infection may thus exacerbate biliary cystogenesis in PCK rats.	\N	\N
22016594	We investigated the clinical characteristics and prognosis of elderly patients with acute lymphoblastic leukemia (ALL). We reviewed the clinical data, laboratory findings, bone marrow findings, and cytogenetic analysis of elderly patients (≥ 60 years) with ALL, and data of an additional 101 younger adult patients (< 60 years) with ALL were reviewed for comparison. Twenty-six elderly patients (≥ 60 years) and 101 younger adult patients (< 60 years) with ALL were retrospectively enrolled. The median follow-up duration was 6.0 months (range, 0.4 to 113.2) in the elderly patients and 21.7 months (range, 1.0 to 122.7) in the adult patients. In total, 34.6% (9 patients) of the elderly patients and 24.8% (25 patients) of the adult patients had Philadelphia chromosome positive ALL. The overall complete remission (CR) rate was much higher in the younger than in the elderly patients (94.1% vs. 57.7%, p < 0.001). The median overall survival (OS) of the younger patients (< 60 years) was 26.3 months, whereas that of the elderly patients (≥ 60 years) was 10.3 months (p = 0.003). In the elderly patients with ALL, T cell lineage and the presence of lymphadenopathy were significant prognostic factors for OS in a univariate analysis (p = 0.033 and 0.041, respectively). The outcomes of Korean elderly patients with ALL were poor, and the shorter OS was mainly due to the low CR rate. T-cell lineage and the presence of lymphadenopathy were significant prognostic factors in Korean elderly patients with ALL.	\N	\N
22017219	Several genetic loci have been suggested to be associated with bipolar disorder but results have been inconsistent. Studying associations between bipolar symptoms and candidate genes may better expose this relationship. Here we investigate the association between bipolar key symptoms and the P2RX7 gene. Key symptoms of mania were rated in two sets of medicated bipolar disorder patients (n=171 and n=475) at two specialized outpatient clinics for affective disorders and three regular psychiatric outpatient units in Sweden. The relationships between all manic symptoms according to DSM-IV were entered in a principal component analysis. We used a case-case model to reduce the genetic heterogeneity and tested associations between four factors related to manic symptoms and their association to four single nucleotide polymorphisms in the P2RX7 gene. The combination of the cognitive symptoms, distractibility, talkativeness, and thought disorder was significantly associated with rs1718119 in the P2RX7 gene in Set 1 [odds ratio (OR) = 1.78; p=0.011]. The association was re-tested in the second set (OR = 1.42; p=0.009). In the total sample, the association was even stronger (OR = 1.49; p<0.001). None of the other factors was associated with the P2RX7 gene. Within the first factor, the distractibility symptom accounted for a significant portion of the association to rs1718119 (p=0.016). There is an association between specific symptoms of bipolar disorder and the P2RX7 gene. This finding may open up new approaches to elucidating the neurobiology behind bipolar symptoms.	\N	\N
22018216	Although endoscopy and angiography have changed the management of lower gastrointestinal bleeding and the majority of patients respond to conservative treatment 10-20% of cases have no recognizable site of hemorrhage. About 10-30% of all patients will require operative intervation. A very rare case of massive lower gastrointestinal bleeding in a young patient who was found to suffer from two causes of gastrointestinal hemorrhage in the same time is reported. The patient had to undergo surgery for the control of bleeding. A 23 years old male Greek patient presented to the emergency department of our hospital because of three episodes of hematochezia during the last 10 hours. He was admitted to the surgical department for monitoring of his condition. In the next 10 hours the hematochezia continued and the patient although being transfused with three units of packed red blood cells, started to become unstable with his vital signs affected, having also a syncoptic episode. Emergent colonoscopy could not recognize the site of hemorrhage or any other pathology in the colon, but revealed an intestinal lumen full of blood from the anus to the cecum. It was decided that the patient should undergo operation to stop bleeding. An extensive right hemicolectomy was performed. After that the patient remained stable and showed no signs of hemorrage. The histopathological examination of the specimen showed an arteriovenous malformation but also lesions of the mucosa compatible with early inflammatory bowel disease. In young patients with massive lower gastrointestinal bleeding of unknown origin, extensive right hemicolectomy provides a good and safe therapeutic choice that will control hemorrhage in most cases with the advantage of lower mortality and morbidity rates compared to subtotal colectomy. Close monitoring of the patient postoperatively is essential.	\N	\N
22023956	Atherosclerotic carotid artery disease remains an important cause of cerebrovascular ischemic disease. We present a patient with residual stenosis of the distal internal carotid artery following carotid endarterectomy that was treated with stenting. The case highlights the potential complimentary benefits of carotid endarterectomy and carotid stenting.	\N	\N
22026553	Evidence suggests that occult adenoma remnants are responsible for persistent Cushing's disease (CD) following transsphenoidal surgery (TSS). To optimize the outcome, we have adapted our microsurgical concept. The influence of our surgical strategy on remission rate and pituitary function is presented. 83 patients undergoing TSS for newly diagnosed CD. An enlarged resection was performed in 36 patients. A modified exploration technique with radial incisions was performed in 19 patients in whom an adenoma was not readily detectable. The overall remission rate of primary surgery was 84·3% (70/83). A remission rate of 87·5% (63/72) was achieved in microadenomas. Six patients with microadenomas were re-operated for persistence, and hypercortisolism was corrected in five of them. With re-operation included, the overall remission rate for microadenomas was 94·4%. No procedure-related complications occurred in primary surgery. Of the patients in remission, 72·5% had early postoperative random cortisol levels below 2 μg/dl, 17·4% had cortisol levels between 2 and 5 μg/dl, and 10·1% had cortisol levels >5 μg/dl. 15·2% of the patients with microadenomas developed postoperative partial hypopituitarism and 3% diabetes insipidus. No increased rate of hypopituitarism was found with enlarged adenomectomy compared to selective adenomectomy. Only a slightly higher rate of partial hypopituitarism (23·1%) was found if extensive exploration was required. With our microsurgical concept, a high initial cure rate is achievable with minimal surgical morbidity. Enlarged adenomectomy has no adverse effect on the rate of postoperative hypopituitarism. Early repeat surgery is a successful option if CD persists.	\N	\N
22034985	Earlier, we identified proteins connecting different disease proteins in the human protein-protein interaction network and quantified their mediator role. An analysis of the networks of these mediators shows that proteins connecting heart disease and diabetes largely overlap with the ones connecting heart disease and obesity. We quantified their overlap, and based on the identified topological patterns, we inferred the structural disease-relatedness of several proteins. Literature data provide a functional look of them, well supporting our findings. For example, the inferred structurally important role of the PDZ domain-containing protein GIPC1 in diabetes is supported despite the lack of this information in the Online Mendelian Inheritance in Man database. Several key mediator proteins identified here clearly has pleiotropic effects, supported by ample evidence for their general but always of only secondary importance. We suggest that studying central nodes in mediator networks may contribute to better understanding and quantifying pleiotropy. Network analysis provides potentially useful tools here, as well as helps in improving databases.	\N	\N
22040839	Coronary artery disease (CAD) is the major cause of morbidity and mortality in type 2 diabetic patients. Severe vitamin D deficiency has been shown to predict cardiovascular mortality in type 2 diabetic patients. We investigated the association among severe vitamin D deficiency, coronary calcium score (CCS), and asymptomatic CAD in type 2 diabetic patients with elevated urinary albumin excretion rate (UAER) >30 mg/24 h. This was a cross-sectional study including 200 type 2 diabetic patients without a history of CAD. Severe vitamin D deficiency was defined as plasma 25-hydroxyvitamin D (p-25[OH]D3) <12.5 nmol/L. Patients with plasma N-terminal pro-brain natriuretic peptide >45.2 ng/L or CCS ≥400 were stratified as being high risk for CAD (n= 133). High-risk patients were examined by myocardial perfusion imaging (MPI; n = 109), computed tomography angiography (n = 20), or coronary angiography (CAG; n = 86). Patients' p-25(OH)D3 levels were determined by high-performance liquid chromatography/tandem mass spectrometry. The median (range) vitamin D level was 36.9 (3.8-118.6) nmol/L. The prevalence of severe vitamin D deficiency was 9.5% (19/200). MPI or CAG demonstrated significant CAD in 70 patients (35%). The prevalence of CCS ≥400 was 34% (68/200). Severe vitamin D deficiency was associated with CCS ≥400 (odds ratio [OR] 4.3, 95% CI [1.5-12.1], P = 0.005). This association persisted after adjusting for risk factors (4.6, 1.5-13.9, P = 0.007). Furthermore, severe vitamin D deficiency was associated with asymptomatic CAD (adjusted OR 2.9, 1.02-7.66, P = 0.047). In high-risk type 2 diabetic patients with elevated UAER, low levels of vitamin D are associated with asymptomatic CAD.	\N	\N
22047508	Hypertension is a common major risk factor for stroke and coronary heart disease. Little is known about how achievement of financially incentivised and non-incentivised indicators of quality of care varies with deprivation, or about the effect of financial incentives on health inequalities in hypertension. General practices in the UK have received financial incentives for high quality care since 2004. This study set out to assess the variations in achievement of incentivised and non-incentivised quality indicators for hypertension by patient area deprivation, before and after the introduction of financial incentives. Achievement of 14 quality indicators for hypertension in 304 patient participants in 18 general practices in Norfolk, England was assessed one year before (2003) and one year after (2005) the introduction of financial incentives. Four indicators were incentivised and 10 were non-incentivised. Each participant's postcode was linked to an index of multiple deprivation score. The range of achievement of incentivised quality indicators was 65-94% in the least deprived third of participants, and 77-94% in the most deprived third in 2003 and 2005 combined. For non-incentivised indicators, the range was 7-85% in the least deprived and 24-93% in the most deprived third.Achievement of incentivised quality indicators in 2003 and 2005 combined did not vary significantly by area deprivation. Achievement of three of 10 non-incentivised indicators was higher in participants from more deprived postcode areas: providing lifestyle advice (odds ratio 1.34, 95% confidence interval 1.00-1.79), assessment of peripheral vascular disease (1.54, 1.02-2.35) and electrocardiography (1.38, 1.04-1.82). Participants from more deprived areas received at least the same, and sometimes better, quality of care than those from less deprived areas. Quality of care for hypertension in general practice may not follow the inequitable distribution seen with some other conditions.	\N	\N
22050270	Vitiligo is a common acquired depigmentation disorder caused by the loss of melanocytes. Despite the numerous treatment modalities available for vitiligo, responses to treatment are still unsatisfactory. For this reason, new treatment modalities and approaches are needed. To investigate the effects of fractional carbon dioxide (CO(2) ) laser therapy followed by systemic narrowband ultraviolet B (NB-UVB) phototherapy on nonsegmental vitiligo (NSV) as a prospective and randomized left-right comparative study. Ten patients with NSV who presented symmetrical vitiligo lesions with no further improvement despite more than 1 year of conventional treatment were enrolled. Two sessions of half-body fractional CO(2) laser therapy were performed at a 2-month interval. NB-UVB phototherapy was then administered to the entire body 5 days after each fractional laser treatment twice a week, increasing the dose incrementally by 15% at each session. Objective clinical assessments were made by two blinded dermatologists using a quartile grading scale, and the patients' overall satisfaction was evaluated using a 10-point visual analogue scale. Two months after the last treatment, mean improvement scores, assessed by physicians, were significantly higher for those treated with half-body fractional CO(2) laser therapy followed by NB-UVB phototherapy, compared with those treated with NB-UVB alone (P=0·034). In addition, according to subjective assessment, the half-body laser treatment followed by NB-UVB showed significantly higher improvements compared with NB-UVB treatment alone (P=0·023). Noticeable adverse events, such as infection, scarring and Koebner phenomenon, were not found in any patient. This study suggests that fractional CO(2) laser therapy followed by NB-UVB phototherapy could be used effectively and safely as an alternative modality for the treatment of refractory vitiligo.	\N	\N
22054870	Age-related cognitive decline is likely promoted by accumulated brain injury due to chronic conditions of aging, including neurodegenerative and vascular disease. Because common neuronal mechanisms may mediate the adaptation to diverse cerebral insults, we hypothesized that susceptibility for age-related cognitive decline may be due in part to a shared genetic network. We have therefore performed a genome-wide association study using a quantitative measure of global cognitive decline slope, based on repeated measures of 17 cognitive tests in 749 subjects from the Religious Orders Study. Top results were evaluated in 3 independent replication cohorts, consisting of 2279 additional subjects with repeated cognitive testing. As expected, we find that the Alzheimer's disease (AD) susceptibility locus, APOE, is strongly associated with rate of cognitive decline (P(DISC) = 5.6 × 10(-9); P(JOINT)= 3.7 × 10(-27)). We additionally discover a variant, rs10808746, which shows consistent effects in the replication cohorts and modestly improved evidence of association in the joint analysis (P(DISC) = 6.7 × 10(-5); P(REP) = 9.4 × 10(-3); P(JOINT) = 2.3 × 10(-5)). This variant influences the expression of 2 adjacent genes, PDE7A and MTFR1, which are potential regulators of inflammation and oxidative injury, respectively. Using aggregate measures of genetic risk, we find that known susceptibility loci for cardiovascular disease, type 2 diabetes, and inflammatory diseases are not significantly associated with cognitive decline in our cohort. Our results suggest that intermediate phenotypes, when coupled with larger sample sizes, may be a useful tool to dissect susceptibility loci for age-related cognitive decline and uncover shared molecular pathways with a role in neuronal injury.	\N	\N
22054881	Lung cancer is a heterogeneous disease clinically, biologically, histologically, and molecularly. Understanding the molecular causes of this heterogeneity, which might reflect changes occurring in different classes of epithelial cells or different molecular changes occurring in the same target lung epithelial cells, is the focus of current research. Identifying the genes and pathways involved, determining how they relate to the biological behavior of lung cancer, and their utility as diagnostic and therapeutic targets are important basic and translational research issues. This article reviews current information on the key molecular steps in lung cancer pathogenesis, their timing, and clinical implications.	\N	\N
22067963	Lewy pathology in Parkinson disease (PD) extends well beyond the CNS, also affecting peripheral autonomic neuronal circuits, especially the enteric nervous system (ENS). The ENS is an integrative neuronal network also referred to as "the brain in the gut" because of its similarities to the CNS. We have recently shown that the ENS can be readily analyzed using routine colonic biopsies. This led us to propose that the ENS could represent a unique window to assess the neuropathology in living patients with PD. In this perspective, we discuss current evidence which indicates that the presence of ENS pathology may by exploited to improve our understanding and management of PD and likely other neurodegenerative disorders.	\N	\N
22068070	Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare adrenergically mediated arrhythmogenic disorder classically induced by exercise or emotional stress and found in structurally normal hearts. It is an important cause of cardiac syncope and sudden death in childhood. Catecholaminergic polymorphic ventricular tachycardia is a genetic cardiac channelopathy with known mutations involving genes affecting intracellular calcium regulation. We present a case of a 14-year-old boy who had cardiopulmonary arrest after an emotionally induced episode of CPVT while attempting to invite a girl to the school dance. Review of his presenting cardiac rhythm, induction of concerning ventricular arrhythmias during an exercise stress test, and genetic testing confirmed the diagnosis of CPVT. He recovered fully and was treated with β-blocker therapy and placement of an implantable cardioverter-defibrillator. In this report, we discuss this rare but important entity, including its molecular foundation, clinical presentation, basics of diagnosis, therapeutic options, and implications of genetic testing for family members. We also compare CPVT to other notable cardiomyopathic and channelopathic causes of sudden death in youth including hypertrophic cardiomyopathy, arrhythmogenic right ventricular dysplasia, long QT syndrome, short QT syndrome, and Brugada syndrome.	\N	\N
22072024	Systemic lupus erythematosus (SLE) can be a severe and potentially life-threatening disease that often represents a therapeutic challenge because of its heterogeneous organ manifestations. Only glucocorticoids, chloroquine and hydroxychloroquine, azathioprine, cyclophosphamide and very recently belimumab have been approved for SLE therapy in Germany, Austria and Switzerland. Dependence on glucocorticoids and resistance to the approved therapeutic agents, as well as substantial toxicity, are frequent. Therefore, treatment considerations will include 'off-label' use of medication approved for other indications. In this consensus approach, an effort has been undertaken to delineate the limits of the current evidence on therapeutic options for SLE organ disease, and to agree on common practice. This has been based on the best available evidence obtained by a rigorous literature review and the authors' own experience with available drugs derived under very similar health care conditions. Preparation of this consensus document included an initial meeting to agree upon the core agenda, a systematic literature review with subsequent formulation of a consensus and determination of the evidence level followed by collecting the level of agreement from the panel members. In addition to overarching principles, the panel have focused on the treatment of major SLE organ manifestations (lupus nephritis, arthritis, lung disease, neuropsychiatric and haematological manifestations, antiphospholipid syndrome and serositis). This consensus report is intended to support clinicians involved in the care of patients with difficult courses of SLE not responding to standard therapies by providing up-to-date information on the best available evidence.	\N	\N
22072546	Recent genome wide association studies have identified susceptibility loci for adult testicular germ cell tumors (GCT) near KITLG, SPRY4, BAK1, and DMRT1. We evaluated variants in these four genes to determine whether these are also susceptibility loci for pediatric GCTs. DNA was isolated from 52 pediatric GCTs (ages 0-21 years) obtained from the Cooperative Human Tissue Network. Control DNA was isolated from de-identified dried blood spots from 141 white newborns. Genotyping was conducted using TaqMan assays (rs4474514) or by PCR and sequencing (rs4324715, rs210138, and rs755383). Associations between variants and GCT were evaluated using logistic regression with adjustment for sex. We also evaluated whether the associations differed by age at GCT diagnosis (0-9 years, 10-21 years), sex, and tumor location (gonadal, non-gonadal). We observed a significant association for rs210138 (BAK1) and pediatric GCT overall (odds ratio (OR) = 1.80, 95% confidence interval (CI) 1.10-2.95, P = 0.02) with non-significant associations similar in magnitude in both the pediatric (P = 0.09) and adolescent (P = 0.06) age groups. The KITLG (rs4474514) and SPRY4 (rs4324715) variants were significantly associated with GCT only in the adolescent age group (rs4474514: OR = 2.28, 95% CI 1.09-4.79, P = 0.03 and rs4324715: OR = 2.40, 95% CI 1.19-4.83, P = 0.01). Associations were mostly similar when stratified by sex. This is the first study to suggest that these loci may also be important in susceptibility to GCTs in the adolescent (KITLG, SPRY4, and BAK1) and pediatric (BAK1) age groups.	\N	\N
22078109	The aim of the present study was to examine abnormalities in the ankle-brachial index (ABI) and related risk factors in patients with type 2 diabetes. Between September 2003 and June 2010, the ABI was determined in 3924 outpatients attending the Diabetes Center of the People's Liberation Army 306th Hospital. In addition, demographic and laboratory data were collected. The risk factors for an abnormal ABI were determined using univariate and stepwise logistic regression analysis. The ABI was normal (0.91-1.3) in 93.1% of patients, low (<0.9) in 5.2%, and high (>1.3) in 1.7%. The prevalence of abnormal lower ABI was greater in elderly (≥ 65 years) patients (12.2%) than in younger (< 65 years) patients (3.6%). Using normal ABI as the reference, low ABI in younger patients was found to be independently associated with HbA1c, the urinary albumin:creatinine ratio, diabetic peripheral neuropathy, diabetic retinopathy, and cerebrovascular disease. A low ABI in elderly patients was found to be independently associated with age, smoking, HbA1c, uric acid, total cholesterol, diabetic peripheral neuropathy, diabetic retinopathy, diabetic nephropathy and cerebrovascular disease. A high ABI in younger patients was associated with being male. The prevalence of an abnormal ABI was high in patients with type 2 diabetes, especially elderly patients. Early identification and intensive treatment are needed to improve the quality of life and overall prognosis of patients with type 2 diabetes.	\N	\N
22079056	Cancer represents a complex group of heterogeneous diseases. While many cancers share fundamental biological processes (hallmarks of cancer) necessary for their development and progression, cancers also distinguish themselves by their dependence on distinct oncogenic pathways. Over the last decade, targeted therapies have been introduced to the clinic with variable success. In truth, single targeted therapies may be successful in only a subset of malignancies but insufficient to address malignancies that often rely on multiple pathways, thus evading single targeted agents. Investigators have recently identified potentially functional components of the human genome that were previously thought to have no biological function. This discovery has added to the already established complexity of gene regulation in the pathogenesis of cancer. Non-coding RNAs represent key regulators of gene expression. Improved knowledge of their biogenesis and function may in turn lead to a better understanding of the heterogeneity of malignancies and eventually be leveraged as diagnostic, prognostic and therapeutic targets. MicroRNAs (miRNAs or miRs) for example, have the capacity for the regulation of multiple genes and thus redirection or reprogramming of biological pathways. However, several other members of the non-coding RNA family may be of equal biological relevance. In this review, we provide a perspective on emerging concepts in the clinical application of miRNA and other non-coding RNAs as biomarkers in cancer with an eye on the eventual integration of both miRNA and other non-coding RNA biology into our understanding of cancer pathogenesis and treatment.	\N	\N
22082049	A growing number of prognostic indices for chronic obstructive pulmonary disease (COPD) is developed for clinical use. Our aim is to identify, summarize and compare all published prognostic COPD indices, and to discuss their performance, usefulness and implementation in daily practice. We performed a systematic literature search in both Pubmed and Embase up to September 2010. Selection criteria included primary publications of indices developed for stable COPD patients, that predict future outcome by a multidimensional scoring system, developed for and validated with COPD patients only. Two reviewers independently assessed the index quality using a structured screening form for systematically scoring prognostic studies. Of 7,028 articles screened, 13 studies comprising 15 indices were included. Only 1 index had been explored for its application in daily practice. We observed 21 different predictors and 7 prognostic outcomes, the latter reflecting mortality, hospitalization and exacerbation. Consistent strong predictors were FEV1 percentage predicted, age and dyspnoea. The quality of the studies underlying the indices varied between fairly poor and good. Statistical methods to assess the predictive abilities of the indices were heterogenic. They generally revealed moderate to good discrimination, when measured. We focused on prognostic indices for stable disease only and, inevitably, quality judgment was prone to subjectivity. We identified 15 prognostic COPD indices. Although the prognostic performance of some of the indices has been validated, they all lack sufficient evidence for implementation. Whether or not the use of prognostic indices improves COPD disease management or patients' health is currently unknown; impact studies are required to establish this.	\N	\N
22082649	INTRODUCTION The identification of novel prognostic markers may help to better assess survival probability in different subgroups of patients with non-small-cell lung cancer (NSCLC) and to tailor treatment according to the molecular profile of the tumour. AIM We sought to examine whether the immunohistochemical expression of excision repair cross-complementing 1 (ERCC1), an essential component of the nucleotide excision repair pathway, may predict prognosis in NSCLC. MATERIAL AND METHOD Formalin-fixed paraffin-embedded tumour samples from 44 Turkish patients with NSCLC treated by adjuvant platinum-based chemotherapy were included in the study. Immunohistochemical expression levels of ERCC1 were correlated with clinical outcomes by Kaplan-Meier curves and multivariable Cox proportional hazards regression analysis. RESULTS A total of 29 patients had ERCC1-negative tumours while 15 had ERCC1-positive tumours. The mean progression- free survival (PFS) was significantly lower in patients with ERCC1-positive tumours (13±2 months) than in those with ERCC1-negative tumours (27±5 months, p<0.05). Similarly, the mean overall survival (OS) was significantly lower in patients with ERCC1-positive tumours (20±3 months) than in those with ERCC1-negative tumours (33±5 months, p<0.05). After allowance for potential confounders, Cox regression analysis demonstrated that ERCC1 expression was significantly associated with both PFS and OS (both p<0.05). CONCLUSION This study provides support for the prognostic value of ERCC1 immunohistochemical expression in patients with NSCLC treated by adjuvant platinum-based chemotherapy. If independently confirmed, these findings may improve prognostic stratification in this group of patients.	\N	\N
22092655	Immunomodulatory T cells are thought to influence development of allergy and asthma, but early life longitudinal data on their phenotype and function are lacking. As part of the Urban Environment and Childhood Asthma (URECA) study, we investigated the development of immunomodulatory T cell phenotype and function, and characterized their relation to allergic disease progression from birth through to 2 years of age. Immunomodulatory T cell phenotype and function in cord blood mononuclear cells (CBMC) and peripheral blood mononuclear cells (PBMC) at 1 and 2 years of age were characterized by analysing CD25(bright) and FoxP3(+) expression, proliferative responses and cytokine production. The relation of immunomodulatory T cell characteristics to allergic sensitization and disease at 1- and 2-years of age was investigated. The proportion of CD4(+)CD25(bright) and CD4(+)CD25(+)FoxP3(+)T cells (n = 114, 83, 82 at birth, 1- and 2-years respectively) increased significantly, whereas there were no significant changes in the suppressive function of CD25(+)T cells (n = 78, 71, 81 at birth, 1- and 2-years respectively). Birth immunomodulatory T cell characteristics were not related to subsequent allergic sensitization or disease. However, increases in the numbers of CD4(+)CD25(bright) cells and their ability to suppress lymphoproliferative responses at 1 year of age were associated with reduced allergic sensitization at 1 (P = 0.03) and 2 (P = 0.02) years of age. Production of the anti-inflammatory cytokine IL-10 by CD25(+)T cells appeared to mediate this protective suppressive function. In contrast, by 2 years of age, we observed the emergence of a positive association of CD4(+)CD25(+) FoxP3(+) T cell numbers with allergic sensitization (P = 0.05) and eczema (P = 0.02). These findings suggest that the relationship between immunomodulatory T cell subsets, allergic sensitization and eczema is developmentally regulated. In the first year of life, CD4(+)CD25(+) IL-10 producing T cells are associated with a reduced incidence of allergic sensitization. Once allergic sensitization or eczema is established, CD4(+)CD25(+)FoxP3(+)T-reg cells expand to potentially counteract the allergic inflammatory response. Understanding the relationship between development of immunoregulatory T cells and early onset atopy could lead to new preventive strategies for allergic diseases.	\N	\N
22104022	Bronchiolitis is the most common respiratory disease in children under 2 years-old and a major cause of hospitalization in young children, especially during the winter. To determine the prevalence and etiology of bronchiolitis in south-east of Spain. A prospective study was conducted during the bronchiolitis season (December-April). Children below 18 months-old admitted to the hospital for a first bronchiolitis episode were included. Nasopharyngeal aspirates were analysed by reverse transcription polymerase chain reaction (RT-PCR) respiratory syncytial virus. A total of 235 children were included during this period, and 235 RT-PCR were performed. A total of 287 viruses were detected in nasopharyngeal aspirates from 204 infants. Respiratory syncytial virus was the virus detected more frequently, followed by rhinovirus. Co-infections were found in the 36% of children. Respiratory viruses were detected in most of the children below 18 months-old hospitalised with bronchiolitis, and 36% of them showed a mixed infection.	\N	\N
22106694	HLA-DQA1, -DQB1, and -DRB1 gene polymorphism were analyzed to study type 1 DM susceptibility in Malay patients from Southeast Asia (Malaysia and Singapore). Patients showed significant increases in the occurrence of DQA1*0501 (50.7% vs. 20.4%; RR = 3.97; Pc < 0.01), DQB1*0201 (48% vs. 19.1%; RR = 3.86; Pc < 0.05), and DRB1*0301 (38.7 vs. 6.8%; RR = 8.36; 95% Pc < 0.05). Conversely, significant decreases were noted in the occurrence of DQA1*0601 (14.7% vs. 35.2%; RR = 0.33; Pc = 0.008) and DQB1*0601 (4% vs. 23.5%; RR = 0.16; Pc < 0.05) in type 1 DM patients. Using a logistic regression model, we derived a risk prediction model for type 1 DM in our indigenous Malay population based on the identified HLA genotypes. The RR for type 1 DM increases by a factor of 5.68 for every unit increase in the number of DRB1*0301 allele (P < 0.001), and decreases by a factor of 0.18 per unit increase in the number of DQB1*0601 allele (P < 0.001). After adjusting for these two HLA genotypes, DQA1*0501, DQB1*0201 and DQA1*0601 were not statistically significant as risk predictors. The lower incidence of type 1 DM in the Malay population may be contributed by the genotypic combinations of DR and DQ genes as well as the linkage disequilibria between susceptible and protective alleles.	\N	\N
22110167	A primary function of B lymphocytes is immunoglobulin production; however, the therapeutic benefit of B cell depletion in autoimmune diseases previously thought to be T cell mediated suggests that some B cells fulfill other roles in autoimmunity. We examined the recently identified human B1 cell population for T cell stimulatory activity. We found two kinds of B1 cells that are distinguished by multiple surface markers and distinct transcriptomic profiles. In both umbilical cord and adult peripheral blood, a CD11b(+) subset constitutes ~1 out of every 8-10 B1 cells, whereas a CD11b(-) subset constitutes the remaining B1 cells. These B1 cell populations differ functionally. CD11b(-) B1 cells spontaneously secrete much more IgM than CD11b(+) B1 cells. In contrast, CD11b(+) B1 cells express more CD86, and more efficiently stimulate allogeneic CD4(+) T cell expansion, than CD11b(-) B1 cells. The frequency of these CD11b(+) B1 cells is markedly elevated in lupus patients. CD11b(+) B1 cells in lupus patients express more CD86 and have increased T cell-stimulating activity in disease. This work distinguishes a novel, T cell-interacting B1 cell population whose abundance and activity may be a reflection of, and a therapeutic target in, autoimmune disease.	\N	\N
22112193	Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and is one of the most common causes of chronic liver disease, worldwide. Lipoprotein-associated phospholipase A2 (Lp-PLA2) was recently characterized as a novel inflammatory biomarker that is correlated with several components constituting the metabolic syndrome. In this study, we determined the serum levels of Lp-PLA2 in patients with definite nonalcoholic steatohepatitis (NASH, n=25), borderline NASH (n=22), simple fatty liver (n=10), and healthy controls without evidence of liver disease (n=38). The levels of Lp-PLA2 were measured by enzyme-linked immunosorbent assay and compared in the four study groups. Moreover, concentrations of Lp-PLA2 were assessed in relation to the general characteristics of the study participants and the results of liver biopsy. Concentrations of Lp-PLA2 were significantly higher in patients with definite NASH (161.8±0.9 μg/L, P<0.001), borderline NASH (135.4±47.7 μg/L, P=0.001), and simple fatty liver (132.4±46.2 μg/L, P=0.042) compared with healthy controls (86.2±40.7 μg/L). Furthermore, the serum Lp-PLA2 level was strongly associated to histological steatosis scores in patients with NAFLD (β=0.32, t=2.50, P=0.016). Although subject to future confirmation, our data suggest that Lp-PLA2 levels are elevated in NAFLD.	\N	\N
22122455	PPAR agonists represent a heterogeneous group of compounds that have been used in the treatment of cardiovascular and metabolic diseases for over thirty years. While the primary indications for PPAR agonist therapy focus on hyperlipidemia and diabetes, there is a growing body of pre-clinical data that suggests they may be beneficial in the treatment of heart failure; a disease marked by abnormal myocardial metabolism, fibrosis and insulin insensitivity. PPAR agonist treatment in numerous animal models of systolic heart failure have demonstrated improvement in cardiac function with decreased fibrosis, improved contractility and endothelial function. However, considerable controversy exists on the cardiac safety profile of PPAR agonists, particularly concern for inducing lipotoxicty and precipitating or worsening heart failure. In addition during pre-clinical testing, many compounds have been associated with increased death and adverse cardiovascular outcomes casting a pall over their future use for treating disorders of myocardial function. This article will review cardiac pathways involved in PPAR activation and their potential regulation of maladaptive pathways involved in heart failure and highlight molecular mechanisms that may contribute to adverse events and raise safety concerns. Specific attention will be focused on PPAR alpha and gamma, subtypes for which commercially available PPAR agonists are currently available.	\N	\N
22122790	Atopic dermatitis (AD) is a kind of eczema with an inflammatory, relapsing, non-contagious, and pruritic skin disorder. It is associated with the local infiltration of T helper type 2 (Th2) cells that secrete interleukin (IL)-4 and IL-5. IL-21 is a member of IL-2 family cytokine mainly expressed by activated CD4+ T lymphocytes. Until now, there is no clinical research in the expression of IL-21 in patients with AD. We analyzed serum levels of total immunoglobulin E (IgE), allergen-specific IgE, and cytokines IL-4, IL-5, IFN-γ, IL-17, and IL-21 in AD cases and controls. In addition, cytokine levels in the culture supernatants of peripheral blood mononuclear cells stimulated with anti-CD3 and anti-CD28 Abs, phytohemagglutin (PHA), or pokeweed mitogen (PWM) were measured. We also assessed clinical skin severity by Scoring of Atopic Dermatitis (SCORAD) index. Our results showed that serum total IgE in the case group was significantly higher than that of control group (365.449 ± 52.945 and 39.243 ± 7.605 IU/ml, respectively). Logistic regression analysis system reveals serum levels of IL-21 and IFN-γ are significantly correlated. However, IL-21 and IL-4, IL-21 and IL-5, as well as IL-21 and IL-17 showed no correlation. A significantly decreased level of IL-21 was observed in children suffering with severe AD compared with controls, suggesting that IL-21 may play a role in AD.	\N	\N
22124677	Colonic ischemia following colorectal surgery is an unusual and serious complication. As it has been reported that the incidence of colonic ischemia was higher after laparoscopic surgery, the aim of this report was to document the clinical features of postoperative colonic ischemia following colorectal surgery. Among 1,201 surgeries for sigmoid colon and rectal cancer by a single surgeon from 2006 to 2010, 10 cases of postoperative colonic ischemia were retrospectively identified (0.83%). IMA high ligation was routinely made in all surgeries. The clinical findings and laboratory data of these 10 cases were evaluated. Of the 10 patients, 9 were male and 1 was female. The mean age was 66.9 years old. The mean BMI was 23.3. Three patients (30%) had a cardiovascular disease other than hypertension. Eight patients (80%) underwent laparoscopic surgery and two patients (20%) underwent open surgery. Intraoperative bleeding occurred in five patients (50%, mean 435 ml). The average day for occurrence of postoperative colonic ischemia was on the 5th day (range 2nd-10th day). A consistent postoperative fever was found in eight patients (80%). Mortality due to postoperative colonic ischemia was 10%. Postoperative colonic ischemia may be considered one of the more important complications of colorectal resection.	\N	\N
22129916	To evaluate the long-term safety and efficacy of etanercept treatment in Polish patients with juvenile idiopathic arthritis (JIA). The study involved patients, fulfilling the JIA criteria of the International League of Associations of Rheumatology (ILAR), who were started on etanercept therapy after methotrexate and other synthetic disease-modifying antirheumatic drugs (DMARDs) had proven ineffective. Patient data were collected in an electronic registry. Disease improvement was assessed based on Giannini's criteria. The statistical analysis involved 188 patients. Significant improvement was observed in all clinical and laboratory parameters after the first month of therapy and was maintained in the following months. ACR Pediatric 30, 50, 70, 90, and 100 improvement was observed in 81.4%, 65.9%, 27.5%, 16.2%, and 15%, respectively, of patients after 3 months and in 94.7%, 88.4%, 62.1%, 34.7%, and 26.3%, respectively, after 24 months of treatment. Throughout the 72-month safety observation period, 1162 adverse events were reported; the exposure-adjusted AE rate was 2.96 per patient per year. In patients with various subtypes of JIA resistant to conventional DMARD treatment, etanercept resulted in significant and long-lasting improvements in disease activity. Combination treatment with etanercept and a DMARD was well tolerated.	\N	\N
22133826	The purpose of clinical assessment of atherosclerosis in aorta is to detect early lesions that are associated with a substantial risk of cardiovascular disease, such as stroke, aortic aneurysm and dissection, and to develop a treatment strategy for reduction of the cardiovascular risk. The pulse wave velocity (PWV) and pulse wave analysis (augmentation index : AI) can reveal atherosclerotic functional vascular abnormalities. On the contrary, plain X-rays, ultrasound examination, computed tomography (CT) , and magnetic resonance imaging (MRI) can be employed to easily assess the severity of atherosclerotic vascular damage morphologically. In these examinations, only PWV, as an index of arterial stiffness, can detect early atherosclerotic change in aorta before organic change. So, considering the importance of detecting early lesion, PWV is the most useful examination of atherosclerosis in aorta.	\N	\N
22134016	In this review, the pitfalls that still exist with the surgical treatment of endometriosisassociatedpelvic pain have been discussed and the best evidence regarding various aspects of surgical techniques have been reviewed. When laparoscopy is performed to evaluate a woman with pelvic pain symptoms, it is important she be counseled that the primary function of the surgery is to confirm the presence (and allow surgical treatment) of endometriosis, and that it is not the penultimate diagnostic modality for her pelvic pain. There are many etiologies of pelvic pain that present with symptoms resembling those of endometriosis-associated pelvic pain that are not diagnosable with laparoscopy, such as interstitial cystitis and irritable bowel syndrome. It is unfortunate that many women are left with the belief that if a laparoscopy fails to provide a diagnosis of a pain generator, then it means there are no diagnoses other than that the “pain is in her head,” often disparagingly termed “supratentorial” byclinicians. In fact, the pain-related diagnoses that are amenable to and possibly require a laparoscopy are quite limited, a group of diagnoses that this author terms the “dirty dozen” because there are just 12, and only the first 4 have good evidence to clearly associate them with chronic pelvic pain:1. Endometriosis 2. Ovarian remnant syndrome 3. Pelvic inflammatory disease 4. Tuberculous salpingitis 5. Adhesions 6. Benign cystic mesothelioma 7. Postoperative peritoneal cysts 8. Adnexal cysts (nonendometriotic)9. Chronic ectopic pregnancy 10. Endosalpingiosis 11. Residual accessory ovary 12. Hernias: ventral, inguinal, femoral, spigelian.I would argue that diagnostic laparoscopy in modern gynecology has a limited, if any role, and that when laparoscopy is planned for women with chronic pelvic pain, it should be with a very high suspicion of a diagnosis and with plans to treat the disease operatively. In this era, a negative diagnostic laparoscopy should be a rare event.	\N	\N
22139583	Omics is the study of proteins, peptides, genes, and metabolites in living organisms. Systems biology aims to understand the system through the study of the relationship between elements such as genes and proteins in biological system. Recently, systems biology emerged as the result of the advanced development of high-throughput analysis technologies such as DNA sequencers, DNA arrays, and mass spectrometry for omics studies. Among a number of analytical tools and technologies, CE and CE coupled to MS are promising and relatively rapidly developing tools with the potential to provide qualitative and quantitative analyses of biological molecules. With an emphasis on CE for systems biology, this review summarizes the method developments and applications of CE for the genomic, transcriptomic, proteomic, and metabolomic studies focusing on the drug discovery and disease diagnosis and therapies since 2009.	\N	\N
22145272	The prognosis of multiple myeloma patients has significantly improved since the introduction of the novel agents thalidomide, bortezomib and lenalidomide. We report the data of a medical need programme with lenalidomide plus dexamethasone, conducted in Belgium between August 2007 and March 2008, and including 98 relapsed refractory multiple myeloma patients. In addition to chemotherapy and steroids, all patients had received prior treatment with bortezomib, and 84% of them had been exposed to thalidomide. In 52 patients response data could be retrieved by post-hoc analysis. A partial remission or better was achieved in 52% (49% partial and 3% complete response) of patients, despite a median of 5 previous anti-myeloma treatment lines. Responses were rapid while the majority of patients received lenalidomide with once weekly (also called low-dose) dexamethasone. Treatment with lenalidomide plus dexamethasone did prolong overall survival by nearly half a year in this population with end-stage myeloma. Overall response and quality of response were independent of previous response to thalidomide and bortezomib, although the time to progression tended to be shorter in thalidomide- and bortezomib-refractory patients. It can be concluded that lenalidomide plus dexamethasone is an effective and safe treatment regimen in highly refractory multiple myeloma patients, and that these responses are irrespective of previous exposure or sensitivity to thalidomide and bortezomib.	\N	\N
22153142	As important members of the health care team, patients and caregivers must be empowered to recognize their asthma status and to act accordingly. Education about asthma, complications, and successful management of asthma provide the best way to empower children and their caregivers. A Shared Medical Appointment (SMA) is a unique health care delivery approach that integrates disease management and patient education. The SMA described here is a 90-minute group appointment for four to nine patients who share a diagnosis of asthma, bronchospasm, or wheeze and their caregivers. The appointment includes a brief individual examination, health education delivered to the group, and the opportunity for interaction between group members. Because a supporting theoretic framework is not identified in the original design proposals for the SMA model or in the literature on its use, for the purposes of this project, Social Cognitive Theory is identified as the theoretical framework that best explains and reinforces the benefits of the SMA. The theoretic framework is important to direct the development and continued success of this treatment model. This project report describes the first nurse practitioner-led SMA as a tool for improving quality of care and service for children with asthma and their caregivers.	\N	\N
22153317	Oral ulcer is the cardinal clinical sign and increased neutrophilic activity is a part of the pathogenesis in Behcet's disease (BD). Saliva, as a part of the innate immune response, contains antimicrobial peptides (AMPs) that are derived from both oral epithelial cells and neutrophils. The aim of this study was to investigate the associations between salivary levels of AMPs HNP 1-3, LL-37 and S100 and disease course in patients with Behcet's disease (BD). Fifty-three patients with BD and 44 healthy controls (HC) were included in the study. Disease severity score reflecting organ involvement was calculated. Salivary HNP 1-3, LL-37 and S100 levels were measured in unstimulated saliva samples by ELISA. Salivary HNP 1-3 and S100 levels in BD patients (2715.2 ± 1333.4 μg/ml and 430.6 ± 203.9 ng/ml) were significantly higher compared to HC (1780.6 ± 933.2 μg/ml and 365.3 ± 84.7 ng/ml) (p = 0.000 and p = 0.004, respectively). Although LL-37 levels were also higher in BD than HC (190.9 ± 189.1 vs 143.1 ± 128.9 ng/ml), no significant difference was observed (p = 0.53). Salivary HNP 1-3 and LL-37 levels were associated with the severity of BD (mild disease: 1975.1 ± 1174.2 μg/ml and 115.9 ± 109.4 ng/ml vs severe disease: 2955.7 ± 1305.6 μg/ml and 215.3 ± 203.8 ng/ml, p=0.020 and p=0.031, respectively). Salivary LL-37 levels also correlated with the number of monthly oral ulcers (r = 0.5 p = 0.000). An increase in salivary HNP 1-3 and S100 levels might be associated with enhanced local and systemic innate responses in BD.	\N	\N
22156557	statin drugs may induce skeletal myopathy, but might also have the potential to improve rehabilitation outcomes by improving sarcopenia or by preventing intercurrent illness. We examined the association between statin use and functional outcomes in the rehabilitation of older people. retrospective cohort study using routinely collected clinical data. Admissions to Royal Victoria Hospital, Dundee for inpatient rehabilitation over a 10-year period were identified. Data were available regarding demographics, statin therapy, antiplatelet therapy, admission and discharge Barthel scores, length of stay and comorbid disease. Multivariate analyses were performed to examine the difference between admission and discharge Barthel score in patients taking statins compared with those not taking statins. a total of 3,422 patients were included. Mean age was 81.4 years; 40% were male. Baseline Barthel scores were similar in the statin/non-statin groups, respectively (10.4/20 versus 10.3/20, P = 0.57). Improvement in the Barthel score between admission and discharge was greater in the statin than non-statin group (3.59 versus 4.30 points, P < 0.001) after adjustment for age, sex, baseline Barthel score and comorbid disease. statin use was associated with improved Barthel scores on discharge from rehabilitation. This gain could contribute to improved outcomes as part of the rehabilitation package and requires further prospective investigation.	\N	\N
22156787	Spinal muscular atrophy is a relatively stable chronic disease. Patients may gradually experience declines in muscle strength and motor function over time. However, functional progression is difficult to document, and the mechanism remains poorly understood. An 11-year-old girl was diagnosed at 19 months and took a few steps without assistance at 25 months. She was evaluated for 54 months in a prospective multicenter natural history study. Outcome measures were performed serially. From 6 to 7.5 years, motor function improved. From 7.5 to 11 years, motor function declined with increasing growth. Manual muscle testing scores minimally decreased. Motor unit number estimation studies gradually increased over 4.5 years. Compared to the published natural history of spinal muscular atrophy type III, our patient lost motor function over time. However, she walked with assistance 2 years longer than expected. Our report highlights possible precipitating factors that could affect the natural history of spinal muscular atrophy type III.	\N	\N
22157156	Rhinitis is a common condition associated with significant under-recognized morbidity and impaired quality of life. The natural history of rhinitis is poorly characterized. Better understanding of its natural history and associated risk factors would improve the ability to effectively manage rhinitis in clinical practice. This review focuses on the current research findings on the natural history of rhinitis and how that is influenced by atopy and sex. Recent work from the Isle of Wight Birth Cohort Study has demonstrated that the prevalence of atopic rhinitis increases steadily in the first 18 years of life in both sexes. However, nonatopic rhinitis behaves differently during adolescence. Its prevalence decreases in boys but continues to increase in girls resulting in a female predominance after puberty. Numerous recent studies have proposed potential roles for sex-related and adipose-related hormonal changes in influencing the course of allergic disease. Further research is needed to establish mechanisms that could underlie such findings. Rhinitis becomes increasingly common through childhood, with prevalence during adolescence being mediated by differential effects of sex and atopy. Mechanisms to explain these findings await elucidation.	\N	\N
22174195	Early rheumatoid arthritis (RA) and very early RA are major targets of research and clinical practice. Remission has become a realistic goal in the management of RA, particularly in early disease. The 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) RA classification criteria, the EULAR treatment recommendations for RA, and the EULAR recommendations for the management of early arthritis focus on early disease and translate the knowledge related to early RA into classification and management. Nevertheless, there is a need for further improvement and progress. Results from 6 recent studies are summarized, evaluating the performance of the 2010 ACR/EULAR RA classification criteria. The data show a significant risk of misclassification, and highlight that overdiagnosis and underdiagnosis may become important issues if the criteria recommend synthetic and biological disease-modifying antirheumatic drugs. Therefore, some considerations are presented on how the current problems and limitations could be overcome in clinical practice and future research. A consensus is needed to better define the early phase of RA and differentiate from other early arthritis. The possible effect of misclassification on spontaneous and drug-induced remission of early and very early RA awaits further elucidation. Such research will eventually lead to more reliable diagnostic and classification criteria for new-onset RA.	\N	\N
22174210	To compare clinical features of patients with remitting seronegative symmetrical synovitis with pitting edema (RS3PE) and patients with polymyalgia rheumatica (PMR) and to explore the purported association between RS3PE and malignancy. We did a retrospective chart review of patients with RS3PE and PMR treated in a community-based hospital between January 2000 and December 2009. Outcomes assessed were clinical course of disease and associated malignancies. We identified 28 patients with RS3PE and 123 with pure PMR. All patients with RS3PE fulfilled PMR criteria as well. Age, comorbidity, erythrocyte sedimentation rate, duration and progression of symptoms, treatment response to initial low-dose steroids, and steroid complication rates were similar in both groups. Patients with RS3PE were more likely to be male (79% vs 41%; p = 0.001) and to have a history of smoking (39% vs 15%; p = 0.008) and a higher rate of depression (11% vs 2%; p = 0.044) at diagnosis. Among those with RS3PE, hip pain was less common (39% vs 74%; p = 0.001) than in the PMR group. No patients with RS3PE and 6 patients with pure PMR (4.9%) developed another rheumatological disease during followup. Seven of 9 patients (78%) with concurrent cancer presented slightly more frequently with systemic symptoms compared to patients without cancer (48%; p = 0.098), especially with fatigue (56% vs 22%; p = 0.037) and anorexia (33% vs 9.0%; p = 0.047). Despite rigorous cancer screening in patients with RS3PE, however, the rate of associated malignancy was not statistically different from that of patients with pure PMR [2 (7%) vs 7 (6%), respectively; p = 0.673]. Despite evidence that RS3PE is clinically distinct from PMR, we observed characteristics, treatment response, and outcomes like those expected in pure PMR. Compared to patients with pure PMR, patients with RS3PE are more likely to be male, to be depressed, and to smoke. Contrary to earlier studies, no clear association of RS3PE with malignancy was found despite rigorous cancer screening, although clinicians should be aware that patients with concurrent cancer may manifest more systemic signs and symptoms, as well as steroid resistance.	\N	\N
22179327	Population allele frequencies of apolipoprotein E (APOE) vary by geographic region. The purpose of this study is to summarize and evaluate published estimates for the prevalence of APOE e4 carrier status among the population diagnosed with Alzheimer's disease (AD) by geographic region and country. A systematic review of English-language publications from January 1, 1985, through May 31, 2010, was conducted. Studies reporting APOE e4 status for patients diagnosed with AD were included in the analysis; trials and autopsies were excluded. APOE e4 data were pooled, and prevalence and 95% confidence intervals (CIs) were calculated. Pooled estimates for APOE e4 carrier prevalence data were derived from 142 independent samples: 48.7% (95% CI: 46.5-51.0), and from 73 samples for e4/4 (homozygotes): 9.6% (95% CI: 8.4-10.8). The highest estimates were in Northern Europe: 61.3% (95% CI: 55.9-66.7), e4/4 prevalence: 14.1% (95% CI: 12.2-16.0). The lowest estimates were in Asia and Southern Europe. Substantial heterogeneity of these prevalence estimates was observed. APOE e4 genotype prevalence varies among AD patients by region and within each country. Further exploration is warranted to better understand the substantial heterogeneity of these prevalence estimates.	\N	\N
22183718	The gut epithelium is a barrier between the 'outside' and 'inside' world. The major function of the epithelium is to absorb nutrients, ions and water, yet it must balance these functions with that of protecting the 'inside' world from potentially harmful toxins, irritants, bacteria and other pathogens that also exist in the gut lumen. The health of an individual depends upon the efficient digestion and absorption of all required nutrients from the diet. This requires sensing of meal components by gut enteroendocrine cells, activation of neural and humoral pathways to regulate gastrointestinal motor, secretory and absorptive functions, and also to regulate food intake and plasma levels of glucose. In this way, there is a balance between the delivery of food and the digestive and absorptive capacity of the intestine. Maintenance of the mucosal barrier likewise requires sensory detection of pathogens, toxins and irritants; breakdown of the epithelial barrier is associated with gut inflammation and may ultimately lead to inflammatory bowel disease. However, disruption of the barrier alone is not sufficient to cause frank inflammatory bowel disease. Several recent studies have provided compelling new evidence to suggest that changes in epithelial barrier function and inflammation are associated with and may even lead to altered regulation of body weight and glucose homeostasis. This article provides a brief review of some recent evidence to support the hypothesis that changes in the gut microbiota and alteration of gut epithelial function will perturb the homeostatic humoral and neural pathways controlling food intake and body weight.	\N	\N
22184604	Assessing the medical history of patients before any treatment is an essential aspect of the dentist's responsibility; however, many dental practitioners assume that their patients are systemically healthy so their medical history is often overlooked. The objective of this study was to determine the prevalence of self-reported medical conditions among a sample of dental school patients at the Institute of Dental Sciences, Bareilly (Uttar Pradesh), India. Detailed medical histories were taken from 3,786 new dental patients in an outpatient setting. The demographic data, medical status, and use of medications from the charts were analyzed. Thirty-eight percent of the total patients had a positive finding in their medical history for at least one systemic condition. The most commonly reported systemic condition was hypertension (15.2 percent) followed by diabetes (11.4 percent), and 26 percent of the patients were taking at least one medication daily. The results of this study reflect the medical complexity of the increasingly aging population.	\N	\N
22185707	Acute pyelonephritis (APN) requires prompt diagnosis and immediate treatment. To develop a simple score to assist in diagnosing treatment deterioration in patients with serious APN. Using data from a retrospective cohort of 193 patients with APN, we developed scores based on multivariate logistic regression after the jackknife procedure. We validated the scores in a prospective cohort of 40 patients. Nine criteria were independently associated with our investigation: Abscess (adjusted odds ratio [OR], 19.8; 95% confidence interval [95% CI] 4.5-72.1), pyonephrosis with or without stone (18.3; 4.8-70.9), pelvicalyceal air (15.5; 3.2-26.9), poor global excretion of contrast (12.3; 2.9-68.5), tachycardia or hypotension (10.1; 2.5-28.0), obliteration of the renal sinus (9.6; 2.5-45.2), persistent fever or pyuria (9.8; 1.9-25.8), diabetes (9.4; 2.0-31.8), and global renal enlargement (7.5; 2.1-35.8). The APN score was based on these nine criteria. Low-risk and high-risk groups were derived from the score (probability, 3.5% [95% CI 0-7.5] and 67% [51-83]). Application of these criteria to the prospective cohort confirmed the diagnostic accuracy of the score (probability 0% [0-15] and 71% [25-100] in the low-risk and high-risk groups, respectively). This easy-to-calculate score may prove useful for diagnosing patients with serious APN who deteriorate with treatment.	\N	\N
22195084	There is increasing interest in leveraging electronic health data across disparate sources for a variety of uses. A fallacy often held by data consumers is that clinical data quality is homogeneous across sources. We examined one attribute of data quality, completeness, in the context of electronic laboratory reporting of notifiable disease information. We evaluated 7.5 million laboratory reports from clinical information systems for their completeness with respect to data needed for public health reporting processes. We also examined the impact of health information exchange (HIE) enhancement methods that attempt to improve completeness. The laboratory data were heterogeneous in their completeness. Fields identifying the patient and test results were usually complete. Fields containing patient demographics, patient contact information, and provider contact information were suboptimal. Data processed by the HIE were often more complete, suggesting that HIEs can support improvements to existing public health reporting processes.	\N	\N
22199325	There have been reports suggesting that continuous administration of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is advantageous for patients in which disease progression was observed after the establishment of clinical benefit from EGFR-TKIs. We retrospectively evaluated the clinical course of patients who received continuous administration of EGFR-TKIs after disease progression was detected solely in bone lesions. The medical records of patients administered gefitinib or erlotinib between 2002 and 2010 were reviewed. We evaluated the progression-free survival (PFS) and overall survival (OS) in patients who had bone metastases after the establishment of clinical benefit from EGFR-TKI and who received radiation therapy for the bone lesion and continuous treatment with EGFR-TKI. Ten patients were enrolled in this study. The median PFS and OS were 88 days and 330 days, respectively. Furthermore, a longer duration from the start of first EGFR-TKI to detection of bone metastases (p=0.0049) was identified as being significantly associated with a longer PFS. Our data suggest that continuous administration of EGFR-TKI is a treatment option for patients with bone metastases who previously benefited from therapy with EGFR-TKI.	\N	\N
22200856	Caveolin-1 (cav-1) has been implicated in the development of human cancers. However, the distribution of cav-1 in non-small cell lung cancer (NSCLC) and its signiﬁcance require further study. Real-time PCR and Western blot assays were performed to detect cav-1 mRNA and protein levels in tumor tissues (TT) and matched tumor-free tissues (TF). The protein expression in 115 paraffin-embedded blocks was examined by immunohistochemical staining (IHC). Correlations between cav-1 mRNA and protein expression by IHC and clinicopathological features were statistically evaluated. For the 136 patients examined, the levels of cav-1 mRNA and protein expression were significantly lower in lung TT compared to matched TF (P<0.05). High cav-1 expression was detected in 60 of 115 (52.2%) NSCLC tissues and this level was significantly lower than cav-1 expression in non-cancerous lung tissues (15 of 19, 78.9%, P<0.05). Up-regulation of cav-1 mRNA expression in lung adenocarcinoma (AC) (29.7%) was higher than that observed in lung squamous cell carcinoma (SCC) (15.8%). Statistical analysis of the correlation between cav-1 protein expression and clinical features showed a statistical association with poorer N-stage (P=0.032) and higher pathological TNM stage (P=0.012) in lung AC patients, that was not found in lung SCC patients. Moreover, lung AC patients with higher cav-1 expression showed significantly shorter life-spans than those with lower cav-1 expression (P=0.032, log-rank test). The levels of cav-1 mRNA and protein expression were significantly lower in lung cancers when compared to matched TF or non-cancerous lung tissues. The higher protein expression correlated with the advanced pathological stage and shorter survival rates in lung AC patients.	\N	\N
22201290	Integrins play myriad and vital roles in development and disease. They connect a cell with its surroundings and transmit chemical and mechanical signals across the plasma membrane to the cell's interior. Dissecting their roles in cell behavior is complicated by their overlapping ligand specificity and shared downstream signaling components. In principle, immobilized synthetic peptides can mimic extracellular matrix proteins by supporting integrin-mediated adhesion, but most short peptide sequences lack selectivity for one integrin over others. In contrast, synthetic integrin antagonists can be highly selective. We hypothesized that this selectivity could be exploited if antagonists, when immobilized, could support cellular adhesion and activate signaling by engaging specific cell-surface integrins. To investigate this possibility, we designed a bifunctional (RGD)-based peptidomimetic for surface presentation. Our conjugate combines a high affinity integrin ligand with a biotin moiety; the former engages the α(v)β(3) integrin, and the latter allows for presentation on streptavidin-coated surfaces. Surfaces decorated with this ligand promote both cellular adhesion and integrin activation. Moreover, the selectivity of these surfaces for the α(v)β(3) integrin can be exploited to capture a subset of cells from a mixed population. We anticipate that surfaces displaying highly selective small molecule ligands can reveal the contributions of specific integrin heterodimers to cell adhesion and signaling.	\N	\N
22211766	Retinol binding protein-4 (RBP-4) is a member of adipocytokines, which is potentially associated with fibrosis, vasodilation, and angiogenesis in addition to insulin resistance. To investigate the clinical significance of serum RBP4 levels in patients with systemic sclerosis (SSc), which is a systemic autoimmune disease characterized by fibrosis and vasculopathy. Serum RBP4 levels were determined by enzyme-linked immunosorbent assay in 62 SSc patients and 19 healthy controls. Similar to patients with chronic kidney disease, serum RBP4 levels inversely correlated with estimated glomerular filtration rate in SSc patients with renal dysfunction. Therefore, analyses were carried out by excluding SSc patients with estimated glomerular filtration rate <60 mL/min/1.73 m(2) . Serum RBP4 levels were significantly lower in diffuse cutaneous SSc (dcSSc) than in control subjects [median (25-75 percentile); 25.8 μg/mL (19.6-47.0) vs. 43.1 μg/mL (31.7-53.4), P < 0.05], while there was no significant difference between limited cutaneous SSc (lcSSc) [28.0 μg/mL (25.4-43.3)] and control subjects. In both of dcSSc and lcSSc, patients with Raynaud's phenomenon had RBP4 levels significantly lower than those without. Furthermore, serum RBP4 levels inversely correlated with pulmonary function test results in dcSSc and with right ventricular systolic pressure in lcSSc. CONCLUSION  Decreased RBP4 levels are associated with the prevalence of Raynaud's phenomenon in dcSSc and lcSSc, with the severity of interstitial lung disease in dcSSc, and with the degree of pulmonary vascular involvement in lcSSc, suggesting the possible contribution of RBP4 to the pathological events in this disorder.	\N	\N
22215125	Primary hyperoxaluria type I is a rare inherited disease that presents a disturbed metabolism of glyoxylate. Consequently, patients suffer from hyperoxaluria, leading to renal failure and subsequent skeletal calcium oxalate deposition. Areas with high concentrations of calcium oxalate, so-called dense metaphyseal bands, are at risk for pathological fracturing. The primary disease is treated by combined liver-kidney transplantation, although pathological fracturing also occurs in the posttransplant period. In the current case, we present a 3-year-old boy with a pathological fracture of his right femur, 2 years after liver-kidney transplantation. We opted for a conservative regime, leading to good fracture healing. As there are limited data in the literature regarding treatment of fractures in these patients, it is important to notify the outcome of conservative treatment of pathological fractures in patients with primary hyperoxaluria type I.	\N	\N
22226887	Cystic fibrosis is a lethal autosomal recessive condition caused by a defect of the transmembrane conductance regulator gene that has a key role in cell homeostasis. A dysfunctional cystic fibrosis transmembrane conductance regulator impairs the efflux of cell anions such as chloride and bicarbonate, and also that of other solutes such as reduced glutathione. This defect produces an increased viscosity of secretions together with other metabolic defects of epithelia that ultimately promote the obstruction and fibrosis of organs. Recurrent pulmonary infections and respiratory dysfunction are main clinical consequences of these pathogenetic events, followed by pancreatic and liver insufficiency, diabetes, protein-energy malnutrition, etc. This complex comorbidity is associated with the extensive injury of different biomolecular targets by reactive oxygen species, which is the biochemical hallmark of oxidative stress. These biological lesions are particularly pronounced in the lung, in which the extent of oxidative markers parallels that of inflammatory markers between chronic events and acute exacerbations along the progression of the disease. Herein, an abnormal flux of reactive oxygen species is present by the sustained activation of neutrophils and other cystic fibrosis-derived defects in the homeostatic processes of pulmonary epithelia and lining fluids. A sub-optimal antioxidant protection is believed to represent a main contributor to oxidative stress and to the poor control of immuno-inflammatory pathways in these patients. Observed defects include an impaired reduced glutathione metabolism and lowered intake and absorption of fat-soluble antioxidants (vitamin E, carotenoids, coenzyme Q-10, some polyunsaturated fatty acids, etc.) and oligoelements (such as Se, Cu and Zn) that are involved in reactive oxygen species detoxification by means of enzymatic defenses. Oral supplements and aerosolized formulations of thiols have been used in the antioxidant therapy of this inherited disease with the main aim of reducing the extent of oxidative lesions and the rate of lung deterioration. Despite positive effects on laboratory end points, poor evidence was obtained on the side of clinical outcome so far. These aspects examined in this critical review of the literature clearly suggest that further and more rigorous trials are needed together with new generations of pharmacological tools to a more effective antioxidant and anti-inflammatory therapy of cystic fibrosis patients. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease.	\N	\N
22237046	PTPN22 is involved in T-cell activation and its R620W single-nucleotide polymorphism (SNP) has been shown to predispose to different autoimmune diseases. The aims of this study were to investigate the role of the PTPN22 R620W SNP in conferring susceptibility to the ANCA-associated vasculitides (AAVs), and to explore potential associations between the PTPN22 genotype and the disease manifestations. PTPN22 R620W SNP was genotyped in a cohort of 344 AAV patients [143 with granulomatosis with polyangiitis (Wegener's) (GPA), 102 with microscopic polyangiitis (MPA) and 99 with Churg-Strauss syndrome (CSS)] and in 945 healthy controls. The frequency of the minor allele (620W) was significantly higher in GPA patients than in controls [P = 0.005, χ(2 )= 7.858, odds ratio (OR) = 1.91], while no statistically significant association was found with MPA or CSS. Among GPA patients, the 620W allele was particularly enriched in ANCA-positive patients as compared with controls (P = 0.00012, χ(2 )= 14.73, OR = 2.31); a particularly marked association was also found with ENT involvement (P = 0.0071, χ(2 )= 7.258, OR = 1.98), lung involvement (P = 0.0060, χ(2 )= 7.541, OR = 2.07) and skin manifestations of all kinds (P = 0.000047, χ(2 )= 16.567, OR = 3.73). The PTPN22 620W allele confers susceptibility to the development of GPA (but not of MPA or CSS), and particularly of its ANCA-positive subset.	\N	\N
22237792	Substantia nigra hyperechogenicity assessed by transcranial sonography is a typical finding in up to 90% of patients with idiopathic Parkinson's disease, although its value as a surrogate marker for disease progression in Parkinson's disease is controversial. (123) I-FP-CIT-single photon emission computed tomography (SPECT) represents an established paraclinical surrogate marker to quantify the nigrostriatal dopaminergic deficit in Parkinson's disease. Whereas most studies found no correlation between extent of substantia nigra echogenicity and the putaminal FP-CIT binding ratio, a more recent analysis reported opposite results. In 92 patients with Parkinson's disease the substantia nigra echogenicity was compared with the putaminal FP-CIT binding ratio using an investigator-independent SPECT analysis protocol and with several clinical parameters. No correlation was found between the substantia nigra hyperechogenicity and the FP-CIT binding ratio or the disease severity. Substantia nigra hyperechogenicity does not reflect the degree of the nigrostriatal degeneration or the clinical state of the disease progression.	\N	\N
22239875	Dual-energy x-ray absorptiometry (DEXA) is a safe, noninvasive, inexpensive tool for managing patients with neuromuscular diseases. Regional and whole-body DEXA can be used to guide clinical treatments, such as determining body composition to guide nutritional recommendations, as well as to monitor disease progression by assessing regional and whole-body lean tissue mass. DEXA can also be used as an outcome measure for clinical trials.	\N	\N
22239959	An inadequate level of bowel preparation can affect the efficacy and safety of colonoscopy. Although some factors have been associated with outcome, there is no strategy to identify patients at high risk for inadequate preparation. We searched for factors associated with an inadequate level of preparation and tested the validity of a predictive clinical rule based on these factors. We performed a prospective study of 2811 consecutive patients who underwent colonoscopy examinations at 18 medical centers; clinical and demographic data were collected before the colonoscopy. Bowel preparation was classified as adequate or inadequate; 925 patients (33%) were found to have inadequate preparation. Multivariate analysis was used to identify factors associated with inadequate preparation, which were expressed as odds ratio (OR) and used to build a predictive model. Factors associated with inadequate bowel preparation included being overweight (OR, 1.5), male sex (OR, 1.2), a high body mass index (OR, 1.1), older age (OR, 1.01), previous colorectal surgery (OR, 1.6), cirrhosis (OR, 5), Parkinson disease (OR, 3.2), diabetes (OR, 1.8), and positive results in a fecal occult test (OR, 0.6). These factors predicted which patients would have inadequate cleansing with 60% sensitivity, 59% specificity, 41% positive predictive value, and 76% negative predictive value; they had an under the receiver operating characteristic curve value of 0.63. Assuming 100% efficacy of a hypothetical regimen to address patients predicted to be at risk of inadequate preparation, the rate would decrease from 33% to 13%. We identified factors associated with inadequate bowel preparation for colonoscopy and used these to build an accurate predictive model.	\N	\N
22241793	Neointimal hyperplasia causes a high rate of hemodialysis synthetic graft failure. Thus, therapies that inhibit neointimal hyperplasia are urgently needed. The Coll-R is a sirolimus-eluting collagen matrix designed for intra-operative perivascular implantation around the graft-venous anastomosis. Sirolimus is an anti-proliferative drug that has proven clinical utility in suppressing neointimal tissue growth in coronary artery disease when delivered locally to the vascular wall by an endovascular drug eluting stent. A cohort of 12 chronic hemodialysis patients underwent surgical placement of 13 polytetrafluoroethylene grafts + Coll-R and were followed for up to 24 months. The primary endpoint was safety (freedom from device related adverse events). Secondary endpoints were pharmacokinetics of sirolimus release, success of Coll-R implantation and primary unassisted graft patency. There were no technical failures, infections, vascular anastomotic or wound-healing problems. Whole blood sirolimus levels rose to a mean peak of 4.8 ng/mL at 6 h and fell to <1 ng/mL at 1 week (n = 5). Twelve and 24-month primary unassisted patencies were 76 and 38%, respectively, and the thrombosis rate was 0.37/patient-year. Perivascular implantation of the Coll-R during graft surgery safely delivered sirolimus to the vascular wall. Systemic sirolimus levels were sub-therapeutic for immunosuppression. This small first-in-human study supports the concept that the Coll-R can safely deliver sirolimus to the graft-venous anastomosis. Safety and patency in this small study were sufficiently encouraging to justify randomized controlled trials to further test the efficacy of the Coll-R.	\N	\N
22248333	We assessed HIV prevalence and associated behaviors and risk factors among men who have sex with men (MSM) in Beijing, China. Five hundred MSM were recruited for a biological and behavioral survey using respondent-driven sampling (RDS) in 2009. Serologic specimens were tested for markers of HIV and syphilis infection. A computer-assisted personal interview (CAPI) administered questionnaire gathered information including demographic characteristics, sexual behaviors, HIV testing, and social norms concerning condom use. The adjusted HIV prevalence was 8.0%, syphilis 22.0%. HIV testing and disclosure was low; only 39.3% had HIV tested in the past 12 months, 49.7% knew their own HIV status and 22.8% knew their last male partner's HIV status. HIV infection was associated with syphilis, ever having sex with a woman, not knowing the HIV status of the most recent male partner, and never buying condoms in the past 12 months. Stronger endorsement of positive social norms around condom use strongly and predicted lower prevalence of HIV infection. Compared to surveys of similar design in the recent past, HIV continues to spread rapidly among Beijing's MSM. Our results identify points of intervention that, if addressed in time, may still alter the course of the epidemic including the promotion of HIV testing and partner disclosure, syphilis control and particularly changing social norms around condom use.	\N	\N
22249461	Kuru was the first human transmissible spongiform encephalopathy (TSE) or prion disease identified, occurring in the Fore linguistic group of Papua New Guinea. Kuru was a uniformly fatal cerebellar ataxic syndrome, usually followed by choreiform and athetoid movements. Kuru imposed a strong balancing selection on the Fore population, with individuals homozygous for the 129 Met allele of the gene (PRNP) encoding for prion protein (PrP) being the most susceptible. The decline in the incidence of kuru in the Fore has been attributed to the exhaustion of the susceptible genotype and ultimately by discontinuation of exposure via cannibalism. Neuropathologically, kuru-affected brains were characterized by widespread degeneration of neurons, astroglial and microglial proliferation, and the presence of amyloid plaques. These early findings have been confirmed and extended by recent immunohistochemical studies for the detection of the TSE-specific PrP (PrP). Confocal laser microscopy also showed the concentration of glial fibrillary acidic protein-positive astrocytic processes at the plaque periphery. The fine structure of plaques corresponds to that described earlier by light microscopy. The successful experimental transmission of kuru led to the awareness of its similarity to Creutzfeldt-Jakob disease and Gerstmann-Sträussler-Scheinker disease and formed a background against which the recent epidemics of iatrogenic and variant Creutzfeldt-Jakob disease could be studied.	\N	\N
22252480	The objective is to evaluate the relationship between cholesterolemia, serum apolipoprotein B (apoB) level and blood pressure in a large sample of general population. The Brisighella Heart Study (BHS) is a prospective, population-based longitudinal epidemiological investigation. For this study, we analysed the data sampled in the 2008 BHS population survey, excluding those participants treated with antihypertensive and/or lipid lowering drugs (N: 2473). In a sex, BMI, smoking habit, physical activity level and serum creatinine adjusted model, low-density lipoprotein-cholesterol (LDL-C) appears to be significantly related to SBP (P < 0.001), DBP (P = 0.026), and pulse pressure (PP) (P < 0.001). In individuals aged less than 52 years, LDL-C was significantly associated to SBP and DBP (P < 0.001), but not PP. In the same model, apoB appears to be mildly but significantly related to SBP (P < 0.001), DBP (P < 0.001), and PP (P < 0.001). In individuals aged less than 52 years, apoB was significantly associated to SBP (P < 0.001), DBP (P < 0.001), and PP (P < 0.001). In individuals aged 52 or more, nor LDL-C neither apoB were significantly associated to blood pressure. Including in the same model LDL-C and apoB, apoB excluded the predicting role of LDL-C as it regards the blood pressure either in the whole population sample and in the younger individuals. On the basis of our observation, either serum LDL-C and apoB are significantly related to the blood pressure level in a large sample of individuals untreated with antihypertensive and lipid-lowering drugs. This association is stronger in younger individuals than in elderly. ApoB seems to be a stronger predictor of either SBP, DBP and PP than LDL-C.	\N	\N
22253312	During past decades, twin studies have played an important role in genetic epidemiology studies of complex traits. The strength of twin studies lies in the ability to disentangle genetic and environmental factors that contribute to a phenotype, by comparing genetically identical monozygotic twins to dizygotic twins, who share on average 50% of genetic variants. Twin studies now offer the opportunity to study epigenetic variation across the genome with two aims. First, twin studies can improve our understanding of the factors regulating epigenetic variability by assessing the heritability of epigenetic variants. Secondly, the use of twins in epigenetic research is increasingly recognized as an important approach to help unravel the complexities associated with human development and disease. The strategic use of identical twins discordant for complex disease has revealed the importance of linking epigenetic disruption to the disease-associated risk in humans. Lastly, we also discuss the possibility that epigenetic effects on disease may in part explain some of the missing heritability in genome-wide association studies. The study of human epigenetic factors in twins can inform the role of genetics, as well as in utero and postnatal environments to the establishment, maintenance and functional consequences of human epigenome variation.	\N	\N
22257051	Extracellular matrix metalloproteinases (MMPs) are a family of zinc-dependent neutral endopeptidases involved in physiological and pathological processes, through the cleavage of extracellular matrix. MMPs are capable of degrading essentially all matrix components, which is crucial for malignant tumor growth, invasion, metastasis and angiogenesis. The vertebrates MMP family includes at least 26 enzymes (23 have been known in humans) with only MMP-1, 2, and 7 experimentally validated as targets for antitumoral drug design. However, inhibition of MMP-1 has been hypothesized to be the cause of the clinically observed musculoskeletal syndrome when broad spectrum inhibitors are used. On the other hand, MMP-9 is a tricky enzyme, since its inhibition might be useful in treating patients with early-stage cancers, but MMP-9 is an anti-target in patients with advanced disease. So, MMP-9 inhibition should also be prevented. Therefore, selective MMP-2 inhibition arises as a pursued profile for MMP binders. Among them, hydroxamates have been extensively studied as small molecule drug candidates characterized by an effective zinc-binding group plus additional side chains responsible for the selectivity. This article pays particular attention to MMP-2 selectivity on hydroxamate-type inhibitors, especially against MMP-9, and their chemical structure, SAR, general synthetic methods, and molecular modelling studies are here reviewed in order to inspire further design of new effective anticancer agents.	\N	\N
22266119	The apicomplexan parasite Plasmodium vivax is responsible for causing more than 70% of human malaria cases in Central and South America, Southeastern Asia and the Indian subcontinent. The rising severity of the disease and the increasing incidences of resistance shown by this parasite towards usual therapeutic regimens have necessitated investigation of putative novel drug targets to combat this disease. The apicoplast, an organelle of procaryotic origin, and its circular genome carrying genes of possible functional importance, are being looked upon as potential drug targets. The genes on this circular genome are believed to be highly conserved among all Plasmodium species. Till date, the plastid genome of P. falciparum, P. berghei and P. chabaudi have been detailed while partial sequences of some genes from other parasites including P. vivax have been studied for identifying evolutionary positions of these parasites. The functional aspects and significance of most of these genes are still hypothetical. In one of our previous reports, we have detailed the complete sequence, as well as structural and functional characteristics of the Elongation factor encoding tufA gene from the plastid genome of P. vivax. We present here the sequences of large and small subunit rRNA (lsu and ssu rRNA) genes, sufB (ORF470) gene, RNA polymerase (rpo B, C) subunit genes and clpC (casienolytic protease) gene from the plastid genome of P. vivax. A comparative analysis of these genes between P. vivax and P. falciparum reveals approximately 5-16% differences. A codon usage analysis of major plastid genes has shown a high frequency of codons rich in A/T at any or all of the three positions in all the species. TTA, AAT, AAA, TAT, and ATA are the major preferred codons. The sequences, functional domains and structural analysis of respective proteins do not show any variations in the active sites. A comparative analysis of these Indian P. vivax plastid genome encoded genes has also been done to understand the evolutionary position of the Indian parasite in comparison to other Plasmodium species.	\N	\N
22267663	Oral candidiasis is often accompanied by severe inflammation, resulting in a decline in the quality of life of immunosuppressed individuals and elderly people. To develop a new oral therapeutic option for candidiasis, a nonpathogenic commensal oral probiotic microorganism, Streptococcus salivarius K12, was evaluated for its ability to modulate Candida albicans growth in vitro, and its therapeutic activity in an experimental oral candidiasis model was tested. In vitro inhibition of mycelial growth of C. albicans was determined by plate assay and fluorescence microscopy. Addition of S. salivarius K12 to modified RPMI 1640 culture medium inhibited the adherence of C. albicans to the plastic petri dish in a dose-dependent manner. Preculture of S. salivarius K12 potentiated its inhibitory activity for adherence of C. albicans. Interestingly, S. salivarius K12 was not directly fungicidal but appeared to inhibit Candida adhesion to the substratum by preferentially binding to hyphae rather than yeast. To determine the potentially anti-infective attributes of S. salivarius K12 in oral candidiasis, the probiotic was administered to mice with orally induced candidiasis. Oral treatment with S. salivarius K12 significantly protected the mice from severe candidiasis. These findings suggest that S. salivarius K12 may inhibit the process of invasion of C. albicans into mucous surfaces or its adhesion to denture acrylic resins by mechanisms not associated with the antimicrobial activity of the bacteriocin. S. salivarius K12 may be useful as a probiotic as a protective tool for oral care, especially with regard to candidiasis.	\N	\N
22270369	α-Dystroglycan (α-DG) is a membrane-associated glycoprotein that interacts with several extracellular matrix proteins, including laminin and agrin. Aberrant glycosylation of α-DG disrupts its interaction with ligands and causes a certain type of muscular dystrophy commonly referred to as dystroglycanopathy. It has been reported that a unique O-mannosyl tetrasaccharide (Neu5Ac-α2,3-Gal-β1,4-GlcNAc-β1,2-Man) and a phosphodiester-linked modification on O-mannose play important roles in the laminin binding activity of α-DG. In this study, we use several dystroglycanopathy mouse models to demonstrate that, in addition to fukutin and LARGE, FKRP (fukutin-related protein) is also involved in the post-phosphoryl modification of O-mannose on α-DG. Furthermore, we have found that the glycosylation status of α-DG in lung and testis is minimally affected by defects in fukutin, LARGE, or FKRP. α-DG prepared from wild-type lung- or testis-derived cells lacks the post-phosphoryl moiety and shows little laminin-binding activity. These results show that FKRP is involved in post-phosphoryl modification rather than in O-mannosyl tetrasaccharide synthesis. Our data also demonstrate that post-phosphoryl modification not only plays critical roles in the pathogenesis of dystroglycanopathy but also is a key determinant of α-DG functional expression as a laminin receptor in normal tissues and cells.	\N	\N
22276367	Evaluation of the fitness of an accused person to participate in legal proceedings is a classic forensic activity. Before the trial, the forensic expert will already assess any preexisting somatic and psychological illnesses and give a written expert opinion describing the condition of the accused at the time of the examination and assessing whether he is fit to stand trial. Nevertheless, decompensation or aggravation of a disease may occur--especially in stress situations as they are to be expected for an accused in the courtroom--so that apart from the current evaluation of the state of health of the accused, emergency treatment may occasionally become necessary in the courtroom. The article tries to answer the question how the expert can meet this challenge.	\N	\N
22280950	Endocardial lead-induced tricuspid regurgitation has not been well recognized, either clinically or echocardiographically, and yet it is likely a preventable iatrogenic disease. In severe cases, it can lead to right ventricular failure and require tricuspid valve surgery. This complication will become increasingly important, because the numbers of permanent pacemakers and implantable cardioverter-defibrillators are expected to increase because of the aging population and the expanding capabilities of these devices. Published studies are largely retrospective, and serial studies to assess the time course of the development of tricuspid regurgitation are lacking. The mechanisms and severity of tricuspid regurgitation may not be well evaluated by two-dimensional echocardiography. Real-time three-dimensional echocardiography appears to be a promising technique to evaluate the mechanism of tricuspid regurgitation and may allow the early detection of patients who will develop severe lead-induced tricuspid regurgitation. A better understanding of the mechanism of lead-induced tricuspid regurgitation will be essential to the development of preventive strategies, which can then be tested in future clinical trials.	\N	\N
22281228	Progressive multifocal leukoencephalopathy (PML) is a subacute central nervous system infection due to reactivation of the JC virus. Most reported cases occurred in HIV-infected patients (80% of cases), patients with lymphoid malignancies (13%) and transplant recipients taking immunosuppressants (5%). Less often, PML has been described in patients with chronic inflammatory joint diseases associated with autoimmune disorders (lupus, rheumatoid arthritis [RA] and vasculitis) (2%). Magnetic resonance imaging of the brain shows suggestive changes and confirmation of the diagnosis is obtained by performing PCR tests to identify the JC virus in the cerebrospinal fluid or, when necessary, a brain biopsy. No treatments have been proven effective. Most patients experience progressive disease that is fatal within a few months or induces incapacitating neurological impairments. The risk of PML is 0.4/100,000 in patients with RA. In the few case-reports of PML in RA patients, the treatments used included methotrexate (five cases) combined with a biological agent such as infliximab (one case), rituximab (four cases), or leflunomide (two cases including one with concomitant rituximab). PML is an extremely rare but devastating complication. Rituximab therapy is associated with an increased prevalence of PML in RA patients (4/100,000), who should be informed of this risk. In patients with lupus, the risk of PML is higher than in RA (4/100,000) and 40% of cases of PML occur during low-dose glucocorticoid therapy without immunosuppressive therapy.	\N	\N
22281918	Sporotrichosis is a subcutaneous fungal infection caused by Sporothrix schenckii and acquired by direct inoculation. Although the majority of cases consist of the classic lymphocutaneous presentation, the frequency of atypical and severe clinical forms of the disease has increased progressively. Systemic and disseminated cutaneous sporotrichosis constitute rare variants and such cases are generally associated with cellular immunodeficiency or debilitated states. The present paper describes the first published case of molluscum-like lesions in disseminated mucocutaneous sporotrichosis. Direct mycological examination and histopathology revealed numerous yeast cells.	\N	\N
22283575	Inhaled dry powder mannitol is well established for use in bronchial provocation testing. Inhaled mannitol also increases mucociliary clearance, and therefore could have a role in treating chronic suppurative lung disease. There have been a number of studies in cystic fibrosis and bronchiectasis. An international Phase III trial has just been published that suggests the use of regular inhaled mannitol increases lung function and reduces exacerbation frequency in cystic fibrosis. Inhaled mannitol exerts its effects in a number of ways, most importantly like hypertonic saline, setting up an osmotic gradient so water flows into the airway lumen, increasing mucus hydration and mucociliary clearance. Its formulation as a dry powder makes it quick and convenient to take.	\N	\N
22288822	Urinary schistosomiasis is caused by the digenetic trematode Schistosoma haematobium, characterized by accumulation of eggs in the genitourinary tract. Cytotoxic T-lymphocyte antigen 4 (CTLA-4) can play an important role in parasitic infection due to its major role as a negative regulator of T-cell activation and proliferation. This study was performed in patients with schistosomiasis and healthy controls to analyze the allele and genotype frequencies of four CTLA-4 gene polymorphisms. The CTLA-4 gene was amplified using Taqman real-time polymerase chain reaction, and allele and genotypes of 49 patients with schistosomiasis were analyzed using allelic discrimination analysis followed by subsequent direct sequencing. The results were compared with healthy control subjects. The frequencies of CTLA-4 rs733618 A allele at position -1722 (p=0.001), rs11571316 C allele at position -1577 (p<0.001), and rs231775 A allele at position +49 (p=0.002) in the patient group were significantly higher than the control group. The rs733618 AA genotype (p=0.001), rs11571316 CC genotype (p<0.001), and rs231775 AA genotype (p=0.007) were also significantly overrepresented. Meanwhile, rs733618 AG genotype (p=0.001), rs11571316 CT genotype (p=0.02), and rs231775 GG genotype (p=0.029) were significantly decreased in the patients with schistosomiasis, as compared with the controls. No significant difference was observed in both allele and genotype of rs16841252. The results of this study suggest that the rs733618, rs11571316, and rs231775 polymorphisms in the CTLA-4 gene may influence susceptibility to schistosomiasis infection in the Gabonese children.	\N	\N
22289889	Accumulating evidence indicates that infiltrating stromal cells contribute directly and indirectly to tumor growth in a wide range of cancers. In follicular lymphoma (FL), malignant B cells are found admixed with heterogeneous lymphoid-like stromal cells within invaded lymph nodes and BM. In addition, mesenchymal stromal cells (MSCs) support in vitro FL B-cell survival, in particular after their engagement toward lymphoid differentiation. We show here that BM-MSCs obtained from patients with FL (FL-MSCs) display a specific gene expression profile compared with MSCs obtained from healthy age-matched donors (HD-MSCs). This FL-MSC signature is significantly enriched for genes associated with a lymphoid-like commitment. Interestingly, CCL2 could be detected at a high level within the FL-cell niche, is up-regulated in HD-MSCs by coculture with malignant B cells, and is overexpressed by FL-MSCs, in agreement with their capacity to recruit monocytes more efficiently than HD-MSCs. Moreover, FL-MSCs and macrophages cooperate to sustain malignant B-cell growth, whereas FL-MSCs drive monocyte differentiation toward a proangiogenic and lipopolysaccharide-unresponsive phenotype close to that of tumor-associated macrophages. Altogether, these results highlight the complex role of FL stromal cells that promote direct tumor B-cell growth and orchestrate FL-cell niche, thus emerging as a potential therapeutic target in this disease.	\N	\N
22299123	Abuse of methamphetamine (meth), a potent central nervous system stimulant, has been associated with significant dental disease. Current descriptions of "meth mouth" are limited in their scope and fail to illuminate the potential pathogenic mechanisms of meth for oral disease. The purpose of this pilot study was to characterize the oral health of subjects with a history of meth abuse as compared to nonabusing control subjects. A total of 28 meth abusers and 16 control subjects were enrolled. Interviews and surveys regarding meth abuse, dental history, oral hygiene, and diet were collected. A comprehensive oral cavity examination including salivary characterization was completed. We observed significantly higher rates of decayed surfaces, missing teeth, tooth wear, plaque, and calculus among meth abusers. No significant difference in salivary flow rates were noted, yet results showed significant trends for lower pH and decreased buffering capacity. These findings suggest that salivary quality may play a more important role in meth mouth than previously considered. Salivary analysis may be useful when managing a dental patient with history of methamphetamine abuse.	\N	\N
22299530	Traditional forms of treatment of the thyroid diseases: pharmacotherapy, radioiodine therapy and surgery can not always be applied. Intolerance, side effects of antithyroid drugs, low iodine uptake, high risk of surgery or disagreement with the proposed treatment was the reason for seeking alternative healing methods. With the development of interventional radiology, and gained experience in the use of arterial embolization, this method has become possible to use in treatment of thyroid diseases. The essence of this treatment is to shut down blood flow in major arteries of the thyroid by direct injection into the vessel's light of adequate size particles containing polyvinyl alcohol (PVA). The consequence of acute ischemia is septic necrosis of the glandular tissue in a field being supplied by this artery. Further repair processes and fibrosis lead to a reduction of active thyroid hormone synthesis and restriction of thyroid gland. Effects of embolization on angiogenesis, apoptosis and autoimmune reactions contribute to compensation thyroid function and significant reduction a goiter volume in course of Graves' disease. Preoperative selective embolization of a huge goiter or thyroid cancer improves surgery outcomes, reduces the risk of hemorrhage and damage to surrounding tissue. Palliative use of embolization in advanced stages of thyroid cancer reduces symptoms and improves quality of life. Little invasive nature of this procedure, the lack of serious undesirable coincidence makes embolization of thyroid arteries an attractive form of a therapy, which may become a therapeutic option in many difficult clinical situations and improve the clinical effectiveness of treatment of thyroid disease.	\N	\N
22299533	Objectification assess the health status of COPD patients poses numerous problems arising from the complexity of both the disease and medical co-operation with the patient. So far, the methods adopted do not correlate with the quality of life. Also, the discrepancy in the evaluation of their symptoms by patients leads to an underestimation of obtained information. Recently proposed a test study of COPD has been validated in many countries and can be implemented into daily practice.	\N	\N
22302706	Homozygous germline mutations of the PARK2 gene are responsible for the development of early-onset Parkinson's disease (PD). Homozygous PARK2 mutations have been also detected in lung adenocarcinoma (LADC). However, since heterozygous PARK2 germline mutations are present in a subset of non-PD individuals, the timing for the occurrence of two-hit PARK2 mutations in LADC progression is unclear. Therefore, we comprehensively analyzed mutations, expression and copy number variations of the PARK2 gene in 267 primary LADCs together with the corresponding noncancerous lung cells and 39 LADC cell lines. Heterozygous germline exonic deletions were detected in five patients with LADC, and loss of heterozygosity including the PARK2 locus was detected in 31/267 (11.6%) LADCs. However, homozygous PARK2 inactivation was not detected in any of them, including the five patients with germline mutations. Homozygous PARK2 inactivation was detected in 6/39 (15%) cell lines, two exonic deletions, one exonic duplication, and three point mutations, while heterozygous PARK2 inactivation was detected in two cell lines (both by exonic deletions). These results strongly indicate that somatic PARK2 mutations occur rarely (or do not occur) in LADC development and that germline PARK2 mutations could contribute to LADC progression but not to LADC development.	\N	\N
22304951	Coronary computed tomography angiography (CTA) is a highly accurate noninvasive test that is increasingly used in symptomatic patients primarily for the diagnosis of coronary artery disease (CAD). Beyond its proven accuracy, data have now clearly demonstrated the incremental prognostic information available from coronary CTA related to the presence, extent, and severity of obstructive and nonobstructive CAD across a variety of clinical settings and patient populations. Current evidence supports the use of coronary CTA not only for the diagnosis of CAD in appropriately selected symptomatic patients but also to further refine their cardiovascular risk assessment following testing.	\N	\N
22306387	Heart disease is one of the leading causes of death in the United States. With the increase in substance abuse, the incidence of acute myocardial infarction (MI) in younger population has been on the rise. Traditionally, cocaine has been blamed for acute MI; however, recently, there have been more incidences of marijuana as an inciting factor. We present a case of marijuana-induced acute MI and discuss the proposed mechanism.	\N	\N
22309448	The aetiology of female pattern hair loss (FPHL) is largely unknown. However, it is hypothesized that FPHL and male pattern baldness (AGA) share common susceptibility alleles. The two major susceptibility loci for AGA are the androgen receptor (AR)/ectodysplasin A2 receptor (EDA2R) locus on the X-chromosome, and a locus on chromosome 20p11, for which no candidate gene has yet been identified. To examine the role of the AR/EDA2R and 20p11 loci in the development of FPHL using 145 U.K. and 85 German patients with FPHL, 179 U.K. supercontrols and 150 German blood donors. Patients and controls were genotyped for 25 single nucleotide polymorphisms (SNPs) at the AR/EDA2R locus and five SNPs at the 20p11 locus. Analysis of the AR/EDA2R locus revealed no significant association in the German sample. However, a nominally significant association for a single SNP (rs1397631) was found in the U.K. sample. Subgroup analysis of the U.K. patients revealed significant association for seven markers in patients with an early onset (P = 0·047 after adjustment for the testing of multiple SNPs by Monte Carlo simulation). No significant association was obtained for the five 20p11 variants, either in the overall samples or in the analysis of subgroups. The observed association suggests that the AR/EDA2R locus confers susceptibility to early-onset FHPL. Our results do not implicate the 20p11 locus in the aetiology of FPHL.	\N	\N
22310615	Due to the severe shortage of deceased donors in Japan, ABO-incompatible living donor kidney transplantation has been performed since the late 1980s. Excellent long-term outcomes have been achieved; the rates of graft survival among these patients are currently similar to those of recipients of ABO-compatible grafts. Our single-center experience describing the immunosuppressive protocols, complications, and grafts survivals is documented in this study. Among 123 patients with end-stage renal disease who underwent living donor kidney transplantation between January 1999 and December 2010, 25 cases were ABO-incompatible grafts. All of these patients were followed until August 2011. Analyzing these patients, we focused on their immunosuppressive protocols, complications, and graft survivals. Patient and graft survival rates were 100%. One patient experienced antibody-mediated rejection and an intractable acute cellular rejection episode, 1 patient an antibody-mediated rejection, and 6 patients had acute cellular rejection episodes. However, there were no severe complications. Although ABO-incompatible kidney transplantation is a high-risk procedure, a short-term graft survival rate of 100% may be expected due to recent significant improvements in desensitization and recipient management.	\N	\N
22312826	Combination anti-HIV therapies revolutionized patient life expectancy in the mid-1990's. Afterwards, in the early 2000's, research focused on the adverse effects caused by HIV drugs. Among these, the most serious ones are myocardial infarction at young age, disturbances of kidney function, liver disorders, pancreatitis and osteoporosis. The worsening of prognosis, for instance in respect of cardiac diseases, observed approximately five years ago in patients due to pauses in HIV medication, has changed perspective. Currently it is being discussed whether the overall prognosis will be improved with HIV medication started as early as possible.	\N	\N
22318137	Herpes simplex virus 1 (HSV-1) and HSV-2 are medically significant pathogens. The development of an effective HSV vaccine remains a global public health priority. HSV-1 and HSV-2 immunodominant "asymptomatic" antigens (ID-A-Ags), which are strongly recognized by B and T cells from seropositive healthy asymptomatic individuals, may be critical to be included in an effective immunotherapeutic HSV vaccine. In contrast, immunodominant "symptomatic" antigens (ID-S-Ags) may exacerbate herpetic disease and therefore must be excluded from any HSV vaccine. In the present study, proteome microarrays of 88 HSV-1 and 84 HSV-2 open reading frames(ORFs) (ORFomes) were constructed and probed with sera from 32 HSV-1-, 6 HSV-2-, and 5 HSV-1/HSV-2-seropositive individuals and 47 seronegative healthy individuals (negative controls). The proteins detected in both HSV-1 and HSV-2 proteome microarrays were further classified according to their recognition by sera from HSV-seropositive clinically defined symptomatic (n = 10) and asymptomatic (n = 10) individuals. We found that (i) serum antibodies recognized an average of 6 ORFs per seropositive individual; (ii) the antibody responses to HSV antigens were diverse among HSV-1- and HSV-2-seropositive individuals; (iii) panels of 21 and 30 immunodominant antigens (ID-Ags) were identified from the HSV-1 and HSV-2 ORFomes, respectively, as being highly and frequently recognized by serum antibodies from seropositive individuals; and (iv) interestingly, four HSV-1 and HSV-2 cross-reactive asymptomatic ID-A-Ags, US4, US11, UL30, and UL42, were strongly and frequently recognized by sera from 10 of 10 asymptomatic patients but not by sera from 10 of 10 symptomatic patients (P < 0.001). In contrast, sera from symptomatic patients preferentially recognized the US10 ID-S-Ag (P < 0.001). We have identified previously unreported immunodominant HSV antigens, among which were 4 ID-A-Ags and 1 ID-S-Ag. These newly identified ID-A-Ags could lead to the development of an efficient "asymptomatic" vaccine against ocular, orofacial, and genital herpes.	\N	\N
22319048	Consumption of high levels of fructose in humans and animals leads to metabolic and cardiovascular dysfunction. There are questions as to the role of the autonomic changes in the time course of fructose-induced dysfunction. C57/BL male mice were given tap water or fructose water (100 g/l) to drink for up to 2 mo. Groups were control (C), 15-day fructose (F15), and 60-day fructose (F60). Light-dark patterns of arterial pressure (AP) and heart rate (HR), and their respective variabilities were measured. Plasma glucose, lipids, insulin, leptin, resistin, adiponectin, and glucose tolerance were quantified. Fructose increased systolic AP (SAP) at 15 and 60 days during both light (F15: 123 ± 2 and F60: 118 ± 2 mmHg) and dark periods (F15: 136 ± 4 and F60: 136 ± 5 mmHg) compared with controls (light: 111 ± 2 and dark: 117 ± 2 mmHg). SAP variance (VAR) and the low-frequency component (LF) were increased in F15 (>60% and >80%) and F60 (>170% and >140%) compared with C. Cardiac sympatho-vagal balance was enhanced, while baroreflex function was attenuated in fructose groups. Metabolic parameters were unchanged in F15. However, F60 showed significant increases in plasma glucose (26%), cholesterol (44%), triglycerides (22%), insulin (95%), and leptin (63%), as well as glucose intolerance. LF of SAP was positively correlated with SAP. Plasma leptin was correlated with triglycerides, insulin, and glucose tolerance. Results show that increased sympathetic modulation of vessels and heart preceded metabolic dysfunction in fructose-consuming mice. Data suggest that changes in autonomic modulation may be an initiating mechanism underlying the cluster of symptoms associated with cardiometabolic disease.	\N	\N
22326991	After age, the second largest risk factor for Alzheimer's disease (AD) is apolipoprotein E (APOE) genotype, where APOE4 is associated with lower apoE protein levels, more severer brain pathology, enhanced inflammation and disease. Small peptides corresponding to the receptor-binding region of apoE mimic the anti-inflammatory activity of the apoE holoprotein. These apoE mimetics greatly improve behavioral outcomes and neuronal survival in head trauma models that display AD pathology and neuronal loss. To determine whether apoE mimetics change behavior, inflammation and pathology in CVND-AD (SwDI-APP/NOS2(-/-)) transgenic mice. Starting at 9 months, apoE peptides were subcutaneously administered 3 times per week for 3 months followed by behavioral, histochemical and biochemical testing. Treatment with apoE mimetics significantly improved behavior while decreasing the inflammatory cytokine IL-6, neurofibrillary tangle-like and amyloid plaque-like structures. Biochemical measures matched the visible pathological results. Treatment with apoE mimetics significantly improved behavior, reduced inflammation and reduced pathology in CVND-AD mice. These improvements are associated with apoE-mimetic-mediated increases in protein phosphatase 2A activity. Testing in additional AD models showed similar benefits, reinforcing this novel mechanism of action of apoE mimetics. These data suggest that the combination of anti-inflammatory and neuroprotective activities of apoE mimetics represents a new generation of potential therapeutics for AD.	\N	\N
22333444	To investigate the feasibility and safety of unilateral incision hybrid fixation using pedicle screws and a translaminar screw in minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF). From January to June 2010, 18 patients with single-level lumbar disc disease were treated with MIS-TLIF under METRx(TM) X-tube. After decompression and fixation using unilateral pedicle screws, a translaminar screw was inserted from the same incision to the other side. The results of perioperative parameters, radiographic images and clinical outcomes were assessed. All patients underwent MIS-TLIF were accomplished unilateral hybrid fixation without any neural complication. The average operative time was (107 ± 19) min, the average operative blood loss was (62 ± 21) ml, and the average postoperative ambulation time was (21 ± 5) h. The average length of translaminar facets screw was (52 ± 2) mm, and the postoperative images showed all screws penetrate through facets joint. During the follow-up the visual analogue scale and Oswestry disability index scores were significant improved compared with preoperative (F = 42.221 - 259.833, P < 0.01). Bilateral hybrid fixation could be completed through unilateral incision by pedicle screws and a translaminar screw in MIS-TLIF, and the advantage including less invasion, quickly recovery, short operative time, and saving fixation cost.	\N	\N
22335481	Optical imaging has seen significant developments over the past decade as an investigational tool for in-vivo visualization of cellular and sub-cellular events. With the recent addition of optoacoustic (photoacoustic) methods, in particular multi-spectral opto-acoustic tomography (MSOT), to the already rich armamentarium of photonic methods the capacity of optical molecular imaging across scales has widened significantly. MSOT brings unique features into optical imaging, namely high resolution optical imaging over several millimeters to centimeters of tissue depth and the ability to simultaneously resolve multiple tissue molecules and extrinsically administered optical or optoacoustic agents with physiological or molecular specificity. Here, we discuss the implications of utilizing MSOT in the context of drug discovery and review suitable optoacoustic agents against disease and drug efficacy biomarkers. The combination of existing knowledge on generating optical targeted contrast, with the high resolution deep tissue visualization offered by MSOT, allows for the development of next-generation biological optical imaging and corresponding drug discovery applications.	\N	\N
22337313	Rubella virus (RV) usually causes a mild disease. However, infection during the first trimester of pregnancy often leads to severe birth defects known as congenital rubella syndrome (CRS). Although wild-type RVs exist and circulate worldwide, their genotypes remain unknown in many countries. The aim of this study was to identify the molecular characteristics of RVs found in Vietnam during the years 2009-2010 and to provide the first data concerning RV genotypes in this country. Throat swab samples were collected between 2009 and 2010 from four CRS cases and nine rubella infection cases visiting one Children's Hospital and one outpatient clinic in Ho Chi Minh City. The 739-nucleotide coding region of the RV E1 gene recommended by the World Health Organization was amplified by reverse transcriptase PCR, and the resulting DNA fragments were then sequenced. Sequences were assigned to genotypes by phylogenetic analysis with RV reference strains. RV RNA was detected in 11 clinical specimens. Phylogenetic analysis of the sequences showed that all 11 strains belonged to 2B genotype. Several variations in amino acids were found, among which five changes were involved in the B and T cell epitopes. These data indicate that viruses of genotype 2B were circulating in Vietnam. The increasing information about RV genotype in Vietnam should aid in the control of rubella infection and CRS in this country.	\N	\N
22339380	Acute pancreatitis is an acute inflammatory condition of the pancreas, which might extend to local and distant extrapancreatic tissues. The global incidence varies between 17.5 and 73.4 cases per 100,000 and the pathogenesis recognizes alcohol exposure and biliary tract disease as the leading causes, ahead of post-endoscopic retrograde cholangiopancreatography, drugs and abdominal trauma. The diagnosis of acute pancreatitis is substantially based on a combination of clinical signs and symptoms, imaging techniques and laboratory investigations. Contrast-enhanced computed tomography is the reference standard for the diagnosis, as well as for establishing disease severity. The assessment of pancreatic enzymes, early released from necrotic tissue, is the cornerstone of laboratory diagnosis in this clinical setting. Although there is no single test that shows optimal diagnostic accuracy, most current guidelines and recommendations indicate that lipase should be preferred over total and pancreatic amylase. Although a definitive diagnostic threshold cannot be identified, cut-offs comprised between ≥ 2 and ≥ 4 times the upper limit of the reference interval are preferable. The combination of amylase and lipase has been discouraged as although it marginally improves the diagnostic efficiency of either marker alone, it increases the cost of investigation. Some interesting biomarkers have been also suggested (e.g., serum and urinary trypsinogen-1, -2 and -3, phospholipase A2, pancreatic elastase, procalcitonin, trypsinogen activated protein, activation peptide of carboxypeptidase B, trypsin-2-alpha1 antitrypsin complex and circulating DNA), but none of them has found widespread application for a variety of reasons, including the inferior diagnostic accuracy when compared with the traditional enzymes, the use of cumbersome techniques, or their recent discovery. The promising results of recent proteomics studies showed that this innovative technique might allow the identification of changes characterizing pancreatic tissue injury, thus highlighting new potential biomarkers of acute pancreatitis.	\N	\N
22353988	Several studies have reported that patients with essential tremor (ET) may also have mild cognitive impairment. Event-related potentials (ERPs) involve cognitive processes in the brain. No detailed investigation has been conducted into auditory ERPs (AERPs) to detect the subclinical cognitive dysfunction in patients with ET. Therefore, this study aimed to clarify the usefulness of AERPs in ET-related cognitive impairment. The AERPs were obtained by using an oddball paradigm in 27 patients with ET and 27 age-matched control subjects. The mean latency and amplitude of the ERPs were compared between the two groups. The correlation between disease duration and the mean values of all components of the potentials was assessed. The association between tremor severity and potentials was also evaluated. The patients with ET showed significant prolongation of all components of the ERP latencies at each electrode site. The N200 and P300 amplitudes were reduced in the ET group. Interestingly, the significant prolongation of N100 and N200 latencies correlated with disease duration, and N200 latencies appeared significantly longer in patients with severe tremor. Significant differences were found between the components of the AERPs and tremor severity and disease duration. This finding implies that ERPs may be useful in evaluating the cognitive functions in ET and that those AERP abnormalities may appear before clinical presentation.	\N	\N
22356008	A 22 year old female with valvular heart disease, moderate mitral valve insufficiency, moderate aortic insufficiency, extensive aneurysmal dilatation of the entire ascending aorta and arch, and segmental dilatation of descending aorta underwent entire anterior aortic replacement. We performed aortic root and valve replacement with a composite graft, followed by coronary artery reimplantation using the Bentall and De Bono technique. Simultaneously, we carried out a graft replacement of the transverse arch and descending aortic aneurysms with a woven Dacron graft using the Elephant Trunk technique. The goal of this surgery was to correct or optimally treat the multiple sites of aortic disease. To the best of our knowledge, there is no reported case from Pakistan with extensive aortic grafting from root to descending aorta using the Bentall and Elephant Trunk technique simultaneously.	\N	\N
22363380	The redox system is an important anti-oxidative system composed of thioredoxin, thioredoxin reductase, and peroxiredoxin (PRx). The fine details of PRx expression and its protective effects in various cells in cardiovascular tissue under oxidative stress created by hydrogen peroxide have not been fully elucidated. Oxidative stress was induced by adding hydrogen peroxide at 0.25 mM for 2 hours to rat neonatal cardiomyocytes (rCMCs), rat vascular smooth muscle cells (rVSMCs), and human umbilical vein endothelial cells (HUVECs). Apoptosis was quantified by flow cytometry and the expression patterns of the six PRx isoforms were evaluated by western blotting in the three cell lines after hydrogen peroxide stimulation. Apoptosis and the cell survival signal pathway were evaluated by PRx1 gene delivery using lentiviral vector in hydrogen peroxide stimulated rCMCs versus green fluorescence protein gene delivery. Hydrogen peroxide induced 25% apoptosis in rCMCs. Furthermore, the PRx1 and 5 isoforms were found to be overexpressed in hydrogen peroxide treated rCMCs, and PRx1 overexpression by gene delivery was found to reduce hydrogen peroxide induced rCMCs apoptosis significantly. In addition, this effect was found to originate from cell survival pathway modification. Hydrogen peroxide induced significant oxidative stress in rCMCs, rVSMCs, and HUVECs, and PRx1 overexpression using a lentiviral vector system significantly reduced hydrogen peroxide induced rCMCs apoptosis by upregulation of cell survival signals and downregulation of apoptotic signals. These findings suggest that PRx1 could be used as a treatment strategy for myocardial salvage in conditions of oxidative stress.	\N	\N
22363739	Southeast Asia has been the focus of considerable investment in pandemic influenza preparedness. Given the wide variation in socio-economic conditions, health system capacity across the region is likely to impact to varying degrees on pandemic mitigation operations. We aimed to estimate and compare the resource gaps, and potential mortalities associated with those gaps, for responding to pandemic influenza within and between six territories in Asia. We collected health system resource data from Cambodia, Indonesia (Jakarta and Bali), Lao PDR, Taiwan, Thailand and Vietnam. We applied a mathematical transmission model to simulate a "mild-to-moderate" pandemic influenza scenario to estimate resource needs, gaps, and attributable mortalities at province level within each territory. The results show that wide variations exist in resource capacities between and within the six territories, with substantial mortalities predicted as a result of resource gaps (referred to here as "avoidable" mortalities), particularly in poorer areas. Severe nationwide shortages of mechanical ventilators were estimated to be a major cause of avoidable mortalities in all territories except Taiwan. Other resources (oseltamivir, hospital beds and human resources) are inequitably distributed within countries. Estimates of resource gaps and avoidable mortalities were highly sensitive to model parameters defining the transmissibility and clinical severity of the pandemic scenario. However, geographic patterns observed within and across territories remained similar for the range of parameter values explored. The findings have important implications for where (both geographically and in terms of which resource types) investment is most needed, and the potential impact of resource mobilization for mitigating the disease burden of an influenza pandemic. Effective mobilization of resources across administrative boundaries could go some way towards minimizing avoidable deaths.	\N	\N
22365640	For an evaluation of the progress achieved in the field of kidney cancer care in the Netherlands in the last decades, we described trends in incidence, treatment, mortality and relative survival. All adult patients newly diagnosed with kidney cancer between 1989 and 2009 (N=32,545) were selected from the Netherlands Cancer Registry. Age-standardised incidence and mortality rates were calculated. Follow-up was completed until January 2010. In order to assess trends estimated annual percentages of change (EAPC) were estimated. The incidence of kidney cancer has been fairly stable between 1989 and 2001 with a European Standardised Rate of approximately 11 per 100,000 person years (PY). Since 2001 the incidence increased to 13 per 100,000 PY in 2009 (EAPC: 2.4%; 95%confidence interval (CI): 1.5 to 3.4%). The mortality rate decreased slightly over time, from 6.2 per 100,000 PY in 1989 to 5.6 in 2010. No changes in treatment were observed, except for the introduction of targeted therapies for stage IV disease, since 2005. The 5-year relative survival improved from 51% in 1989-1994 to 58% in 2005-2009 (EAPC: 0.9%; 95%CI 0.7 to 1.2%). Improvement in survival was especially seen in males, younger age groups and low stages. The incidence of kidney cancer has increased slightly, and survival improved modestly, resulting in a decreasing mortality. A positive effect of the introduction of targeted therapies for metastatic kidney cancer was observed in 1-year relative survival. For progress in kidney cancer care, effective prevention strategies and new therapies remain warranted.	\N	\N
22370242	This review describes the features of modern infrared imaging technology and the standardization protocols for thermal imaging in medicine. The technique essentially uses naturally emitted infrared radiation from the skin surface. Recent studies have investigated the influence of equipment and the methods of image recording. The credibility and acceptance of thermal imaging in medicine is subject to critical use of the technology and proper understanding of thermal physiology. Finally, we review established and evolving medical applications for thermal imaging, including inflammatory diseases, complex regional pain syndrome and Raynaud's phenomenon. Recent interest in the potential applications for fever screening is described, and some other areas of medicine where some research papers have included thermal imaging as an assessment modality. In certain applications thermal imaging is shown to provide objective measurement of temperature changes that are clinically significant.	\N	\N
22383586	To report the annual incidence of occupational diseases (ODs) in economic sectors in The Netherlands. In a 5-year prospective cohort study (2009-2013), occupational physicians were asked to participate in a sentinel surveillance system for OD notification. The inclusion criteria for participation were (1) covering a population of employees, (2) reporting the economic sectors and the size of their employee population and (3) willingness to report all diagnosed ODs. In this study, an OD was defined as a disease with a specific clinical diagnosis that was predominantly caused by work-related factors. The economic sectors (n=21) were defined according the NACE (Nomenclature des Activités Économiques dans la Communauté Européenne) classification. In a total working population of 514,590 employees, 1782 ODs were reported over 12 months in 2009. The estimated annual incidence for any OD was 346 (95% CI 330 to 362) per 100,000 worker-years. Of all the ODs, mental diseases were reported most frequently (41%), followed by musculoskeletal (39%), hearing (11%), infectious (4%), skin (3%), neurological (2%) and respiratory (2%) diseases. The four economic sectors with the highest annual incidences per 100,000 workers were construction (1127; 95% CI 1002 to 1253), mining and quarrying (888; 95% CI 110 to 1667), water and waste processing (832; 95% CI 518 to 1146) and transport and storage (608; 95% CI 526 to 690). ODs are reported in all economic sectors in The Netherlands. Up to 91% of all ODs are mental, musculoskeletal and hearing diseases. Efforts to increase the effective assessment of ODs and compliance in reporting activities enhance the usability of incidence figures for the government, employers and workers.	\N	\N
22394620	The longitudinal degradation mechanism of extracellular matrix (ECM) in the interbertebral disc remains unclear. Our objective was to elucidate catabolic and anabolic gene expression profiles and their balances in intervertebral disc degeneration using a static compression model. Forty-eight 12-week-old male Sprague-Dawley rat tails were instrumented with an Ilizarov-type device with springs and loaded statically at 1.3 MPa for up to 56 days. Experimental loaded and distal-unloaded control discs were harvested and analyzed by real-time reverse transcription-polymerase chain reaction (PCR) messenger RNA quantification for catabolic genes [matrix metalloproteinase (MMP)-1a, MMP-2, MMP-3, MMP-7, MMP-9, MMP-13, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4, and ADAMTS-5], anti-catabolic genes [tissue inhibitor of metalloproteinases (TIMP)-1, TIMP-2, and TIMP-3], ECM genes [aggrecan-1, collagen type 1-α1, and collagen type 2-α1], and pro-inflammatory cytokine genes [tumor necrosis factor (TNF)-α, interleukin (IL)-1α, IL-1β, and IL-6]. Immunohistochemistry for MMP-3, ADAMTS-4, ADAMTS-5, TIMP-1, TIMP-2, and TIMP-3 was performed to assess their protein expression level and distribution. The presence of MMP- and aggrecanase-cleaved aggrecan neoepitopes was similarly investigated to evaluate aggrecanolytic activity. Quantitative PCR demonstrated up-regulation of all MMPs and ADAMTS-4 but not ADAMTS-5. TIMP-1 and TIMP-2 were almost unchanged while TIMP-3 was down-regulated. Down-regulation of aggrecan-1 and collagen type 2-α1 and up-regulation of collagen type 1-α1 were observed. Despite TNF-α elevation, ILs developed little to no up-regulation. Immunohistochemistry showed, in the nucleus pulposus, the percentage of immunopositive cells of MMP-cleaved aggrecan neoepitope increased from 7 through 56 days with increased MMP-3 and decreased TIMP-1 and TIMP-2 immunopositivity. The percentage of immunopositive cells of aggrecanase-cleaved aggrecan neoepitope increased at 7 and 28 days only with decreased TIMP-3 immunopositivity. In the annulus fibrosus, MMP-cleaved aggrecan neoepitope presented much the same expression pattern. Aggrecanase-cleaved aggrecan neoepitope increased at 7 and 28 days only with increased ADAMTS-4 and ADAMTS-5 immunopositivity. This rat tail sustained static compression model mimics ECM metabolic imbalances of MMPs, aggrecanases, and TIMPs in human degenerative discs. A dominant imbalance of MMP-3/TIMP-1 and TIMP-2 relative to ADAMTS-4 and ADAMTS-5/TIMP-3 signifies an advanced stage of intervertebral disc degeneration.	\N	\N
22407767	Cryptic subtelomeric chromosomal aberrations are responsible for 5-10% of moderate/severe and 1% of mild intellectual disability. Unbalanced subtelomeric chromosomal rearrangements result in variable phenotypes which seem to be highly influenced by both the size of the duplication/deletion and the chromosomes involved in the translocation. We report on three related patients with moderate intellectual disability, language delay, hypotonia, facial dysmorphism, cardiac anomalies, scoliosis, and kyphosis in whom a familial (maternal) unbalanced submicroscopic translocation was found by subtelomeric fluorescence in situ hybridization (FISH). This rearrangement resulted in a partial trisomy 10pter and partial monosomy 21qter. The karyotype was 46,XY.ish der(21)t(10;21)(p14;q22.2). Confirmation of a 6.7 Mb size distal duplication of the p15.3-14 region of chromosome 10 and a 5.6 Mb distal deletion of the q22.2-22.3 region of chromosome 21 was obtained by array-CGH. To our best knowledge, such a composition of subtelomeric unbalanced translocations has not yet been published. Detection of this aberration in successive pregnancies of carrier members of the family by prenatal FISH could prevent the recurrence of the disease. Furthermore, detection of the rearrangements and identification of genes located in the chromosomal regions involved might be of interest.	\N	\N
22412958	This study identified sex differences in progression of cutaneous melanoma. Of 7,338 patients who were diagnosed as an invasive primary CM without clinically detectable metastases from 1976 to 2008 at the University of Tuebingen in Germany, 1,078 developed subsequent metastases during follow up. The metastatic pathways were defined in these patients and analyzed using the Kaplan-Meier method. Multivariate survival analysis was performed using Cox modeling. In 18.7% of men and 29.2% of women (P<0.001) the first metastasis following diagnosis of primary tumor was locoregional as satellite/in-transit metastasis. The majority of men (54.0%) and women (47.6%, P = 0.035) exhibited direct regional lymph node metastasis. Direct distant metastasis from the stage of the primary tumor was observed in 27.3% of men and 23.2% of women (P = 0.13). Site of first metastasis was the most important prognostic factor of survival after recurrence in multivariate analysis (HR:1.3; 95% CI: 1.0-1.6 for metastasis to the regional lymph nodes vs. satellite/in-transit recurrence, and HR:5.5; 95% CI: 4.2-7.1 for distant metastasis vs. satellite/in-transit recurrence, P<0.001). Median time to distant metastasis was 40.5 months (IQR, 58.75) in women and 33 months (IQR, 44.25) in men (P = 0.002). Five-year survival after distant recurrence probability was 5.2% (95% CI: 1.4-2.5) for men compared with 15.3% (95% CI: 11.1-19.5; P = 0.008) for women. Both, the pattern of metastatic spread with more locoregional metastasis in women, and the time course with retracted metastasis in women contributed to the more favorable outcome of women. Furthermore, the total rate of metastasis is increased in men. Interestingly, there is also a much more favorable long term survival of women after development of distant metastasis. It remains a matter of debate and of future research, whether hormonal or immunologic factors may be responsible for these sex differences.	\N	\N
22417127	In approximately 5-8% patients with primary ovarian insufficiency (POI), the disease is caused by an autoimmune process made evident by the appearance of autoantibodies against steroidogenic enzymes (SCA-POI). Anti-müllerian hormone (AMH) is the best marker of the residual follicular pool. To evaluate the rate of loss of the residual follicle pool in women with SCA-POI after clinical diagnosis. One hundred and thirty-two women with POI were tested for 21-hydroxylase autoantibodies, 17α-hydroxylase autoantibodies and P450scc autoantibodies, and 35 patients with SCA-POI were identified. AMH was analysed at the time of the first visit in all women with POI, and in follow-up, serum samples were taken 1-3 years after in 11 women with SCA-POI and detectable AMH. 12/35 (35%) women with SCA-POI had AMH levels within the normal range at the time of first sampling, as compared to 6/97 (6%) with idiopathic POI (P < 0·001). 11/17 (65%) women with SCA-POI with <6 years disease duration had normal serum AMH concentration. A progressive decline in AMH concentration was observed at longitudinal follow-up in all 11 AMH-positive women with SCA-POI, at an estimated average rate of 1·6 μg/l AMH/year (corresponding to an average 57% of preserved follicle pool/previous year) (R(2)  = 0·219, P = 0·028). After 6 years of disease duration, only 1/18 (6%) women with SCA-POI had detectable levels of AMH, similar to women with idiopathic POI (5/78, 6%). Most women with SCA-POI present at clinical diagnosis with a preserved follicle pool that is progressively lost within a few years.	\N	\N
22426166	Natural killer (NK) cells are the effector cells of innate immunity that respond to infection and tumor. Interactions between killer cell immunoglobulin like receptors (KIR) and human leukocyte antigen (HLA) class I molecules regulate NK cells responses to eliminate infected and transformed cells. To investigate the impact of KIR genes, HLA ligand genes, and KIR-HLA combinations on susceptibility to tuberculosis (TB) in Lur population of Iran. The genomic DNA of 50 patients with TB from Lorestan province of Iran was genotyped for sixteen KIR genes and their five major HLA class I ligands were determined by a polymerase chain reaction-sequence-specific primers (PCR-SSP) assay. The results were compared with those of 200 healthy unrelated Iranian individuals. In Lur population of Iran, a significant decrease in frequency of KIR3DS1 was found in TB patients compared to control group (24% vs. 44.5%, OR=0.394, CI=0.194-0.798, p=0.013). Also, among the three activating genes that may use HLA class I molecules as their ligands, a significant decrease was shown in frequency of KIR3DS1 with HLA-B Bw4Ile80 ligand in TB patients compared to control group (4% vs. 23%, OR=0.14, CI=0.033-0.596, p=0.004). These findings imply a genetic imbalance between activating and inhibitory KIR genes and KIR-HLA combinations in Lur TB patients. Low level of activating KIR3DS1 and its combination with HLA-B Bw4Ile80 ligand might have an influence on the susceptibility to TB in Lur population of Iran.	\N	\N
22433620	The aim of this study was to define body fat percentiles for German children and adolescents aged 3-16 years using the largest German database. The study population included 11,632 girls and 11,604 boys. Data were pooled from: i) Kiel Obesity Prevention Study (KOPS), acquisition period: 1996-2008, n = 12,237; ii) 'Better diet. More exercise. KINDERLEICHT-REGIONS', acquisition period: 2007, n = 9,405; and iii) examination of Jena schoolchildren, acquisition period: 2005, n = 1,594. Body fat mass was measured by bioelectrical impedance analysis using a population-specific algorithm. Data were weighted to achieve a representative sample for Germany. Percentile curves were constructed by the LMS method and proved by Worm plots and Q-statistic. In both genders, the higher body fat percentile curves sloped downwards to age 7 years, whereas the lower percentiles declined up to 8.5 years. Thereafter fat mass remained nearly constant with age in boys and increased in girls. The 10th percentile achieved a minimum of 10-11% body fat in both genders, whereas the 90th percentile curve fluctuated between 29 and 44% in boys or 30-43% in girls. The association between fat mass and blood pressure was too weak to define disease-related cut-offs. These body fat percentiles are suitable reference values for German children and adolescents.	\N	\N
22434759	The aim of our study was to evaluate the physical and sedentary activities and energy expenditure (EE) in a group of children affected by non-alcoholic fatty liver disease (NAFLD), compared with normal and obese subjects, using a physical activity questionnaire (PAQ) and a SenseWear armband (SWA). Forty NAFLD (10 females), 41 lean (NRM; 11 females) and 30 obese (OB; 10 females), age- and pubertal stage-matched, children were included. Sedentary activity (PAQ) was similar in NAFLD and NRM but less in OB, while SWA showed that NAFLD spent less time in physical activity and more in sedentary activities compared with NRM, but not with OB. Insulin sensitivity index result is related to active EE (cal kg(-1)  d(-1) ) in NAFLD, while homeostatic model assessment index result was negatively related to total EE in OB. Regular physical activity must be encouraged in all obese children affected by NAFLD or not, and SWA might be a possible valid tool for evaluating actual EE.	\N	\N
22458506	The roles of cysteine protease (CP) enzymes in the biochemistry and infectivity of the three trypanosomal parasitic infections, Chagas' disease, leishmaniasis and human African trypanosomiasis, which have been elucidated over the last three decades are summarized. Inhibitors of these enzymes, which act through trapping the active site cysteine with an electrophilic warhead, hold huge potential as therapeutic agents but the promise of these has yet to be realized in clinical studies. The article addresses aspects that ought to be considered in order to develop orally active CP inhibitors that are safe and effective therapies for trypanosomiasis. This article reviews learnings from CP research in the trypanosomal field and recent advances in developing cysteine protease inhibitors (CPIs) of human cathepsin K, a related enzyme. Considerations such as intra- and extracellular localization of the CPs, off-target activities against human cathepsin enzymes, basic versus neutral and potential pro-drug inhibitors are reviewed. A description of odanacatib, a cathepsin K inhibitor currently in late stage development, is made to illustrate the attributes of a clinically viable CPI. The emerging role of CPs in a wide array of parasitic diseases is highlighted with the vision that CP inhibitors could become the 'β-lactams' of anti-parasitic treatments in the coming decades. New CPI research will see the optimization of intra- and extracellular enzyme targeting, reduction of off-target activities and better understanding of pharmacokinetic-pharmacodynamic interactions which will all lead to compounds with much improved efficacy and viability as clinical therapies.	\N	\N
22458804	Over the past few years, there has been a rapid rise in the older segments of the world population, which has brought along with it a major health concern: dementia. Alzheimer's disease, considered to be the most common cause of dementia, has become a prospect feared by the elderly. Inflammation of the brain is strongly implicated in Alzheimer's disease which could be enhanced by systemic inflammation. Periodontitis being a chronic inflammatory condition, which can cause systemic inflammation, the question is whether chronic periodontitis can initiate or hasten the rate of progression of Alzheimer's disease in susceptible individuals. In this article, the authors outline the proposed oral systemic link between periodontitis and Alzheimer's disease.	\N	\N
22463746	Evaluation of peritoneal involvement in colonic cancer (CC) can be difficult. We studied pT4N0 cancers and their association with pathological prognostic markers, including tumour budding. Tumours were classified as (i) at the peritoneal surface or free in the peritoneal cavity (pT4a subgroup n = 44); (ii) directly invading adjacent organ (pT4b subgroup n = 8); or (iii) showing inflammatory involvement of the peritoneum (pT4I subgroup n = 25). A published pT3N0 cohort was used to compare Stage II subgroups. Standard pathological markers including tumour budding were assessed. Elastin staining was performed in the pT4I subgroup. Seventy-seven Stage II CCs met inclusion criteria. There was no significant difference in survival across subgroups. pT4b tumours were larger than pT4a tumours (P < 0.001). Over-represented features in pT4a versus pT4b tumours were tumour budding (P = 0.02) and infiltrative margin (P = 0.02). Tumour budding did not predict survival. Using multivariate analysis, neural invasion was the only parameter predictive of survival (hazard ratio = 2.8; 95% CI 1.2-6.4; P = 0.02). Stage II pT4I CCs have a similar outcome to T4a/b tumours. Elastin staining is useful in defining this group. Tumour budding may facilitate peritoneal invasion in pT4a tumours, but does not predict outcome in pT4N0 disease. Only neural invasion independently predicted poor outcome.	\N	\N
22466542	Most common type of head and neck malignant tumors is squamous cell carcinoma reaching 3% of all human cancers. Oral squamous cell carcinoma (OSCC) has tendency of increasing incidence and mortality worldwide with an overall 5 year survival rate of <60%. In order to explore this disease, different in vivo mouse models have been introduced. In this study we analyzed clinical and morphological characteristics of OSCC in vivo nude mouse model. 80% of mice which were injected with human oral squamous cancer cells developed orthotopic tumors with the mean volume of 146 mm(3), from which 62% exhibited metastatic spread. Morphology of the cancer tissue was characterized with invasive phenotype and inflammation. Proliferation activity rate of orthotopicly grown tumors were 55,7 ± 4,7 mitotic cells/optical field and displayed weakly developed vascular network. OSCC in vivo orthotopic nude mouse model can mimic pathological and clinical picture of the malignant disease and may be effectively used in oncology research.	\N	\N
22472026	Patients with Crohn's disease (CD) may need anti-inflammatory drugs for decades. Anti-TNF-α agents have good efficacy and adverse events similar to placebo in randomized controlled trials (RCTs), but there are still questions about long-term safety and efficacy. In this respect, reports from clinical practice may be useful. We currently report on the clinical experience with infliximab and adalimumab in a single-center cohort of patients with CD. Patients with CD treated with infliximab or adalimumab from 2000 to 2010 were reviewed. Patient and disease characteristics at start, reason for discontinuation, and adverse events were recorded retrospectively. Corticosteroid use, the need for hospitalization, and surgeries before and during anti-TNF-α therapy were recorded. Eighty-three patients had received anti-TNF-α treatment against CD, median treatment duration was 11.4 months (0.2-99.5), and follow-up time 59 months (8-135). Eighteen of 43 patients using corticosteroids at treatment start discontinued corticosteroids during TNF-α therapy. Need for hospitalizations (6.13 vs. 3.28 days/year, p < 0.001) and surgeries (0.56 vs. 0.16 operations/year, p < 0.001) were lower during anti-TNF-α therapy than before treatment. Twenty-six percent discontinued therapy due to adverse events and 26% due to lack or loss of response. Two of four deaths observed during follow-up were believed to be related to anti-TNF-α treatment. Anti-TNF-α therapy was beneficial in many patients with CD, but the majority of patients discontinued treatment during follow-up. Reports from clinical experience with anti-TNF-α treatment may be valuable for clinicians treating patients with CD.	\N	\N
22483567	Anti tumor necrosis factor alpha (TNFα) agents have become widely used in pediatric inflammatory bowel disease (IBD). So far, only few studies examined the long-term results of anti-TNFα treatment in children with IBD. The long-term outcome of pediatric patients with IBD was assessed retrospectively in a multicenter cohort of children treated with anti-TNFα beyond induction treatment. Short- and long-term response rates, predictors for loss of response, data on growth and laboratory parameters were assessed. 120 patients [101 crohn's disease (CD), 19 ulcerative colitis (UC) or indeterminate colitis (IC)] received either infliximab or adalimumab. The mean age at initiation of anti-TNFα was 13.4 ± 3.9 years and the median duration of anti-TNFα treatment was 15 months (range: 2-90). Overall, 89% of the cohort experienced short-term response following induction. Response was associated with improvement in weight and BMI Z-scores (p<0.001) but not with linear growth. Responders experienced a significant decrease in erythrocyte sedimentation rate (ESR) and C reactive protein (CRP) during treatment (p<0.001). Albumin and hemoglobin both improved but only albumin increased significantly (p<0.001). The cumulative probability of losing response to anti-TNFα treatment was 17%, 38%, and 49% after 1, 3, and 5 years, respectively. Responders had a significantly lower weight and BMI Z-scores at initiation of anti-TNFα treatment in compared to non-responders (p=0.04 and 0.02 respectively). Our long term cohort supports the current evidence on the effectiveness and safety of anti-TNFα treatment in children with IBD. Response to treatment was interestingly associated with lower weight and BMI.	\N	\N
22484574	To determine the incidence of radiographic lumbar spondylosis (LS)and lower back pain, and their risk factors in Japan using a large-scale population from the nationwide cohort Research on Osteoarthritis/osteoporosis Against Disability (ROAD) Study. Participants in the ROAD study who had been recruited between 2005 and 2007 were followed up with lumbar spine radiography for 3 years. A total of 2,282 paired radiographs (75% of the original sample) were scored using Kellgren and Lawrence (KL) grades, and the incidence and progression rate of radiographic LS was analyzed. The incidence of lower back pain was also examined. In addition, associations between risk factors and incident and progressive radiographic LS as well as incident lower back pain were tested. Given a 3.3-year follow-up, the incidence of KL≥2 radiographic LS was 50.0% and 34.4% (15.3% and 10.5% per year), while that of KL≥3 LS was 15.3% and 23.7% (4.6% and 7.2% per year) in men and women, respectively. The progression rate of LS was 20.5% and 27.4% (6.2% and 8.3% per year) in men and in women, respectively. In addition, the incidence of lower back pain was 28.3% and 31.2% (8.6% and 9.5% per year) in men and women. Lower back pain was not significantly associated with incident radiographic LS, while a more severe KL grade at baseline was associated with incident lower back pain. The present longitudinal study revealed a high incidence of radiographic LS in Japan.	\N	\N
22484921	Sarcoidosis is a multi-systemic disease. A 21-year-old female patient was admitted to our department with lymphadenopathy, B symptoms, erythema nodosum and joint pain. Sarcoidosis showed a very atypical course, lacking any pulmonary symptoms or typical laboratory values. The diagnosis was finally confirmed histologically and thus various differential diagnoses such as microbiological and malignant diseases could be excluded. Oral steroid medication led to remission.	\N	\N
22484998	Populations living in poverty in the developing world suffer a heavy burden caused by infectious diseases, most of them zoonoses. The poorer populations also tend to be marginalised from the health sector and so are many of the diseases that affect them. The poor in every society, and particularly in developing countries, bear a disproportionately high share of the disease burden. There is a broad range of viral, bacterial, mycotic, chlamydial, rickettsial and parasitic diseases of global and regional importance given their major impact on the health and socio-economic development of many populations. Endemic infectious diseases, including zoonoses, together with emerging and re-emerging diseases, are mostly shouldered by poor and vulnerable populations. Livestock are important in supporting the livelihoods of poor farmers, consumers and traders throughout the developing world. The animals of poor people are particularly vulnerable to disease because of costs, absence or unsuitability of the animal health sector, etc. The impact of endemic animal diseases are mainly felt at the farm level, while a broader economic impact can occur with these diseases through the restriction of trade in livestock and their products. Addressing comprehensive and sustainable solutions to public health problems created by endemic infections cannot be achieved solely by the public health sector alone. Partnerships with other sectors, particularly agriculture, environment, education, local administration, will be necessary to contain and effectively control zoonotic and foodborne diseases that affect mainly the poor. International organisations could support developing countries by coordinating national intersectoral activities, promoting appropriate technology and public health education, community participation and encouraging decision-makers to commit themselves. This is the only perspective for improved quality of life of poor and marginalised populations.	\N	\N
22485050	Immunogenicity and safety of ACWY-TT compared with licensed ACWY polysaccharide vaccine (MenPS) in healthy adults, and lot-to-lot consistency of three ACWY-TT lots were evaluated in a phase 3, open, controlled study. Adults aged 18-55 y were randomized to receive ACWY-TT (one of three lots) or MenPS. Serum bactericidal antibodies (rSBA) were measured pre- and 1 mo post-vaccination. Adverse events (AEs) were assessed 4 d (solicited symptoms) and 31 d (unsolicited symptoms) post-vaccination. Serious AEs were reported up to 6 mo after vaccination. The number of vaccinated subjects was 1247 (ACWY-TT, n = 935; MenPS, n = 312). ACWY-TT lot-to-lot consistency and non-inferiority of ACWY-TT as compared with MenPS groups were demonstrated according to pre-specified criteria. The percentages of subjects with a vaccine response (VR = rSBA titer ≥ 1:32 in initially seronegative; ≥ 4-fold increase in initially seropositive) to ACWY-TT vs. MenPS were 80.1%/69.8% (serogroup A), 91.5%/ 92.0% (C), 90.2%/85.5% (W-135), 87.0%/78.8% (Y). Exploratory analyses showed that for serogroups A, W-135 and Y, VR rates and GMTs were significantly higher for ACWY-TT compared with MenPS. For each serogroup, ≥ 98.0% of subjects had rSBA titers ≥ 1:128. Grade 3 solicited AEs were reported in ≤ 1.6% of subjects in any group. The immunogenicity of ACWY-TT vaccine was non-inferior to MenPS for all four serogroups in adults, with significantly higher VR rates to serogroups A, W-135 and Y and an acceptable safety profile. Consistency of 3 ACWY-TT production lots was demonstrated. These data suggest that, if licensed, ACWY-TT conjugate vaccine may be used for protection against invasive meningococcal disease in healthy adults.   This study is registered at clinicaltrials.gov NCT00453986.	\N	\N
22486286	Patients with chronic kidney disease are exposed to oxidative stress (OS) that contributes to deterioration of health. Decrease in renal excretory capacity contributes to the accumulation of pro-oxidative substances that are detrimental not only to kidney but to the whole organism including the cardiovascular system. Components of antioxidant system play an important role in the elimination of the OS. The monitoring of antioxidant levels and products of oxidative damage in these patients and the correct interpretation of relationship between these markers and the function of kidney and other organs may contribute to the more effective treatment and health improvement of the patients.	\N	\N
22494938	The whipworms Trichuris trichiura and Trichuris suis in humans and pigs, respectively, are believed to be two different species yet closely related. Morphologically, adult worms, eggs and larvae of the two species are indistinguishable. The aim of this study was to examine the genetic variation of Trichuris sp. mainly recovered from natural infected pigs and humans. Worm material isolated from humans and pigs living in the same geographical region in Uganda were analyzed by PCR, cloning and sequencing. Measurements of morphometric characters were also performed. The analysis of the ITS-2 (internal transcribed spacer) region showed a high genetic variation in the human-derived worms with two sequence types, designated type 1 and type 2, differing with up to 45%, the type 2 being identical to the sequence found in pig-derived worms. A single human-derived worm showed exclusively the type 2-genotype (T. suis-type) and three cases of 'heterozygote' worms in humans were identified. However, the analysis showed that sympatric Trichuris primarily assorted with host origin. Sequence analysis of a part of the genetically conserved β-tubulin gene confirmed two separate populations/species but also showed that the 'heterozygote' worms had a T. suis-like β-tubulin gene. A PCR-RFLP on the ITS-2 region was developed, that could distinguish between worms of the pig, human and 'heterozygote' type. The data suggest that Trichuris in pigs and humans belong to two different populations (i.e. are two different species). However, the data presented also suggest that cross-infections of humans with T. suis takes place. Further studies on sympatric Trichuris populations are highly warranted in order to explore transmission dynamics and unravel the zoonotic potential of T. suis.	\N	\N
22498694	Although many of the effects of estrogens on the brain are mediated through estrogen receptors (ERs), there is evidence that neuroprotective activity of estrogens can be mediated by non-ER mechanisms. Herein, we review the substantial evidence that estrogens neuroprotection is in large part non-ER mediated and describe in vitro and in vivo studies that support this conclusion. Also, we described our drug discovery strategy for capitalizing on enhancement in neuroprotection while at the same time, reducing ER binding of a group of synthetic non-feminizing estrogens. Finally, we offer evidence that part of the neuroprotection of these non-feminizing estrogens is due to enhancement in redox potential of the synthesized compounds.	\N	\N
22503230	To investigate whether single nucleotide polymorphisms (SNPs) in interleukin (IL)-1β, IL-6, and IL-12β are associated with the susceptibility and severity of contact lens-related keratitis. Retrospective, case control study. One hundred twelve cases of keratitis and 225 controls were recruited from studies conducted at Moorfields Eye Hospital and in Australia during 2003 through 2005. Buccal swab samples were collected on Whatman FTA cards and were mailed by post for analysis. IL-1β (-31), IL-6 (-174, -572, -597), and IL-12B (3'+1158) genotypes were analyzed with pyrosequencing and analyzed using a regression model for susceptibility (sterile, microbial keratitis, controls) and severity. Statistical significance was set at 0.05. The relative risk of developing contact lens-related keratitis and more severe forms of the disease based on allele, genotype, and haplotype associations. Carriers of IL-6 SNPs were more likely to experience moderate and severe events compared with those with nonmutated genotypes (-174 heterozygous: odds ratio [OR], 3.1; 95% confidence interval [CI], 1.1-8.3; homozygous: OR, 6.4; 95% CI, 1.4-28.4; -174/-597: OR, 4.1; 95% CI, 1.6-11.0). More severe keratitis and microbial keratitis were less likely to occur in wearers with the nonmutated IL-6 haplotype (severity OR, 0.4 [95% CI, 0.2-0.7]; microbial OR, 0.6 [95% CI, 0.4-0.9]). Wearers carrying an IL-12B SNP had an increased risk of sterile keratitis (OR, 9.7; 95% CI, 1.2-76.9) compared with controls. The IL-6 SNPs are known to reduce protein expression of this cytokine and thus ocular immune defense, and carriers of these SNPs were more likely to experience more severe and microbial keratitis, suggesting that IL-6 decreases the severity and susceptibility of contact lens-related keratitis. Carriers of a functional SNP of IL-12B that is known to increase IL-12 expression and stability are more likely to experience sterile keratitis, suggesting that this is associated with the intense inflammatory reaction that occurs in this condition.	\N	\N
22505009	To evaluate inhibin-A immunoreactivity and its utility in the differential diagnosis of nervous system neoplasms and non-neoplastic lesions. An immunohistochemical study of 252 central and peripheral nervous system tumors and 40 non-neoplastic lesions was undertaken. Brain lesions included the basic spectrum of astrocytic, oligodendroglial, and ependymal neoplasms, as well as glioneuronal, pineal parenchymal, choroid plexus, and embryonal. Meningeal neoplasms, basic peripheral nerve tumors, and uncommon sellar lesions were also assessed. Non-neoplastic lesions included demyelinating disease, progressive multifocal leukoencephalopathy, organizing infarct, and reactive gliosis. Diffuse cytoplasmic, membranous, and perinuclear cytoplasmic staining patterns were observed. Significant immunoreactivity was noted in glioblastoma (12 of 20), pleomorphic xanthoastrocytoma (6 of 10), ganglioglioma (8 of 10), meningioma (14 of 20), and hemangioblastoma (10 of 10). Peripheral nerve and sellar tumors as well as non-neoplastic lesions were entirely immunonegative. In our study that investigated the inhibin-A immunoreactivity in a broad spectrum of nervous system lesions, inhibin-A positivity was established in various low-grade and high-grade central nervous system tumors. Thus, inhibin-A is not a specific marker of hemangioblastoma and may be of limited utility in the differential diagnosis of astrocytic and meningothelial neoplasms. Its pathophysiologic role in these various tumors remains to be determined. Further evaluation of the possible significance of staining patterns and degrees of reactivity relative to pathobiology and/or prognosis significance is required.	\N	\N
22507833	Osteoporosis, a major health problem among postmenopausal women, is influenced by dietary factors. The purpose of the present study was to evaluate the hypothesis that erythrocyte levels of n-3 polyunsaturated fatty acid (PUFA) and the dietary intake of fish are associated with risk of osteoporosis and correlate with bone mass in postmenopausal Korean women with the disease. Fifty cases and 100 controls were recruited. Osteoporosis was defined according to the International Society for Clinical Densitometry guideline as a score lower than -2.5 SD below the T-score for lumbar vertebrae L₁-L₄, femoral neck or femoral total. The T-score of the femoral neck was positively correlated with erythrocyte levels of n-3 PUFA, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and the intake of fish, and was negatively correlated with the ratio of n-6/n-3 PUFA after adjusting for age, years after menopause and height. In addition, the risk of osteoporosis was positively associated with erythrocyte levels of saturated fatty acids but negatively associated with EPA + DHA. Erythrocyte levels of n-3 PUFA and the intake of fish were positively correlated with bone mass. In particular, erythrocyte levels of EPA + DHA reduced the risk of osteoporosis in postmenopausal Korean women.	\N	\N
22509749	Mast cells are tissue-resident immune cells that participate in a variety of allergic and inflammatory conditions. Limited attention has been given to the role of mast cells in periodontal diseases, and the effects of mast cell degranulation on the chronic stages of non-allergic inflammation, particularly in periodontitis, are not known. The present study analyzes the relationship between the mast cell degranulation and human periodontal disease progression. A total of 50 clinical specimens including moderate periodontitis (n = 17), advanced periodontitis (n = 18), and healthy control tissues (n = 15) were used in this study. All specimens were fixed in 10% buffered formalin and stained with hematoxylin and eosin for histopathology, with toluidine blue for identifying mast cells, and by immunohistochemistry for the expressions of mast cell tryptase in periodontal tissues. The total and degranulated mast cell densities (per high-power field) were quantified in the specimens. Compared with healthy controls, there were significantly increased both total and degranulated mast cell densities in human moderate (P <0.01) and advanced (P <0.01) periodontitis groups by toluidine blue staining, and there were significantly higher densities of both total and degranulated tryptase-positive mast cell subpopulation in the moderate periodontitis group (P <0.01) and even significantly higher subpopulation densities in the advanced periodontitis group by immunohistochemical staining, in which both total and degranulated mast cell densities were significantly higher in the advanced periodontitis group than those in the moderate periodontitis group (P <0.01) by both toluidine blue staining and immunohistochemical staining. There was significantly more severe periodontal inflammatory pathology in the advanced periodontitis group than in the moderate periodontitis group (P <0.01). These findings indicate a significant correlation among tryptase-positive mast cell density, the degree of their degranulation, and the human periodontitis severity, and the results of this study further indicate that mast cell degranulation appears to be associated with human periodontal disease.	\N	\N
22511575	We sought to examine the contemporary use of thrombectomy during primary percutaneous coronary intervention (PCI) in the United States. Adjunctive thrombectomy during primary PCI for patients with ST-segment elevation myocardial infarction (STEMI) has demonstrated mixed results. While earlier studies showed either unfavorable or neutral effects with rheolytic thrombectomy, recent clinical trials have shown benefits with manual or rheolytic thrombectomy when compared to PCI alone. We analyzed data from 122,449 patients undergoing primary PCI for STEMI from 1,181 centers reported to the CathPCI Registry® between July 2009 and December 2010. We used logistic regression analysis to examine factors associated with the use of manual and rheolytic thrombectomy. Thrombectomy was performed in 23,195 patients (18.9%): 22,404 (18.3%) had manual thrombectomy and 791 (0.6%) had rheolytic thrombectomy. The use of manual thrombectomy increased over time (P < 0.05). The use of rheolytic thrombectomy did not change. There was significant variation in the use of thrombectomy across hospitals. The strongest predictors of manual versus no thrombectomy included TIMI 0/1 flow (odds ratio 1.69), younger age (OR 0.90 per 10 year increase), saphenous vein graft (OR 2.22), glycoprotein IIb/IIIa inhibitor (OR 1.34), single-vessel disease (OR 1.13), and year of admission (OR 1.20 per year; all P < 0.001). The strongest predictor of manual versus rheolytic thrombectomy was year of admission (OR 1.23, P < 0.001). Our data show that thrombectomy is performed infrequently in the US during primary PCI for STEMI. There is significant variation in the use of thrombectomy across US hospitals.	\N	\N
22515999	Myocarditis is defined as inflammation of the myocardium accompanied by myocellular necrosis. Acute myocarditis must be considered in patients who present with recent-onset of cardiac failure or arrhythmia. Fulminant myocarditis is a distinct entity characterized by sudden onset of severe congestive heart failure or cardiogenic shock, usually following a flu-like illness, parvovirus B19, human herpesvirus 6, coxsackievirus and adenovirus being the most frequently viruses responsible for the disease. Treatment of myocarditis remains largely supportive, since immunosuppression has not been proven to be beneficial for acute lymphocytic myocarditis. Trials of antiviral therapies, or immunostimulants such as interferons, suggest a potential therapeutic role but require further investigation. Lastly, early recognition of patients rapidly progressing to refractory cardiac failure and their immediate transfer to a medical-surgical center experienced in mechanical circulatory support is warranted. In this setting, ECMO should be the first-line mechanical assistance. For highly unstable patients, a Mobile Cardiac Assistance Unit, that rapidly travels to primary care hospitals with a portable ECMO system and hooks it up before refractory multiorgan failure takes hold, is the preferred option.	\N	\N
22523117	Podocyturia, i.e. urinary loss of viable podocytes, may serve as a diagnostic tool for pre-eclampsia and as a marker of active renal disease. The current method to detect podocyturia is technically complex, lengthy and requires a high level of expertise for interpretation. The aim of this study was to develop a new technique for the identification of urinary podocytes, based on the detection of podocyte-specific tryptic peptides by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS), which will provide an operator-independent and highly reproducible method. The diagnosis of pre-eclampsia was confirmed in the presence of hypertension (>140/90 mmHg) and proteinuria >0.3 g/24 h urine. The diagnosis of HELLP was confirmed based on the accepted clinical criteria of hemolysis, elevated liver enzymes and low platelet count. Random urine samples within 24 h prior to delivery were collected and centrifuged. One half of the sediment was cultured for 24 h to select for viable cells and then stained with a podocin antibody, followed by a secondary fluorescein isothiocyanate-labeled antibody to identify podocytes. The second half of the pellet was solubilized, digested and analyzed by LC-MS/MS using an internal standard. We have recruited 13 patients with pre-eclampsia and 6 patients with pre-eclampsia/HELLP syndrome. The presence of podocytes was confirmed in all patients by the podocyte culture method. In the respective samples, the presence of a podocin-specific tryptic peptide was confirmed with LC-MS/MS technology. The LC-MS/MS method is a reliable technology for the identification of urinary podocytes, based on the presence of podocyte-specific proteins in the urine.	\N	\N
22525341	Epoxyeicosatrienoic acids (EETs) are natural angiogenic mediators regulated by soluble epoxide hydrolase (sEH). Inhibitors of sEH can stabilize EETs levels and were reported to reduce atherosclerosis and inhibit myocardial infarction in animal models. In this work, we investigated whether increasing EETs with the sEH inhibitor t-AUCB would increase angiogenesis related function in endothelial progenitor cells (EPCs) from patients with acute myocardial infarction (AMI). EPCs were isolated from 50 AMI patients and 50 healthy subjects (control). EPCs were treated with different concentrations of t-AUCB for 24h with or without peroxisome proliferator activated receptor γ (PPARγ) inhibitor GW9662. Migration of EPCs was assayed in trans-well chambers. Angiogenesis assays were performed using a Matrigel-Matrix in vitro model. The expression of vascular endothelial growth factor (VEGF), hypoxia-inducible factor 1α (HIF-1α) mRNA and protein in EPCs was measured by real-time PCR or Western blot, respectively. Also, the concentration of EETs in the culture supernatant was detected by ELISA. The activity of EPCs in the AMI patient group was reduced compared to healthy controls. Whereas increasing EET levels with t-AUCB promoted a dose dependent angiogenesis and migration in EPCs from AMI patients. Additionally, the t-AUCB dose dependently increased the expression of the angiogenic factors VEGF and HIF-α. Lastly, we provide evidence that these effects were PPARγ dependent. The results demonstrate that the sEH inhibitor positively modulated the functions of EPCs in patients with AMI through the EETs-PPARγ pathway. The present study suggests the potential utility of sEHi in the therapy of ischemic heart disease.	\N	\N
22527997	Early life stress, such as maternal separation, causes adaptive changes in neural mechanisms that have adverse effects on the neuroplasticity of the brain in adulthood. As a consequence, children who are exposed to stress during development may be predisposed to neurodegenerative disorders in adulthood. A possible mechanism for increased vulnerability to neurodegeneration may be dysfunctional mitochondria. Protection from neurotoxins, such as 6-hydroxydopamine (6-OHDA), has been observed following voluntary exercise. The mechanism of this neuroprotection is not understood and mitochondria may play a role. The purpose of this study was to determine the effects of maternal separation and exercise on mitochondrial function in a rat model of Parkinson's disease. Maternally separated (pups separated from the dam for 3 h per day from postnatal day (P) 2-14) and non-separated rats were placed in individual cages with or without attached running wheels for 1 week prior to unilateral infusion of 6-OHDA (5 μg/4 μl, 0.5 μl/min) into the left medial forebrain bundle at P60. After 2 h recovery, rats were returned to their cages and wheel revolutions recorded for a further 2 weeks. On P72, the rats' motor function was assessed using the forelimb akinesia test. On P74, rats were sacrificed for measurement of mitochondrial function. Exercise increased the respiratory control index (RCI) in the non-lesioned hemisphere of 6-OHDA-lesioned rats. This effect was evident in the striatum of non-separated rats and the prefrontal cortex of maternally separated rats. These results suggest that early life stress may reduce the adaptive response to exercise in the striatum, a major target of dopamine neurons, but not the prefrontal cortex in this model of Parkinson's disease.	\N	\N
22531706	To identify the underlying mutation and describe the phenotype in a consanguineous Kurdish family with Leber's congenital amaurosis (LCA)/early onset severe retinal dystrophy (EOSRD). Members of the index family were followed up to 22 years by ophthalmological examinations, including best corrected visual acuity (BCVA), Goldmann visual field (GVF), two-color-threshold perimetry (2CTP) and Ganzfeld electroretinogram (ERG), fundus photographs, fundus autofluorescence (FAF), and optical coherence tomography (OCT). After excluding seven of nine known LCA/EOSRD genes in the index patient, linkage analysis was performed in the family using a microarray followed by microsatellite fine mapping and direct sequencing of candidate genes. RD3 was screened by direct sequencing of 85 independent patients with LCA/EOSRD presenting with a BCVA ≥ 1.0 LogMAR before the age of 2 years to assess the prevalence of RD3 mutations in LCA/EOSRD. Since RD3 and RetGC1 have a functional relation, study authors screened for a modifying effect of RD3 mutations in 17 independent patients with mutations in GUCY2D. BCVA was severely reduced from the earliest examinations (as early as 3 months), never exceeding 1.3 LogMAR. The disease presented as cone-rod dystrophy with dystrophic changes in the macula and bone spicules in the periphery on progression. Linkage analysis narrowed the region of interest towards the LCA12 locus. Direct sequencing of RD3 revealed a homozygous nonsense mutation (c.180C > A) in all affected members tested. Screening of additional unrelated LCA/EOSRD patients revealed only polymorphisms in RD3. This is the second family reported so far with mutations in RD3. Mutations in RD3 are a very rare cause of LCA associated with an extremely severe form of retinal dystrophy.	\N	\N
22533114	Although the number of tuberculosis cases in the US is at an all-time low, with progressive declines seen for the past 17 years, many goals in the tuberculosis elimination process remain unrealized. This report describes a cluster of four tuberculosis cases in a family, including one case of acquired multidrug resistant tuberculosis. It also underscores some important issues in tuberculosis control today, including significant disparities in the foreign-born population with multidrug resistant tuberculosis as a looming problem, as well as utilization of therapeutic drug level monitoring in complicated cases.	\N	\N
22533233	Hen's egg is one of the main causes of food allergy in children. Accidental exposure is common in food-allergic patients. However, the few studies that analyze this problem focus mainly on peanut allergy. We sought to calculate the frequency of accidental exposure reactions in children allergic to hen's egg during a 12-month period, to analyze the clinical characteristics and circumstances surrounding the reactions, and to identify risk factors for the most severe reactions. Ninety-two egg-allergic children (55 boys; median age, 52 months) were included in the study. A systematic questionnaire about accidental exposure was administered. Reactions were classified as mild, moderate, and severe. Egg white-specific immunoglobulin (Ig) E antibody titers were determined. Nineteen (21%) children had 24 reactions in the previous year (42% mild, 50% moderate, and 8% severe). Most reactions took place at home (50%) under routine circumstances (83%). Children with severe or moderate reactions had higher specific IgE levels to egg white (adjusted odds ratio for every 0.1-unit increase in the decimal logarithm, 1.15; 95% CI, 1.03-1.28; P = .008) and lower serum total IgE (adjusted odds ratio for every 1-unit increase in the decimal logarithm, 0.16; 95% CI, 0.05-0.54; P = .001) than those children with mild or no reactions. Reactions to accidental exposure are frequent in children with egg allergy. The proportion of severe or moderate reactions was 58%. The risk factors for such reactions included high titers of specific IgE to egg white and low titers of serum total IgE.	\N	\N
22545160	Successful and sustainable intervention against human helminthiases depends on optimal utilisation of available control measures and development of new tools and strategies, as well as an understanding of the evolutionary implications of prolonged intervention on parasite populations and those of their hosts and vectors. This will depend largely on updated knowledge of relevant and fundamental parasite biology. There is a need, therefore, to exploit and apply new knowledge and techniques in order to make significant and novel gains in combating helminthiases and supporting the sustainability of current and successful mass drug administration (MDA) programmes. Among the fields of basic research that are likely to yield improved control tools, the Disease Reference Group on Helminth Infections (DRG4) has identified four broad areas that stand out as central to the development of the next generation of helminth control measures: 1) parasite genetics, genomics, and functional genomics; 2) parasite immunology; 3) (vertebrate) host-parasite interactions and immunopathology; and 4) (invertebrate) host-parasite interactions and transmission biology. The DRG4 was established in 2009 by the Special Programme for Research and Training in Tropical Diseases (TDR). The Group was given the mandate to undertake a comprehensive review of recent advances in helminthiases research in order to identify notable gaps and highlight priority areas. This paper summarises recent advances and discusses challenges in the investigation of the fundamental biology of those helminth parasites under the DRG4 Group's remit according to the identified priorities, and presents a research and development agenda for basic parasite research and enabling technologies that will help support control and elimination efforts against human helminthiases.	\N	\N
22547770	Crizotinib (PF02341066, Xalkori; Pfizer) was recently approved by the U.S. Food and Drug Administration for treatment of ALK-positive non-small cell lung cancer (NSCLC) as defined by a jointly approved diagnostic test using a break-apart fluorescence in situ hybridization assay. The approval was based on dramatic response rates in ALK-positive NSCLC patients of 54% to 61% in phase I and II trials. To date, the overall disease control rates in these trials are close to 90%. Progression-free survival approaches 10 months. This review focuses on the ALK-inhibitory activity of crizotinib in preclinical and clinical trials that led to approval, as well as the diagnostic methods to classify patients with ALK-positive NSCLC. Although these patients represent a small subset of all patients with NSCLC, the rapid time course from identification of this unique target to an approved targeted therapy with striking benefit serves as a paradigm for the development of targeted therapeutics in an era of personalized medicine.	\N	\N
22548237	Ochroconis spp. are dematiaceous fungi and have recently become recognized as the cause of human disease. Infections due to members of this genus have primarily occurred in patients with impaired immunity following organ transplantation or chemotherapy for hematologic malignancies. There is no universally agreed upon therapy or duration of treatment, but amphotericin B and/or triazoles are typically employed. We present a case of Ochroconis gallopava infection in a patient with chronic granulomatous disease (CGD). The organism exhibited elevated minimal inhibitory concentrations against itraconazole (0.5 μg/ml) and voriconazole (2 μg/ml) in comparison with results from other studies reported in the literature. This case illustrates the complexities associated with antibiotic susceptibility testing, selection of appropriate drugs, and management in patients with Ochroconis infections. We also review the literature of human infections with Ochroconis to date, and discuss its microbiology to apprise both clinicians and laboratory personnel of this infrequently encountered but potentially aggressive pathogen.	\N	\N
22559253	Polyphenols, a ubiquitous group of secondary plant metabolites sharing at least one aromatic ring structure with one or more hydroxyl groups, represent a large group of natural antioxidants abundant in fruits, vegetables, and beverages, such as grape juice, wine, and tea, and are widely considered to contribute to health benefits in humans. However, little is yet known concerning their bioactive forms in vivo and the mechanisms by which they may alter our metabolome, which ultimately contribute toward disease prevention. Here we report a study to determine the metabolic fate of polyphenolic components in a Chinese tea (Pu-erh) in human subjects using a metabonomic profiling approach coupled with multivariate and univariate statistical analysis. Urine samples were collected at 0 h, 1 h, 3 h, 6 h, 9 h, 12 h, and 24 h within the first 24 h and once a day during a 6 week period including a 2 week baseline phase, a 2 week daily Pu-erh tea ingestion phase, and a 2 week "wash-out" phase, and they were analyzed by gas chromatography mass spectrometry and liquid chromatography mass spectrometry. The dynamic concentration profile of bioavailable plant molecules (due to in vivo absorption and the hepatic and gut bacterial metabolism) and the human metabolic response profile were measured and correlated with each other. This study demonstrates that the metabonomic strategy will enable us to integrate the overwhelming amount of metabolic end points as a systems' response to the absorption, metabolism, and disposition of a multicomponent botanical intervention system, leading to a direct elucidation of their mechanisms of action.	\N	\N
22571342	In carcinogenesis, methylation of DNA promoter regions results in inactivation of tumor-suppressing genes. MG98 was designed to inhibit DNA methyltransferases enzyme 1 production. This multicenter study explored two schedules of MG98 with Interferon-α-2β to identify schedule and dose for patients with metastatic RCC. Doses of IFN 9 MIU/MG98 125 mg/m(2) for a continuous schedule and IFN 9 MIU/MG98 200 mg/m(2) for an intermittent schedule were considered the MTDs. Treatment resulted in one PR and eight SD. MG98 combined with IFN was safe and resulted in clinical activity.	\N	\N
22573749	The increase of severe cases of acute tonsillitis (AT) is presently marked. Severe cases of AT disturb immune and metabolic homoeostasis initiating the development of disease. Therapy optimization is required to select the best treatment. In patients with severe cases of AT of mixed viral/bacterial etiology before the treatment it is revealed the increase of general activity of lactatedehydrigenase (LDH) and increase of the level of cathode "anaerobic" factions LDH4+5 and the decline of concentration ATP in the blood. There was a compensatory rise of level of ADP and АМP. The substantial decline of serum interferon (CIF) activity and diminishing maintenance of α-interferon (α-IFN) and γ-interferon (γ-IFN) in the blood of the patients, that testified to oppressing of interferonogenesis. Treatment of severe cases of AT of mixed viral/bacterial etiology of modern detoxic preparation reamberin and immunoactive preparation cycloferon combination positively influences the studied laboratory indexes. The improvement of power metabolism is marked, that was characterized by normalization of level adenine nucleotides (ATP, АDP, АМP) and general activity of LDH and its izoenzimes spectrum. At the same time the increase of CIF level is set, maintenances α-IFN and γ-IFN in the blood, that testified to the improvement of interferonogenesis. The results demonstrate the therapeutic potential of reamberin and cycloferon combination for treatment of patients with AT of mixed viral/bacterial etiology.	\N	\N
22582962	Infants with viral bronchiolitis are often hospitalised with a proportion requiring respiratory support. The aim of this review was to examine the use of nasal prong continuous positive airway pressure (CPAP) as a management strategy for infants with a diagnosis of bronchiolitis, who required stabilisation and transport to a tertiary centre. A retrospective audit of infants with bronchiolitis requiring CPAP during transport between January 2003 and June 2007. Nasal CPAP was initiated in 54 infants with 51 of these (34 ex-preterm, 17 term) subsequently continuing on CPAP during retrieval. Mean CPAP pressure was 7 cmH(2)O. Oxygenation improved between stabilisation and the end of retrieval (P < 0.01). During retrieval, there was no significant increase in transcutaneous CO(2), no infant required endotracheal ventilation and no adverse events were noted. Five infants were intubated within the first 24 h of admission at the receiving hospital. This review demonstrated that use of nasal prong CPAP to transport infants with bronchiolitis was a safe management strategy in those with moderate to severe disease severity.	\N	\N
22595407	The authors used multidetector computed tomography (MDCT) to study the relation between culprit plaque characteristics and cardiac troponin T (cTnT) elevation after percutaneous coronary intervention (PCI). Percutaneous coronary intervention is often complicated by post-procedural myocardial necrosis manifested by elevated cardiac biomarkers. Stable angina patients (n = 107) with normal pre-PCI cTnT levels underwent 64-slice MDCT before PCI to evaluate plaque characteristics of culprit lesions. Patients were divided into 2 groups according to presence (group I, n = 36) or absence (group II, n = 71) of post-PCI cTnT elevation ≥3 times the upper limit of normal (0.010 ng/ml) at 24 h after PCI. Computed tomography attenuation values were significantly lower in group I than in group II (43.0 [26.5 to 75.7] HU vs. 94.0 [65.0 to 109.0] HU, p < 0.001). Remodeling index was significantly greater in group I than in group II (1.20 ± 0.18 vs. 1.04 ± 0.15, p < 0.001). Spotty calcification was observed significantly more frequently in group I than in group II (50% vs. 11%, p < 0.001). Multivariate analysis showed presence of positive remodeling (remodeling index >1.05; odds ratio: 4.54; 95% confidence interval: 1.36 to 15.9; p = 0.014) and spotty calcification (odds ratio: 4.27; 95% confidence interval: 1.30 to 14.8; p = 0.016) were statistically significant independent predictors for cTnT elevation. For prediction of cTnT elevation, the presence of all 3 variables (CT attenuation value <55 HU; remodeling index >1.05, and spotty calcification) showed a high positive predictive value of 94%, and their absence showed a high negative predictive value of 90%. MDCT may be useful in detecting which lesions are at high risk for myocardial necrosis after PCI.	\N	\N
22610716	A 320-row multidetector CT provides the capability for prospective electrocardiogram (ECG)-gated coronary CT angiography (CTA) and tube current modulated cardiac function assessment (CFA). We assessed and compared the effective radiation dose of these two modes. On a prospective basis, we performed ECG-gated cardiac CT on 119 patients (87 were males). For heart rates (HRs) </=65 beats/min (bpm), we used one-heartbeat acquisition and half-scan reconstruction. HRs from 66 to 79 bpm and >/=80 bpm were scanned with either two or three heartbeats acquisitions, respectively. We used two types of scans. One type was based on a prospective ECG-gated CTA mode and the other using a tube current modulated CFA mode covering an entire R-R interval. The mean BMI of patients was 25.4 (range 18.8-49.3). Fifty-one patients (42.9 %) underwent CFA scanning, while the remaining 68 (57.1 %) had CTA. The majority of patients completed the scan in a single heartbeat (59.7 %). The mean dose of CTA mode at 65-85 % phase window for one and two heartbeats was 3.68 mSv (2.40-7.23) and 8.61 mSv (6.76-10.60), respectively. The mean dose of CFA mode for a single heartbeat measurement with dose modulation (25 % dose for CFA, and 100 % dose during 65-85 % phase window for CTA) was 6.32 mSv (4.69-8.89). CTA with prospective ECG-gating allows for acceptable image quality and radiation dose. HR reduction is mandatory to minimize radiation exposure. Global left ventricle function can be assessed with a single heartbeat within an acceptable radiation dose.	\N	\N
22616529	Global climate warming for the last 10 years actualized the problem of mortality rise in some European countries in anomalous summer heat. Russia faced this problem in July-August 2010 when extreme heat entailed a significant elevation of mortality in 31 regions of the country primarily due to coronary heart disease and cerebrovascular diseases. The analysis of foreign researches has shown that old age and living in cities are leading risk factors of deat in anomalous heat. Experience of the European countries and USA evidences that stay in conditioned apartments and early referral for medical assistance are most effective death preventive measures in heat.	\N	\N
22621617	Graves' disease (GD) is one of the most common autoimmune thyroid disorders and has a striking characteristic of female preponderance. The main objective of this study was to investigate whether IL12B gene polymorphisms were associated with either GD itself or with gender bias in GD. GD patients (151 males, 97 females) and 211 healthy control subjects without antithyroid autoantibodies or a family history of autoimmune disorders were recruited for this study. The G/C polymorphism (rs6887695) of the IL12B gene was analyzed using the polymerase chain reaction-restriction fragment length polymorphism, and the deletion and insertion polymorphism (rs41292470) in the IL12B promoter was detected after polyacrylamide gel electrophoresis-silver staining method. There was no significant difference between GD patients and normal subjects, and no differences in frequencies of genotypes or alleles of either polymorphism between male and female GD subjects. We conclude that these IL12B gene polymorphisms were not associated with sex bias in GD and do not confer susceptibility to Graves' disease (GD) in the Chinese population.	\N	\N
22626277	Inflammation in the ovary, including ovulation and pelvic inflammatory disease, has been proposed to play a role in the pathogenesis of ovarian cancer. Endometriotic lesions trigger a local inflammatory reaction and have been reported to be associated with an increased risk of epithelial ovarian cancer. However, the precise molecular mechanisms of ovarian cancer arising from endometriosis are still to be elucidated. To clarify the involvement of mismatch repair (MMR) abnormalities in the inflammation-associated malignant transformation of endometriosis, the immunohistochemical expression of mismatch repair proteins (human mutL homolog 1 [hMLH1] and human mutS homolog 2 [hMSH2]) was examined in 27 cases of ovarian endometriosis, 25 cases of ovarian carcinoma accompanied by endometriosis, and 39 cases of solitary ovarian carcinoma. In addition, the relationship between mismatch repair abnormalities including the microsatellite instability, PTEN (phosphatase and tensin homolog) mutation, and clinicopathologic parameters was analyzed. The expression of mismatch repair proteins was stepwisely decreased in endometriosis, ovarian carcinoma accompanied by endometriosis, and ovarian carcinoma. Tumors harboring multiple microsatellite instability (high-frequency microsatellite instability [MSI-H]) were detected in 4 (14.8%) of 27 cases of endometriosis and 7 (30.4%) of 23 cases of ovarian carcinomas. The frequency of PTEN mutations was higher in MSI-H cases than in microsatellite instability-stable (MSI-S) cases. In 2 cases of ovarian carcinoma accompanied by endometriosis, the decreased expression of mismatch repair proteins and MSI-H was observed in both the endometriosis and carcinoma lesions. Clinicopathologically, the MSI-H cases were associated with elevated serum levels of C-reactive protein and higher white blood cell counts. These findings suggest that mismatch repair abnormalities might be involved in the malignant transformation of ovarian endometriosis and that inflammation induces mismatch repair abnormalities during ovarian carcinogenesis arising from endometriosis.	\N	\N
22639889	Neuronal protein α-synuclein (α-syn) is an essential player in the development of neurodegenerative diseases called synucleinopathies. A spontaneous autosomal recessive rat model for neurodegeneration was developed in our laboratory. These rats demonstrate progressive increases in α-syn in the brain mesencephalon followed by loss of dopaminergic terminals in the basal ganglia (BG) and motor impairments. The severity of pathology is directly related to the overexpression of α-syn and parallel decrease in dopamine (DA) level in the striatum (ST) of affected rats. The neurodegeneration in this model is characterized by the presence of perikarya and neurites Lewis bodies (LB) and diffuse marked accumulation of perikaryal α-syn in the substantia nigra (SN), brain stem (BS), and striatum (ST) along with neuronal loss. Light and ultrastructural analyses revealed that the process of neuronal degeneration is a 'dying back' type. The disease process is accompanied by gliosis and release of inflammatory cytokines. This neurodegeneration is a multisystemic disease and implicate α-syn as a major factor in the pathogenesis of this inherited autosomal recessive animal model. Decrease dopamine (DA) and overexpression of α-syn in the brain mesencephalon may provide a naturally occurring animal model for Parkinson's disease (PD) and other synucleinopathies that reproduces significant pathological, neurochemical, and behavioral features of the human disease.	\N	\N
22644412	To evaluate retrospectively whether technical factors of hepatic arterial embolization affect the prognosis of patients with hepatocellular carcinoma (HCC). Inclusion criteria of this study were the following: (1) patients received embolization as the initial treatment during 2003-2004, (2) Child A or B liver profile, (3) five or fewer HCCs with maximum diameter of 7 cm or smaller, and (4) no extrahepatic metastasis. Patient data were gathered from 43 centers. Prognostic factors were evaluated using univariate and multivariate analyses. Eight hundred fifteen patients were enrolled. The 1-, 3-, 5-, and 7-year overall survival rates were 92.0 % (95 % CI 90.1-93.9), 62.9 % (95 % CI 59.3-66.6), 39.0 % (95 % CI 35.1-43.0), and 26.7 % (95 % CI 22.6-30.8) in all patients. Univariate analysis showed a Child-Pugh class-A, alpha-fetoprotein level lower than 100 ng/ml, tumor size of 3 cm or smaller, tumor number of 3 or fewer, one-lobe tumor distribution, nodular tumor type, within the Milan criteria, stage I or II, no portal venous invasion, use of iodized oil, and selective embolization were significantly better prognostic factors. In the multivariate Cox model, the benefit to survival of selective embolization remained significant (hazard ratio 0.68; 95 % CI 0.48-0.97; p = 0.033). Selective embolization contributes to survival in patients with HCCs.	\N	\N
22652723	Anemia is a significant cause of morbidity and lowers the quality of life of patients suffering from chronic kidney disease (CKD). Iron deficiency is the most important cause of erythropoietin (EPO) hyporesponsiveness in CKD. EPO administration significantly increases the costs of CKD management. It follows that paramount importance must be given to enhancing responsiveness to EPO thereby ensuring that the patient derives maximum benefit. Intravenous iron (IVI) administration has been used for decades to replenish body iron stores. Multiple preparations of Iron are available in the market. However, IVI administration is fraught with dangers like adverse drug reactions, susceptibility to infection, and, as recently postulated, direct cellular toxicity. Traditional approaches to IVI administration have focused on multiple administrations of lower doses for fear of adverse reactions. However, recent studies have demonstrated that higher doses can be safely administered in a single infusion, thereby reducing hospitalization costs and patient inconvenience. Newer preparations of IVI are relatively safer, easier to administer and efficacious. Preparations like Iron sucrose, ferumoxytol, ferric carboxymaltose and iron isomaltoside do not require test doses and allow higher doses to be administered at a time with cost and effect benefits.	\N	\N
22655515	Recently we reported a cytoplasmic sodium overload to cause a severe osmotic oedema in Duchenne muscular dystrophy (DMD). Our results suggested that this dual overload of sodium ions and water precedes the dystrophic process and persists until fatty muscle degeneration is complete. The present paper addresses the questions as to whether these overloads are important for the pathogenesis of the disease, and if so, whether they can be treated. As a first step, we investigated the effects of various diuretic drugs on a cell model of DMD, i.e. rat diaphragm strips previously exposed to amphotericin B. We found that both carbonic anhydrase inhibitors and aldosterone antagonists were able to repolarise depolarised muscle fibres. Since carbonic anhydrase inhibitors are known to have acidifying effects and this might be detrimental to the ventilation of DMD patients, we mainly concentrated on the modern spironolactone derivative, eplerenone. This drug had a very high repolarizing power, the parameter considered by us as being most relevant for a beneficial effect. In a pilot study we administered this drug to a 22-yr-old female DMD patient who was bound to an electric wheelchair and has had no corticosteroid therapy before. Eplerenone decreased both cytoplasmic sodium and water overload and increased muscle strength and mobility. We conclude that eplerenone has beneficial effects on DMD muscle. In our opinion the cytoplasmic oedema is cytotoxic and should be treated before fatty degeneration takes place.	\N	\N
22658853	Pulmonary complications associated with Sjögren syndrome (SS) have attracted attention in recent years. Sjögren syndrome has been associated with small cyst formation in salivary glands, thymus, and lungs and has been recently brought to the forefront by radiologists due to high-resolution techniques. However, pathologists are less aware of this finding unless clinico-radiologic-pathologic correlation is sought. Formation of large bullae in SS is a rare complication with potential for confusion with other diseases. Here, we present the clinical, radiologic, and pathologic findings in 3 patients with SS associated with multiple pulmonary cystic lesions. All 3 patients had a variable mixed restrictive and obstructive component of the disease. There was good correlation with the pulmonary function tests (PFTs), high-resolution computed tomographic scan, and morphology with regard to the restrictive component. The small cysts appear to correlate with the extent of obstructive changes on the PFTs. However, the large bullae do not, implying noncommunication with the conducting airways. This noncorrelation between the PFTs and extent of bullous disease with predominant involvement of lower lobes in SS enables distinction from bullous emphysema. The mechanism of bulla formation in SS appears to be different from bullous emphysema. A check valve mechanism has been proposed previously in SS, which does not explain cyst formation in the thymus. Alternately, inflammation may play a role with the key suspects being CD4 T-helper cells and perhaps NK cells. This is the first report of a clinico-radiologic-pathologic correlation with analysis of lymphocyte subsets.	\N	\N
22669091	Aim of the study was to analyze outcome in patients who underwent surgery following type A aortic dissections and to evaluate the long-term survival rates in patients 70 years of age and older and those under 70 years of age, and in males as compared to females. Between September 1997 and October 2008, 154 patients were retrospectively enrolled. There were 102 males (66.2%) and 52 females (33.8%) with a mean age of 63.5±12; seven patients (4.5%) were over 80 years of age, 46 (29.8%) were between 70 and 80 years of age and 101 were under 70 years of age at the time of surgery. We compared patients 70 years of age and older with those under 70 years of age, analyzing the early and long-term survival results and postoperative complications. Overall in-hospital mortality was 17.5% and permanent neurological dysfunction occurred in 10 patients (6.5%). Twenty patients (12.9%) died during follow-up. Among the males, the long-term survival rate was 80%, 68% and 51% at 1, 5 and 10 years, respectively. Among the females, survival rate was 84.6%, 72.3% and 47.5% at 1, 5 and 10 years, respectively. Five- and 10-year survival rates were 78.1% and 59.4%, respectively, for patients under 70 years of age, and 50.8% at 5 years and 26.1% at 10 years for those over 70. Patients might not be excluded from surgical intervention for acute type A aortic dissection (ATAAD) only due to age. It is important to consider biological age and the clinical features of the patients at the time of surgery. Age is a relative but not absolute contraindication for surgery in ATAAD. Long-term survival was not statistically different between males and females.	\N	\N
22689018	Ampullary and extensive periampullary lesions can be difficult to treat and often require pancreaticoduodenectomy (PD) for complete removal, even if benign. However, PD may be overtreatment for noninvasive lesions, and pancreas-sparing total duodenectomy (PSTD) is an emerging valid surgical option for selected cases. We reviewed patients undergoing PSTD at our institution over 16 months and a comparison group who had undergone PD for benign duodenal disease over the past 15 years. We also reviewed cases in the English-language literature and performed a meta-analysis of those patients who had undergone PSTD. PSTD had been performed in four patients, who had an average hospital length of stay (LOS) of 13 days; two of them experienced complications. None required conversion to PD, experienced a postoperative fistula or endocrine or exocrine insufficiency, or required intensive care. Two of the PSTDs were performed laparoscopically. Open PD for benign duodenal disease was performed in 22 patients, with overall morbidity and pancreas fistula rates of 82 and 27 %, respectively. The meta-analysis found 128 unique cases of PSTD with morbidity and mortality rates of 46.4 and 2.3 %, respectively. Pancreaticobiliary leak was seen in 20 %, with an average LOS of 17 days. Although PSTD can be used to avoid PD and can be performed laparoscopically, it is technically challenging and still associated with morbidity.	\N	\N
22691438	To describe the small retinal and systemic vessel involvement in Takayasu's arteritis. We described 3 patients with Takayasu's arteritis and small retinal vessel occlusion seen in our department between 2004 and 2011. We performed an extensive literature review and provided a global analysis of small retinal vessel involvement in Takayasu arteritis (i.e., total number of patients analyzed=9). Seven patients had small retinal artery occlusion, and two had venous involvement. Four cases were inaugural of the disease (44.4%). Takayasu's arteritis was extended (Type V) in the majority of patients presenting with small retinal vessel occlusion (5/9, 55.6%), and 8/9 reported cases (88.9%) presented with involvement of the supra-aortic branches. Immunosuppressive regimen allowed an improvement in 5/9 patients and stabilization in 1/9, but the situation worsened in 3/9 patients. The visual outcome was severe, and 3/9 patients (33.3%) experienced irreversible blindness. Occlusion of small retinal vessels is a rare and severe microcirculatory complication in Takayasu's arteritis, as well as necrotizing cutaneous vasculitis or myocarditis. Small retinal vessel involvement can be inaugural of the disease and seriously impact the visual prognosis in TA patients.	\N	\N
22696253	Accumulating evidence demonstrated that bone marrow-derived mesenchymal stem cells (BMSCs) may transdifferentiate into cardiomyocytes and replace apoptotic myocardium so as to improve functions of damaged hearts. However, little information is known about molecular mechanisms underlying myogenic conversion of BMSCs. microRNAs as endogenous noncoding small molecules function to inhibit protein translation post-transcriptionally by binding to complementary sequences of targeted mRNAs. Here, we reported that miR-124 was remarkably downregulated during cardiomyocyte differentiation of BMSCs induced by coculture with cardiomyocytes. Forced expression of miR-124 led to a significant downregulation of cardiac-specific markers-ANP, TNT, and α-MHC proteins as well as reduction of cardiac potassium channel currents in cocultured BMSCs. On the contrary, the inhibition of endogenous miR-124 with its antisense oligonucleotide AMO-124 obviously reversed the changes of ANP, TNT, and α-MHC proteins and increased cardiac potassium channel currents. Further study revealed that miR-124 targeted the 3'UTR of STAT3 gene so as to suppress the expression of STAT3 protein but did not affect its mRNA level. STAT3 inhibitors AG490, WP1066, and S3I-201 were shown to attenuate the augmented expression of ANP, TNT, α-MHC, GATA-4 proteins, and mRNAs in cocultured BMSCs with AMO-124 transfection. Moreover, GATA-4 siRNA reduced the expression of ANP, TNT, α-MHC, and GATA-4 proteins but did not impact STAT3 protein in cocultured BMSCs, indicating GATA-4 serves as an effector of STAT3. In summary, we found that miR-124 regulated myogenic differentiation of BMSCs via targeting STAT3 mRNA, which provides new insights into molecular mechanisms of cardiomyogenesis of BMSCs.	\N	\N
22697349	α-1 anti-trypsin (AAT) is the most abundant circulating serine protease inhibitor (serpin) and an acute phase reactant. Systemic deficiency in AAT (AATD) due to genetic mutations can result in liver failure and chronic lung disease such as emphysema. Considered the prototypic serpin, the emphysema observed in patients with AATD, consisting of progressive destruction of the alveoli and small airway structures, formed the basis of the protease/anti-protease imbalance theory of chronic obstructive pulmonary disease (COPD). Over the past decade, however, investigations of AATD have described multiple functions of AAT beyond those generally attributed to its antiprotease activity. Evidence now suggests that AAT plays an important role in modulating immunity, inflammation, proteostasis, apoptosis, and possibly cellular senescence programs. When integrated in vivo, these processes contribute to the lung maintenance program which preserves the lung despite a constant bombardment by damage associated molecular patterns (DAMPs) and/or pathogenassociated molecular patterns (PAMPs) initiated by cigarette smoke, pollutants, or infections. In this review, we discuss the clinical aspects of AATD as they pertain to emphysema; including similarities and differences to cigarette smoke-induced emphysema. Examining the lung maintenance program, we next consider the multiple mechanisms of airspace destruction and explore the role AATD contributes. Finally, we consider the data regarding treatment of AATD, including AAT supplementation and its current limitations, and suggest further avenues of research informed by the multiple functions of AAT.	\N	\N
22697357	We describe two siblings with epiphora, telecanthus, expressionless face, thick facial skin, bulky nose and profound sensorineural hearing loss. Constellation of these features presented a phenotypic overlap with Blepharo-naso-facial syndrome (BNFS) and Nablus mask-like syndrome (NMLS). They in addition had posterior helical pits. The molecular basis of NMLS is known, while BNFS remains an elusive disorder. We report the first Indian family with features having significant overlap between the two but we attempt to summarize the frequency of reported features and bring out the most consistent features for these two syndromes for the treating clinician.	\N	\N
22699458	Innate and adaptive immune responses in neurodegenerative diseases have become recently a focus of research and discussions. Parkinson's disease (PD) is a neurodegenerative disorder without known etiopathogenesis. The past decade has generated evidence for an involvement of the immune system in PD pathogenesis. Both inflammatory and autoimmune mechanisms have been recognized and studies have emphasized the role of activated microglia and T-cell infiltration. In this short review, we focus on dendritic cells, on their role in initiation of autoimmune responses, we discuss aspects of neuroinflammation and autoimmunity in PD, and we report new evidence for the involvement of neuromelanin in these processes.	\N	\N
22699661	Hashimoto's thyroiditis as well as lichen planus has been associated to a number of disorders, generally of auto-immune origin. A novel possible association between oral lichen planus (OLP) and Hashimoto's thyroiditis (HT) is here proposed on the basis of a cross-sectional survey. One hundred and five unrelated OLP patients were considered. Diagnosis of HT was based on positive serum anti-TPO, anti-Tg, TSH levels and the typical ultrasound pattern of the thyroid gland. In the present survey, the prevalence of HT in the OLP group was 14.3 % whereas the prevalence of HT-related hypothyroidism in the general population was reported to be equal to 1 %. By Fisher's exact test, it was revealed that the difference between our data and historical prevalence of HT was found statistically significant. Actually, there is no definitive hypothesis that could explain the coexistence of OLP and HT. However, considering the onset timing of HT followed by OLP in 93.3 % of our series, we suspected a causal or predisposing role for HT. Specifically, we believe that in HT patients, circulating thyroid antibodies could contribute to trigger an organ-specific auto-immune response also in the oral mucosa or skin, leading to the development of LP lesions. Because of the large number of cases of asymptomatic chronic auto-immune thyroiditis, it would be useful that women over 40 years of age affected by OLP were screened for thyroid dysfunction, particularly HT.	\N	\N
22711587	This study investigated associations between chronic inflammation and coagulation and incident locomotor disability using prospective data from the British Women's Heart and Health Study. Locomotor disability was assessed using self-reported questionnaires in 1999/2000, and 3 and 7 years later. Scores for inflammation and coagulation were obtained from summation of quartile categories of all available biomarkers from blood samples taken at baseline. 534 women developed locomotor disability after 3 years, 260 women after 7 years, while 871 women remained free of locomotor disability over the whole study period. After adjustment for demographic characteristics, lifestyle factors and health conditions, we found associations between inflammation and incident locomotor disability after three (OR per unit increase in score = 1.08, 95 % confidence interval (CI): 1.03, 1.13) and 7 years (OR = 1.10, 95 % CI: 1.03, 1.18) and between coagulation and incident locomotor disability after 3 (OR = 1.06, 95 % CI: 0.98, 1.14) and 7 years (OR = 1.09, 95 % CI: 1.00, 1.18). This corresponds to ORs between 1.8 and 2.4 comparing women with highest to lowest inflammation or coagulation scores. These results support the role of inflammation and coagulation in the development of locomotor disability in elderly women irrespective of their lifestyle factors and underlying age-related chronic diseases.	\N	\N
22713729	As science matures, it becomes more mathematical, progressing from enumeration to the use of equations to the formulation of models. Clinical pharmacology has developed to the stage where models play an increasingly important role in predicting and analyzing drug pharmacokinetics and pharmacodynamics, and even in characterizing disease progression and therapeutic response. Useful models have two characteristics that are in ostensible conflict: (i) they must accurately represent the essential features of the underlying system and (ii) the representation must be sufficiently simplified to enable its salient features to be identified and investigated through further experimentation.	\N	\N
22726388	Accurate diagnostic and monitoring tools for ulcerative colitis (UC) are missing. Our aim was to describe the proteomic profile of UC and search for markers associated with disease exacerbation. Therefore, we aimed to characterize specific proteins associated with inflamed colon mucosa from patients with acute UC using mass spectrometry-based proteomic analysis. Biopsies were sampled from rectum, sigmoid colon and left colonic flexure from twenty patients with active proctosigmoiditis and from four healthy controls for proteomics and histology. Proteomic profiles of whole colonic biopsies were characterized using 2D-gel electrophoresis, and peptide mass fingerprinting using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) was applied for identification of differently expressed protein spots. A total of 597 spots were annotated by image analysis and 222 of these had a statistically different protein level between inflamed and non-inflamed tissue in the patient group. Principal component analysis clearly grouped non-inflamed samples separately from the inflamed samples indicating that the proteomic signature of colon mucosa with acute UC is strong. Totally, 43 individual protein spots were identified, including proteins involved in energy metabolism (triosephosphate isomerase, glycerol-3-phosphate-dehydrogenase, alpha enolase and L-lactate dehydrogenase B-chain) and in oxidative stress (superoxide dismutase, thioredoxins and selenium binding protein). A distinct proteomic profile of inflamed tissue in UC patients was found. Specific proteins involved in energy metabolism and oxidative stress were identified as potential candidate markers for UC.	\N	\N
22739032	Vascular disease and medical factors are associated with cognitive decline and cardiovascular events. We examined the association between vascular risk factors and events in the Alzheimer's Disease Neuroimaging Initiative cohort. The association between vascular risk factors and cardiovascular events in a cohort of 810 participants, including 400 with mild cognitive impairment, 184 with Alzheimer's, and 226 controls was investigated using a longitudinal hazard model. There were 31 events including 11 strokes, 7 myocardial infarctions, 5 revascularizations, and 8 deaths during an average follow-up of 31 months. Longitudinal cardiovascular event rates were low and similar between diagnostic groups. All baseline vascular risk factors that were expected to be associated with longitudinal cardiovascular events were, or were trending toward, associating with cardiovascular events except atrial fibrillation, depression, and apolipoprotein E genotype. Despite differences in baseline vascular risk factors, longitudinal cardiovascular event rates were similar between diagnostic groups.	\N	\N
22740450	Cyclin dependent kinase (CDK) inhibitors, such as flavopiridol, demonstrate significant single-agent activity in chronic lymphocytic leukemia (CLL), but the mechanism of action in these nonproliferating cells is unclear. Here we demonstrate that CLL cells undergo autophagy after treatment with therapeutic agents, including fludarabine, CAL-101, and flavopiridol as well as the endoplasmic reticulum (ER) stress-inducing agent thapsigargin. The addition of chloroquine or siRNA against autophagy components enhanced the cytotoxic effects of flavopiridol and thapsigargin, but not the other agents. Similar to thapsigargin, flavopiridol robustly induces a distinct pattern of ER stress in CLL cells that contributes to cell death through IRE1-mediated activation of ASK1 and possibly downstream caspases. Both autophagy and ER stress were documented in tumor cells from CLL patients receiving flavopiridol. Thus, CLL cells undergo autophagy after multiple stimuli, including therapeutic agents, but only with ER stress mediators and CDK inhibitors is autophagy a mechanism of resistance to cell death. These findings collectively demonstrate, for the first time, a novel mechanism of action (ER stress) and drug resistance (autophagy) for CDK inhibitors, such as flavopiridol in CLL, and provide avenues for new therapeutic combination approaches in this disease.	\N	\N
22744150	To provide information about occurrence and patterns of geriatric morbidity and need for long-term care in patients newly diagnosed with dementia compared to controls without dementia. An analysis of administrative data was conducted to compare the geriatric outpatient diagnoses and the patterns of care dependency of 1,848 incident dementia patients and 7,385 matched non-dementia controls older than 65 years in the incidence year. In most cases the geriatric characteristics show an increased (partly statistically significant) prevalence in the group with dementia as compared to controls. Moreover, dementia patients show a higher number of geriatric comorbidities in contrast to non-dementia controls. Furthermore, the percentage of persons with need for long-term care in the dementia-group is significantly higher than for controls (44.4 vs. 12.9 %). Prevention, early recognition or treatment of attendant symptoms are very important in daily clinical and nursing care in patients with dementia to ameliorate the progression of the disease and to improve the patients' quality of life.	\N	\N
22744504	Screening for idiopathic scoliosis is not very popular in Poland. Some Polish towns and cities have prevention programmes aimed at discovering spine dysfunctions and disorders in children and adolescents. An assessment of the angle of trunk rotation (ATR) is a reliable, effective and non-invasive action that allows use to determine trunk asymmetry. Since then the scoliometer has spread throughout the United States and other countries, where it is a popular device in the clinical practice of diagnosing scoliosis. 9,500 children aged 7-10 were examined as part of a disease prevention programme entitled "Poznan Chooses Health - Bad Posture Prophylaxis in Class I-IV Primary School Children in Poznan". The analysis included results obtained in 2010 during initial posture assessment in 1000 children, Trunk asymmetry was measured by means of the Bunnell scoliometer. The measurement of the angle of trunk rotation was the spontaneous standing position with use the scoliometer during bending (Adams forward test) at three levels: proximal thoracic, main thoracic and lumbar. For the proximal thoracic section the 0° ATR value was found in 6 children, values of 1°-3° were recorded in 883 children, values of 4°-6° in 108 children, 7° or higher in 3 of the examined children. For the main thoracic section the 0° ATR value was found in 101 children, values of 1°-3° were recorded in 735 children, 4°-6° in 155 children, 7° or higher in 9 of the examined children. For the lumbar section ATR values of 0°, 1°-3°, 4°-6°, and 7° or higher were found, respectively, in 147, 883, 108 and 11 of the examined children.	\N	\N
22744756	In newly diagnosed glioblastoma multiforme, surgery, combined radio and chemotherapy, and adjuvant chemotherapy with temozolomide is the standard of care. Therapy for recurrent glioblastoma is less well established and comprises re-operation, re-irradiation, chemotherapy, targeted therapy, inhibition of neoangiogenesis, and others. In this observational study we recorded the efficacy and toxicity of a combination of procarbazine, carmustine, and vincristine (PBV) for 69 patients with recurrent and/or progressive glioblastoma after surgery, concomitant radio and/or chemotherapy, and adjuvant first-line temozolomide therapy. Of 41 patients evaluable for response by MRI, partial response was observed for one, minor response for three, stable disease for at least 6 weeks for ten, and immediate progression for 27. Median PFS was 15 weeks, and PFS-6 was 21 % for 57 patients who could be followed; 12 other patients were lost to follow-up after application of the first PBV cycle. Grade III or IV leucopenia and/or grade III or IV thrombocytopenia were seen in 26 % and 26 % of cycles, respectively. Haematological complications led to interruption of treatment for four (7 %) patients. Non-haematological toxicity was moderate. Salvage PBV therapy in recurrent and/or progressive glioblastoma, pre-treated with temozolomide-based chemotherapy as first-line treatment, is of limited efficacy with a small number of long-term survivors, but is hampered by relevant myelotoxicity.	\N	\N
22753355	Hepatic arterial infusional (HAI) chemotherapy combined with systemic chemotherapy is effective palliative therapy for unresectable colorectal cancer liver metastases (CRLM). Some patients considered for HAI have evidence of minimal extrahepatic disease (EHD), and the role of HAI in these situations is unknown. All patients with unresectable CRLM treated with HAI and systemic chemotherapy from 2000 to 2009 were included. Survival of patients who were ultimately proven to have low-volume EHD was compared to those without EHD. Three hundred seventy-three patients were included in this study. Seventy-nine percent of patients were previously treated with chemotherapy. One hundred forty-five patients (39%) ultimately proved to have EHD. Median overall survival from HAI pump placement in patients without EHD was 32 months compared to 16 months for patients with EHD, P < 0.001. Median overall survival from HAI pump placement in patients with a single site of EHD was 18 months compared to 9 months for those with multiple sites of EHD, P = 0.01. In this study of heavily pre-treated patients, overall survival was favorable in patients who proved to have EHD at one site.	\N	\N
22761515	To explore areas of consensus and disagreement concerning the interhospital transfer of patients with a clinical diagnosis of ruptured abdominal aortic aneurysm. A three-round Delphi questionnaire approach was used among vascular and endovascular surgery and emergency medicine specialists to explore patient characteristics and clinical management issues for emergency interhospital transfer. Analysis is based on 38 responses to rounds 2 and 3 (19 vascular surgeons, 6 interventional radiologists, 13 emergency care specialists) with agreement reported when 70% of respondents were in agreement. Initially there was agreement that transfer patients should be <85 years of age, either alert or with fluctuating consciousness, with moderate or minimal systemic disease, needing no/some help with daily living. Round 3 clarified that patients requiring inotropes and those institutionalised for mental infirmity should be transferred. Those with cardiac arrest in current episode should not be transferred. There was no agreement as to whether those institutionalised with physical infirmities, unconscious/intubated patients or those with severe systemic disease should be transferred. Speed was accepted as important, with agreement for specialty trainees to arrange transfer if consultants were not on site. Consultant-consultant discussion was recommended for patients with severe systemic disease. CT confirmation of diagnosis was considered unnecessary before transfer but ultrasound assessment was desirable, and transfers should not be delayed by waiting for specific tests. There was no agreement about blood tests and ECG before transfer or whether blood should accompany the patient being transferred. There was no agreement as to whether specific staff/facilities needed to be in place at the specialist hospital. A systolic blood pressure ≥70 mm Hg was sufficient for transfer without the need for intravenous fluids unless deterioration occurred. There is broad agreement about the type of patient who should be eligible for transfer but disagreements about patient management before and during transfer remain.	\N	\N
22766701	Cardiovascular disease (CVD) is one of the main causes of mortality in the world representing around 30% of all deaths. It constitutes also an important factor in morbidity and incapacity. There are several related CVD risk factors such as hypertension, metabolic syndrome (MetS) and hypercoagulability. The exact mechanisms that underlie the relation between those factors and CVD are not sufficiently known yet; pathogenic explanations are lacking also for the mechanisms relating metabolic factors to insulin resistance (IR) and the association with the development of atherosclerosis and thrombosis. The possible links between hypertension, hemostasis alterations and MetS are examined in this report.	\N	\N
22766888	Metabolic syndrome (MS) is a cluster of risk factors that predispose to major cardiovascular diseases and its complications, determining liver and kidney impairment. In the last decade, the indications to transplantation are increasing, with a linear incidence of the complications of the procedure. MS represents one of the commonest, being in turn may the consequence of the underlying disease that required the transplantation, or the result of the medical treatment, as well as one of the most important factor influencing the morbidity and mortality of the transplanted patients. Due to the growing incidence of the MS in these patients, it is crucial to focus and clarify the leading causes determining the onset of the metabolic disarrangement, its outcome and the hypothetical mechanism through which the clinicians could reduce the impact of the disease. In fact, prevention, early recognition, and treatment of the factor that could predict the onset or progression of the MS after the transplantation may impact long term survival of patients, that is again the scope of the same transplant. This review will update the different mechanisMS of the pathogenesis of MS in this population, the clinical effects of the presence of the MS, observing the risk factors to be treated before and after the transplantation and suggesting the management of the follow-up.	\N	\N
22767670	This phase I study evaluated the safety, pharmacokinetics, pharmacodynamics, and efficacy of the investigational oral drug MLN8237 (alisertib), a small-molecule Aurora A kinase (AAK) inhibitor, in 87 adult patients with advanced solid tumors. Sequential cohorts of patients received MLN8237 5 to 150 mg orally once daily or twice daily for 7, 14, or 21 days, followed by 14 days' rest per cycle. MLN8237 pharmacokinetics was characterized, and the relative bioavailability of an enteric-coated tablet (ECT) formulation was evaluated in reference to the original powder-in-capsule (PIC) formulation. Pharmacodynamic effects of MLN8237 on inhibition of AAK activity were evaluated in skin biopsies. Tolerability and response to treatment were assessed. Common toxicities included fatigue, nausea, and neutropenia. Plasma exposures increased dose proportionally (5-150 mg/d), and were similar for PIC and ECT. The terminal half-life was 23 hours. At the maximum tolerated dose of 50 mg twice daily on the 7-day schedule, the mitotic index of the skin basal epithelium was increased within 24 hours after MLN8237 administration on days 1 and 7, a finding consistent with AAK inhibition. One (1%) patient achieved a partial response lasting for more than 1 year and received MLN8237 for 51 cycles; 20 (23%) patients achieved stable disease for ≥3 months. This first-in-human trial of MLN8237 showed tolerability and favorable pharmacokinetics in this patient population. The recommended phase II dose of MLN8237 is 50 mg twice daily orally for 7 days in 21-day cycles, which is being evaluated further in the treatment of various solid tumors and hematologic malignancies.	\N	\N
22804715	Peripheral arterial disease (PAD) is a chronic, progressive disease with a significant cardiovascular and cerebrovascular risk burden and a considerable impact on functional capacity and quality of life (QoL). Exercise programmes result in significant improvements in walking distances but long-term effects are uncertain. The aim of this study was to assess the one-year effects of participation in a 12-week supervised exercise programme on functional capacity and QoL for PAD patients. Patients were randomly allocated to a control (n = 16) or an exercise (n = 28) group. Data regarding functional capacity (Walking Impairment Questionnaire WIQ), disease-specific QoL (Intermittent Claudication Questionnaire ICQ) and generic QoL (SF-36) were collected at baseline, 12 weeks and 1 year. At 12 weeks, there was a trend towards improved QoL in both groups, with a tendency for greater improvement in the exercise group (p = 0.066) and a trend towards improved functional capacity (WIQ Stair-climbing p = 0.093) in the exercise group. At 1 year, ICQ scores in the exercise group were considerably better than those in the control group (p = 0.058), reflecting improved QoL and maintenance of benefits. Participation in a supervised exercise programme results in improvements in functional capacity and QoL at 1 year post-participation.	\N	\N
22819313	Controversy exists regarding the extent of pelvic lymph node dissection (PLND) in radical prostatectomy (RP) for prostate cancer. Impact of the extent of PLND may be determined by the disease risk. The aim of our study was to find the association between the extent of PLND on biochemical progression and disease risk. The study included 360 consecutive patients treated with RP for clinically localized prostate cancer at our department between 2000 and 2003. Patients were randomized to receive extended PLND (n = 180) and standard PLND (n = 180) at RP. Clinical and pathological data were prospectively collected. The patients did not receive any neoadjuvant or adjuvant therapy. The relation of disease risk and the extent of PLND to biochemical progression-free survival (BPFS) were examined. There were no significant differences in age, prostate-specific antigen, and other preoperative features in patients who underwent standard and extended PLND. Mean patient age was 68 y old and median follow-up was 74 mo. BPFS for the standard PLND group and the extended PLND group was 90.1% and 91.3% in low risk disease (log rank P = 0.807), 73.1% and 85.7% in intermediate risk disease (log rank P = 0.042), and 51.1% and 71.4% in high risk disease (log rank P = 0.036), respectively. In multivariate Cox proportional hazard analysis, extended PLND was an independent prognostic factor of biochemical progression-free survival when adjusting for other clinical and pathologic features. In intermediate and high risk patients, extended PLND positively affects BPFS. In low risk patients, extended PLND may be omitted to reduce operation time and complications.	\N	\N
22822599	Proctocolectomy and ileoanal anastomosis as a treatment of ulcerative colitis Sphincter-saving proctocolectomy, construction of ileal pouch (J pouch) and associated ileoanal anastomosis constitute an established surgical procedure in the treatment of patients having ulcerative colitis. The procedure has been found to improve the condition: the patient is usually relieved of medications and possible associated adverse effects, the cancer risk associated with the disease is minimized and the quality of life will improve. The most common complication is inflammation of the ileal pouch, developing in half of the patients.	\N	\N
22824112	Metabolomics is the systematic study of the unique chemical fingerprints of small molecules or metabolite profiles that are related to a variety of cellular metabolic processes in a cell, organ, or organism. Although messenger RNA gene expression data and proteomic analyses do not tell the whole story of what might be happening in a cell, metabolic profiling provides direct and indirect physiologic insights that can potentially be detectable in a wide range of biospecimens. Although not specific to cardiac conditions, translating metabolomics to cardiovascular biomarkers has followed the traditional path of biomarker discovery from identification and confirmation to clinical validation and bedside testing. With technological advances in metabolomic tools (such as nuclear magnetic resonance spectroscopy and mass spectrometry) and more sophisticated bioinformatics and analytical techniques, the ability to measure low-molecular-weight metabolites in biospecimens provides a unique insight into established and novel metabolic pathways. Systemic metabolomics may provide physiologic understanding of cardiovascular disease states beyond traditional profiling and may involve descriptions of metabolic responses of an individual or population to therapeutic interventions or environmental exposures.	\N	\N
22825384	Asthma is an inflammatory disease of the airways. It is suggested by characteristic history of recurrent episodes of wheezing, breathlessness, chest tightness, and/or cough especially at night or in early morning. In asthmatic patients spirometry or pulmonary function tests demonstrate airflow obstruction that improves significantly, defined as both a 12% and 200 ml improvement in either FEV1 in response to inhaled bronchodilator. Measurement of airways responsiveness to methacholine in specialized pulmonary function laboratories may help to diagnose asthma. The goals for successful management of asthma are to achieve and maintain control of symptoms and to prevent asthma exacerbations.	\N	\N
22825649	This review summarizes and discusses the role and efficacy of moisturizers, particularly the more recently introduced ceramide-based formulations, in the skin care regimen of patients with both active and quiescent atopic dermatitis (AD). It is now well established that a complex interplay of environmental and genetic factors are responsible for disease onset and chronicity. Indeed, several novel genetic mechanisms have been recently discovered to be associated with AD pathogenesis. Moreover, it is increasingly recognized that the epidermal barrier plays a critical role in the initiation, perpetuation, and exacerbation of AD. The skin of patients with AD harbors several defects in epidermal barrier function, including filaggrin and ceramides. An improved understanding of these etiopathogenic factors has led to the development of topical ceramide-dominant moisturizers to replace the deficient molecules and re-establish the integrity of barrier defenses. Some of these products have demonstrated efficacy in the treatment of adult and childhood AD that are similar to mid-potency topical steroids. More importantly, they have been shown to be safe with very few associated side-effects. We recommend the addition of such new agents as both the first step of treatment and in the maintenance of clinically quiescent skin of patients with AD.	\N	\N
22828371	Due to the limited incidence of posttransplant lymphoproliferative disorders (PTLD) in pediatric liver graft recipients, there is a scarcity of data on the characteristics of the disease in this population. We aimed to analyze the special features and behavior of PTLD arising after pediatric liver transplantation. A comprehensive search of the literature was conducted for the available data on PTLD in pediatric liver recipients pediatric PTLD through a search of Pubmed and Google Scholar using appropriate terms. We sought data on liver recipients younger than 18 years of age at the time of transplantation. From 51 reports, 43 fulfilled the inclusion criteria. Overall 250 cases of PTLD (212 pediatric PTLD) were found from 43 reports. Data on pediatric patients was compared to adults. Pediatric PTLD lesions were more likely of the polymorphic type (P=.004) and polyclonal (when age cut-off was defined at 12 years; P=.023). Remission rates, metastasis frequency and organ involvements were not different between the groups (P>.1 for all). Survival analysis showed no disparity between pediatric PTLD and adult patients (P>.1); but when data was reanalyzed for patients surviving at least 4 months post diagnosis, the log rank test showed that pediatric patients have a superior outcome compared to adults (P=.045). Pediatric liver recipients developing PTLD have relatively better disease presentation and behavior than that in adults. Stomach involvement was also more frequently seen in patients younger than 12 years, and should be more intensively evaluated. Future studies with a prospective approach and larger population size are needed for confirming our results.	\N	\N
22828643	Several bacteria cause community-acquired invasive bacterial disease in children; many are vaccine preventable. Knowledge of pathogens causing community-acquired invasive bacterial disease is important when selecting antimicrobial therapy and implementing vaccine prevention strategies. We describe bacteriology of community-acquired invasive disease observed among 31,641 blood and sterile fluid cultures from children aged 28 days to 36 months in 3 Latin American countries over 2 years.	\N	\N
22830284	Features of spread of cowpox in the contemporary conditions are examined. A decrease of population immunity to pox in the population of Russia caused by cancellation of pox immunization, hidden circulation of cowpox virus in various species of rodents, as well as lack of vigilance to pathogenic orthopoxviurses in healthcare workers were noted to create the real preconditions for the emergence of infection of humans caused by cowpox virus. Thereby presence of means of express laboratory diagnostics of cowpox and means of effective medical protection for the prevention of development of this disease in the population of Russia becomes an actual necessity.	\N	\N
22833442	Multiple myeloma is a heterogeneous disease, which is characterized by the occurrence of specific genomic abnormalities that are both of diagnostic and prognostic relevance. Since the detection of these abnormalities through molecular-genetic techniques is hampered by the overall low percentage of plasma cells present in primary bone marrow aspirates, we assessed the efficacy of these techniques in enriched plasma cell fractions from 61 multiple myeloma patients. Using interphase FISH, genomic abnormalities could be detected in 96% of the enriched samples as compared to 61% in the cultured whole bone marrow samples. We also found that microarray-based genomic profiling of enriched plasma samples facilitates the detection of additional, possibly clinically relevant, genomic abnormalities. We conclude that the genomic delineation of enriched plasma cells from multiple myeloma patients results in a significantly increased detection rate of clinically relevant genomic abnormalities. In order to facilitate molecular-genetic data interpretation, we recommend morphological assessment of plasma cell purity after enrichment.	\N	\N
22844693	The restorative integral support (RIS) model is a whole person response that assists people to overcome adversity. The adverse childhood experiences (ACE) Study conducted by Kaiser Permanente and the Centers for Disease Control and Prevention shows the association between stressors in childhood and multiple later-life health and social problems. Older adults experiencing co-occurring disorders are an under-served and vulnerable population where gaps in both practice models and research to inform effective service provision exist. The current empirical case study presents Senior Hope as one social service agency employing RIS to intervene on the linkage between ACEs and co-occurring disorders to assist older adults. RIS usefully articulates the way in which Senior Hope is developing ACE-informed programs that mobilize resilience and recovery to help older adults achieve positive mental health outcomes. Implementation and research on the RIS model is recommended to enhance services for groups with ACE characteristics.	\N	\N
22847755	Putative animal reservoirs and environmental samples were studied to investigate potential routes of transmission for indigenous hepatitis E virus (HEV) infection in Hokkaido, Japan. A total of 468 liver samples and 954 environmental samples were collected from 2003 to 2011 for this study. Four swine livers (1 %) were positive for HEV RNA; two strains belonged to genotype 3 and the other two strains were genotype 4. Genotype 3 HEV was detected in a sewage sample and a seawater sample. HEV strains derived from swine liver, seawater and raw sewage samples shared 93-100 % sequence similarity with human HEV strains.	\N	\N
22849219	This paper examines the State's assumption of medical care for patients with "permanent needs" in 19th century Spain. These patients were the incurably ill, the chronically ill and the elderly. This process is contextualized within the liberal reforms of the Spanish healthcare system in the reign of Isabel 11 (1833-1868). The goal of these reforms was the creation and consolidation of a national health system that would gradually replace the religious health charities. Healthcare reform became necessary due to the increase in migration that started in the 1830's and intensified in the 1850's. Traditional care networks formed by the family, local community and religious charities were no longer available to those who had left their village or town. In addition, many religious charities were bankrupted by the seizure of their properties in a programme of confiscation. Similar healthcare reform processes were taking place in the United Kingdom, France and Germany, among other European countries, and involved significant changes in the lives of patients, who became strictly controlled and medicalised. My aim was to identify changes in the patients' experience of illness through a case study of the living conditions of inmates at the Nuestra Señora del Carmen Hospital for Incurable Men, based in Madrid from 1852 to 1949. This was one of the institutions devoted to caring for patients with "permanent needs" and was under the direct control of the General State Administration.	\N	\N
22851496	Nitrotyrosine is a post-translationally modified amino acid with distinctly different properties than tyrosine or any other of the genetically encoded amino acids. Detecting proteins containing nitrotyrosine is the first step towards a better understanding of the role of nitrotyrosine in health and disease. Moreover, quantifying the extent of nitrotyrosine and determining its location in a protein forms the basis for a better understanding of the effect of tyrosine nitration on biological function. Described in this unit is a method to detect tyrosine-nitrated proteins in tissue sections and on western blots after creating a fluorescent complex between aminotyrosine, salicylaldehyde, and Al(3+). In addition, an approach is detailed for labeling aminotyrosine with biotin to enrich peptides from complex samples. Both methods require reduction of nitrotyrosine to aminotyrosine, which can be achieved with sodium dithionite or hemin plus dithiothreitol.	\N	\N
22869886	Anti-GD2 monoclonal antibody (MoAb) combined with granulocyte-macrophage colony-stimulating factor (GM-CSF) has shown efficacy against neuroblastoma (NB). Prognostic variables that could influence clinical outcome were explored. One hundred sixty-nine children diagnosed with stage 4 NB (1988 to 2008) were enrolled onto consecutive anti-GD2 murine MoAb 3F8 ± GM-CSF ± 13-cis-retinoic acid (CRA) protocols after achieving first remission (complete remission/very good partial remission). Patients enrolled in regimen A (n = 43 high-risk [HR] patients) received 3F8 alone; regimen B (n = 41 HR patients), 3F8 + intravenous GM-CSF + CRA, after stem-cell transplantation (SCT); and regimen C (n = 85), 3F8 + subcutaneous GM-CSF + CRA, 46 of 85 after SCT, whereas 28 of 85 required additional induction therapy and were deemed ultra high risk (UHR). Marrow minimal residual disease (MRD) was measured by quantitative reverse transcription polymerase chain reaction. Survival probability was calculated by the Kaplan-Meier method, and prognostic variables were analyzed by multivariate Cox regression model. At 5 years from the start of immunotherapy, progression-free survival (PFS) improved from 44% for HR patients receiving regimen A to 56% and 62% for those receiving regimens B and C, respectively. Overall survival (OS) was 49%, 61%, and 81%, respectively. PFS and OS of UHR patients were 36% and 75%, respectively. Relapse was mostly at isolated sites. Independent adverse prognostic factors included UHR (PFS) and post-cycle two MRD (PFS and OS), whereas the prognostic factors for improved outcome were missing killer immunoglobulin-like receptor ligand (PFS and OS), human antimouse antibody response (OS), and regimen C (OS). Retrospective analysis of consecutive trials from a single center demonstrated that MoAb 3F8 + GM-CSF + CRA is effective against chemotherapy-resistant marrow MRD. Its positive impact on long-term survival can only be confirmed definitively by randomized studies.	\N	\N
22870861	Newborn screening for the inborn error of metabolism, classical galactosaemia prevents life-threatening complications in the neonatal period. It does not however influence the development of long-term complications and the complex pathophysiology of this rare disease remains poorly understood. The objective of this study was to report the development of a healthcare database (using Distiller Version 2.1) to review the epidemiology of classical galactosaemia in Ireland since initiation of newborn screening in 1972 and the long-term clinical outcomes of all patients attending the National Centre for Inherited Metabolic Disorders (NCIMD). Since 1982, the average live birth incidence rate of classical galactosaemia in the total Irish population was approximately 1:16,476 births. This reflects a high incidence in the Irish 'Traveller' population, with an estimated birth incidence of 1:33,917 in the non-Traveller Irish population. Despite early initiation of treatment (dietary galactose restriction), the long-term outcomes of classical galactosaemia in the Irish patient population are poor; 30.6 % of patients ≥ 6 yrs have IQs <70, 49.6 % of patients ≥ 2.5 yrs have speech or language impairments and 91.2 % of females ≥ 13 yrs suffer from hypergonadotrophic hypogonadism (HH) possibly leading to decreased fertility. These findings are consistent with the international experience. This emphasizes the requirement for continued clinical research in this complex disorder.	\N	\N
22873223	Chronic fibrotic liver diseases such as viral hepatitis eventually develop liver cirrhosis, which causes occurrence of hepatocellular carcinoma (HCC). Given the limited therapeutic efficacy in advanced HCC, prevention of HCC development could be an effective strategy for improving patient prognosis. However, there is still no established therapy to meet the goal. Studies have elucidated a wide variety of molecular mechanisms and signaling pathways involved in HCC development. Genetically-engineered or chemically-treated experimental models of cirrhosis and HCC have been developed and shown their potential value in investigating molecular therapeutic targets and diagnostic biomarkers for HCC prevention. In this review, we overview potential targets of prevention and currently available experimental models, and discuss strategies to translate the findings into clinical practice.	\N	\N
22882216	The use of monoclonal antibodies in the treatment of malignancy and autoimmune diseases has rapidly expanded in the last decade. Rituximab, a monoclonal antibody to the CD20 antigen on B cells, was first approved by the US FDA in 1997 to treat non-Hodgkin's B-cell lymphoma. It is now used, however, for a variety of diseases in both on- and off-label uses. It was approved by the FDA for use in refractory rheumatoid arthritis in 2007, and in April 2011 it was approved for the treatment of anti-neutrophil cytoplasmic antibody-associated vasculitides (including granulomatosis with polyangiitis [Wegener's granulomatosis] and microscopic polyangiitis), based on the promising results of the RAVE trial. Within the field of nephrology, in addition to its use in anti-neutrophil cytoplasmic antibody-associated vasculitides, it is has been used in the treatment of membranous nephropathy, membranoproliferative glomerulonephritis and lupus nephritis.	\N	\N
22882559	To test a theoretically and empirically supported model of the relationships among percent truncal fat (truncal obesity); disease severity (carbon monoxide diffusing capacity [DLCO]); symptoms (dyspnea); functional capacity (6-min walk test distance); and functional performance (functional performance index) of elderly people with chronic obstructive pulmonary disease (COPD). A model of functional performance was proposed using a multidimensional framework as expounded by Leidy, and incorporating Wilson and Cleary's model for the relationship between symptoms and functional status. Path analysis was used to examine the relationships among variables. The researchers used a descriptive, cross-sectional design. Subjects were phone screened and completed electrocardiography, physical examination, spirometry testing, and a 4-min walk test as part of initial screening. Enrolled subjects completed a whole-body dual-energy x-ray absorptiometry scan to measure truncal obesity, 6-min walk test, upper body functional performance test, and questionnaires. Subjects were grouped into normal weight, overweight, or obese according to body mass index. The sample consisted of 76 people 55 years of age and older with mild to severe COPD. Percent truncal fat (truncal obesity) did not affect functional performance directly, but did affect it indirectly through dyspnea. The 6-min walk test distance, dyspnea, and DLCO accounted for 29% of the variability in functional performance. We believe that the effectiveness of pulmonary rehabilitation will be enhanced when nurses consider weight loss as a controllable factor for overweight and obese clients. The increasing prevalence of obesity in this population may dictate collaboration between dieticians and pulmonary rehabilitation nurses for effective rehabilitation programs. These findings suggest that percent truncal fat (truncal obesity) may be an indirect factor in the performance of daily activities of people with COPD. We anticipate that clinicians will use knowledge derived from this study to develop interventions to reduce or minimize truncal fat (truncal obesity) and its effects on people with COPD.	\N	\N
22883409	To establish a rat model of ulcerative colitis with syndrome of spleen deficiency and dampness stagnancy. Sixty rats were divided into normal control group, ulcerative colitis group, ulcerative colitis with syndrome of spleen deficiency and dampness stagnancy group (model group) and strengthening spleen for resolving dampness group. Ulcerative colitis in rats was induced by enema containing trinitrobenzene sulfonic acid (TNBS) and ethanol. The rats in the model group were suffered from standing in water, limiting sleeping time and abnormal diet based on administration of TNBS and ethanol. The rats in the spleen strengthening and dampness resolving group were gastrically administered with Shenlin Baizhu Powder, a compound traditional Chinese herbal medicine. Symptoms, signs and pathological changes in colon tissue of rats were observed after modeling. The levels of interleukin (IL)-6, IL-8 and tumor necrosis factor-α (TNF-α) in serum of rats were measured by enzyme-linked immunosorbent assay. The rats in the model group showed lethargy, poor appetite, loss of energy, diarrhea and bloody stool. Their body weight decreased significantly compared with the normal control group, and similar changes were found in the comparison of food intake, drinking amount, urine amount, stool wet weight and assay of spontaneous activity (P<0.05). When observed under a light microscope, the colon tissues of rats in the model group showed mucosal edema, congestion, inflammatory cell infiltration and ulceration. The degree of colon injury and IL-6, IL-8 and TNF-α levels were significantly increased (P<0.05) as compared to those in the normal control group. The changes mentioned above were improved by Shenlin Baizhu Powder (P<0.05). The rat model of ulcerative colitis with syndrome of spleen deficiency and dampness stagnancy is successfully induced and has the characteristics of ulcerative colitis of humans both in pathological changes and in syndrome.	\N	\N
22888223	Membranous nanostructures, such as nanovesicles and nanotubules, are an important pool of biological membranes. Recent results indicate that they constitute cell-cell communication systems and that cancer development is influenced by these systems. Nanovesicles that are pinched off from cancer cells can move within the circulation and interact with distant cells. It has been suggested and indicated by experimental evidence that nanovesicles can induce metastases from the primary tumor in this way. Therefore, it is of importance to understand better the mechanisms of membrane budding and vesiculation. Here, a theoretical description is presented concerning consistently related lateral membrane composition, orientational ordering of membrane constituents, and a stable shape of nanovesicles and nanotubules. It is shown that the character of stable nanostructures reflects the composition of the membrane and the intrinsic shape of its constituents. An extension of the fluid mosaic model of biological membranes is suggested by taking into account curvature-mediated orientational ordering of the membrane constituents on strongly anisotropically curved regions. Based on experimental data for artificial membranes, a possible antimetastatic effect of plasma constituents via mediation of attractive interaction between membranous structures is suggested. This mediated attractive interaction hypothetically suppresses nanovesiculation by causing adhesion of buds to the mother membrane and preventing them from being pinched off from the membrane.	\N	\N
22892258	The emergency department (ED) is a common setting for evaluation of patients with urolithiasis based on acute symptoms and a propensity for recurrent disease. We sought to characterize practice patterns in the emergency treatment of stone disease, and to identify potential disparities in care based on non-medical factors. We performed a cross-sectional analysis of ED visits using the National Hospital Ambulatory Medical Care Survey from 2005-2009. Visits with a diagnosis of urolithiasis were identified. The associations between patient, provider and institutional characteristics were analyzed with regard to timing of clinical assessment, use of diagnostic imaging, and use of medical expulsive therapy (MET). The likelihood of a delay in clinical assessment ranged from 30.8%-37.9%. Neither patient nor provider characteristics were associated with a delay in assessment, although urban location (p = 0.004) was more likely, and proprietary ownership was less likely (p = 0.002) to be associated with delay. Factors associated with use of CT included ambulance arrival (p = 0.043), initial ED visit (p = 0.000), and Northeast region (p = 0.030). Patients seen by a resident/intern were more likely to receive MET (p = 0.028). Overall, 10.8% of patients were presenting for follow up treatment, and 7.1% had been seen in the same ED within the last 72 hours. Kidney stones are associated with a high rate of repeated presentations to the ED. Certain non-medical factors did impact details of management. Future efforts should focus on optimizing clinical pathways to improve the efficiency of acute care for kidney stone patients.	\N	\N
22910631	Like many intracellular microbes, the protozoan parasite Toxoplasma gondii injects effector proteins into cells it invades. One group of these effector proteins is injected from specialized organelles called the rhoptries, which have previously been described to discharge their contents only during successful invasion of a host cell. In this report, using several reporter systems, we show that in vitro the parasite injects rhoptry proteins into cells it does not productively invade and that the rhoptry effector proteins can manipulate the uninfected cell in a similar manner to infected cells. In addition, as one of the reporter systems uses a rhoptry:Cre recombinase fusion protein, we show that in Cre-reporter mice infected with an encysting Toxoplasma-Cre strain, uninfected-injected cells, which could be derived from aborted invasion or cell-intrinsic killing after invasion, are actually more common than infected-injected cells, especially in the mouse brain, where Toxoplasma encysts and persists. This phenomenon has important implications for how Toxoplasma globally affects its host and opens a new avenue for how other intracellular microbes may similarly manipulate the host environment at large.	\N	\N
22911240	In this study, the clinical outcome and prognostic factors of adult medulloblastoma patients receiving multimodal treatment were investigated. The clinical manifestations, treatment variables, and outcome of adult patients with medulloblastoma at our institution between 1983 and 2009 were retrospectively reviewed. A total of 20 adult patients were included (median age 22 years). Craniospinal irradiation (CSI) was given postoperatively. The craniospinal axis received a median of 30 Gy (range 23.4-39.6 Gy) in fractions of 1.6-2 Gy/day, and the tumor was boosted to a total median dose of 50 Gy (range 50-55.25 Gy). The 3-year disease-free survival (DFS) and overall survival (OS) rates for all patients were 45% and 50%, respectively. In univariate analysis, Karnofsky Performance Scale (KPS) > 70, neurologic symptoms duration > 30 days, lateral tumor location, standard risk patients, no hydrocephalus, radiotherapy (RT) treatment field (CSI + brain boost), and CSI dose ≥ 30 Gy were associated with better DFS. Standard-risk patients, RT treatment field (CSI + brain boost), and CSI dose ≥ 30 Gy were also significantly associated with better OS. The combined modality treatment results in a favorable outcome for adult medulloblastoma patients. Further investigation of the prognostic factors, radiation-related factors, and systemic chemotherapy is needed.	\N	\N
22917170	Diarrhea is a common clinical feature of inflammatory bowel diseases and may be accompanied by abdominal pain, urgency, and fecal incontinence. The pathophysiology of diarrhea in these diseases is complex, but defective absorption of salt and water by the inflamed bowel is the most important mechanism involved. In addition to inflammation secondary to the disease, diarrhea may arise from a variety of other conditions. It is important to differentiate the pathophysiologic mechanisms involved in the diarrhea in the individual patient to provide the appropriate therapy. This article reviews microscopic colitis, ulcerative colitis, and Crohn's disease, focusing on diarrhea.	\N	\N
22924030	Although many parameters were investigated about weaning and mortality in critical patients in intensive units, no studies have yet investigated predictors in prolonged mechanical ventilation (PMV) patients following successful weaning. A cohort of 142 consecutive PMV patients with successful weaning in our respiratory care center was enrolled in this study. Successful weaning is defined as a patient having smooth respiration for more than 5 days after weaning. The results showed as follows: twenty-seven patients (19%) had the reinstitution within 14 days, and 115 patients (81%) had the reinstitution beyond 14 days. Renal disease RIFLE-LE was associated with the reinstitution within 14 days (P = 0.006). One year mortality rates showed significant difference between the two groups (85.2% in the reinstitution within 14 days group versus 53.1% in the reinstitution beyond 14 days; P < 0.001). Kaplan-Meier analysis showed that age ≥70 years (P = 0.04), ESRD (P = 0.02), and the reinstitution within 14 days (P < 0.001) were associated with one-year mortality. Cox proportional hazards regression model showed that only the reinstitution within 14 days was the independent predictor for mortality (P < 0.001). In conclusion, the reinstitution within 14 days was a poor predictor for PMV patients after successful weaning.	\N	\N
22931913	Prediction of outcome for melanoma patients with surgically resected macroscopic nodal metastases is very imprecise. We performed a comprehensive clinico-pathologic assessment of fresh-frozen macroscopic nodal metastases and the preceding primary melanoma, somatic mutation profiling, and gene expression profiling to identify determinants of outcome in 79 melanoma patients. In addition to disease stage <II at initial presentation, the following clinical and pathologic factors were independent predictors of improved outcome (odds ratios for survival >4 years, 90% confidence interval): the presence of a nodular component in the primary melanoma (6.8, 0.6-76.0), and small cell size (11.1, 0.8-100.0) or low pigmentation (3.0, 0.8-100.0) in the nodal metastases. Absence of BRAF mutation (20.0, 1.0-1000.0) or NRAS mutation (16.7, 0.6-1000.0) were both favorable prognostic factors. A 46-gene expression signature with strong overrepresentation of immune response genes was predictive of better survival (10.9, 0.4-325.6); in the full cohort, median survival was >100 months in those with the signature, but 10 months in those without. This relationship was validated in two previously published independent stage III melanoma data sets. We conclude that the presence of BRAF mutation, NRAS mutation, and the absence of an immune-related expressed gene profile predict poor outcome in melanoma patients with macroscopic stage III disease.	\N	\N
22933250	Renal xenobiotic transporters are important determinants of urinary secretion and reabsorption of chemicals. In addition to glomerular filtration, these processes are key to the overall renal clearance of a diverse array of drugs and toxins. Alterations in kidney transporter levels and function can influence the efficacy and toxicity of chemicals. Studies in experimental animals have revealed distinct patterns of renal transporter expression in response to sex hormones, pregnancy, and growth hormone. Likewise, a number of disease states including diabetes, obesity, and cholestasis alter the expression of kidney transporters. The goal of this review is to provide an overview of the major xenobiotic transporters expressed in the kidneys and an understanding of metabolic conditions and hormonal factors that regulate their expression and function.	\N	\N
22933945	The aim of the study was to evaluate the clinical efficacy of superselective intra-arterial targeted neo-adjuvant chemotherapy in the treatment of estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and human epidermal growth factor receptor 2 (HER2)-negative (triple-negative) breast cancer. PATIENTS AND METHODS.: A total of 47 triple-negative breast cancer patients (29 at stage II, 13 at stage III and 5 at stage IV) were randomly assigned to two groups: targeted chemotherapy group (n=24) and control group (n=23). Patients in the targeted chemotherapy group received preoperative superselective intra-arterial chemotherapy with CEF regimen (C: cyclophosphamide [600 mg/m(2)]; E: epirubicin [90 mg/m(2)]; F: 5-fluorouracil [600 mg/m(2)]), and those in the control group received routine neoadjuvant chemotherapy with CEF. The duration of the treatment, changes in lesions and the prognosis were determined. The average course of the treatment was 15 days in the targeted chemotherapy group which was significantly shorter than that in the control group (31 days) (P<0.01). The remission rate of lesions was 91.6% in the targeted chemotherapy group and 60.9% in the control group, respectively. Among these patients, 9 died within two years, including 2 (both at IV stage) in the targeted chemotherapy group and 7 (2 at stage II, 4 at stage III and 1 at stage IV) in the control group. As an neoadjuvant therapy, the superselective intra-arterial chemotherapy is effective for triple-negative breast cancer, with advantages of the short treatment course and favourable remission rates as well as prognoses.	\N	\N
22934539	The existing literature suggests that theories and models can serve as valuable frameworks for the design and evaluation of health interventions. However, evidence on the use of theories and models in social marketing interventions is sparse. The purpose of this systematic review is to identify to what extent papers about social marketing health interventions report using theory, which theories are most commonly used, and how theory was used. A systematic search was conducted for articles that reported social marketing interventions for the prevention or management of cancer, diabetes, heart disease, HIV, STDs, and tobacco use, and behaviors related to reproductive health, physical activity, nutrition, and smoking cessation. Articles were published in English, after 1990, reported an evaluation, and met the 6 social marketing benchmarks criteria (behavior change, consumer research, segmentation and targeting, exchange, competition and marketing mix). Twenty-four articles, describing 17 interventions, met the inclusion criteria. Of these 17 interventions, 8 reported using theory and 7 stated how it was used. The transtheoretical model/stages of change was used more often than other theories. Findings highlight an ongoing lack of use or underreporting of the use of theory in social marketing campaigns and reinforce the call to action for applying and reporting theory to guide and evaluate interventions.	\N	\N
22935019	Heart failure is seen as a complex disease caused by a combination of a mechanical disorder, cardiac remodeling and neurohormonal activation. To define heart failure the systems biology approach integrates genes and molecules, interprets the relationship of the molecular networks with modular functional units, and explains the interaction between mechanical dysfunction and cardiac remodeling. The biomechanical model of heart failure explains satisfactorily the progression of myocardial dysfunction and the development of clinical phenotypes. The earliest mechanical changes and stresses applied in myocardial cells and/or myocardial loss or dysfunction activate left ventricular cavity remodeling and other neurohormonal regulatory mechanisms such as early release of natriuretic peptides followed by SAS and RAAS mobilization. Eventually the neurohormonal activation and the left ventricular remodeling process are leading to clinical deterioration of heart failure towards a multi-organic damage. It is hypothesized that approaching heart failure with the methodology of systems biology we promote the elucidation of its complex pathophysiology and most probably we can invent new therapeutic strategies.	\N	\N
22940074	A 33-year-old woman with Wernicke's encephalopathy (WE) due to poor oral intake after allogeneic stem cell transplantation for acute myeloid leukemia showed a sequential development of bilateral gaze-evoked nystagmus (GEN), rightward gaze palsy, and upbeat nystagmus. Initial MRIs obtained when she had GEN only showed a lesion involving the medullary tegmentum, and follow-up MRIs revealed additional lesions in the pontine and midbrain tegmentum along with development of rightward gaze palsy, and finally bilateral medial thalamus lesions in association with upbeat nystagmus. The evolution of abnormal ocular motor findings and serial MRI changes in our patient with WE provide imaging evidence on relative vulnerability of the neural structures, and on the progression of lesions and ocular motor findings in thiamine deficiency.	\N	\N
22956992	Cerebral palsy (CP) is an upper motor neuron disease that results in a spectrum of movement disorders. Secondary to the neurological lesion, muscles from patients with CP are often spastic and form debilitating contractures that limit range of motion and joint function. With no genetic component, the pathology of skeletal muscle in CP is a response to aberrant complex neurological input in ways that are not fully understood. This study was designed to gain further understanding of the skeletal muscle response in CP using transcriptional profiling correlated with functional measures to broadly investigate muscle adaptations leading to mechanical deficits.Biopsies were obtained from both the gracilis and semitendinosus muscles from a cohort of patients with CP (n = 10) and typically developing patients (n = 10) undergoing surgery. Biopsies were obtained to define the unique expression profile of the contractures and passive mechanical testing was conducted to determine stiffness values in previously published work. Affymetrix HG-U133A 2.0 chips (n = 40) generated expression data, which was validated for selected transcripts using quantitative real-time PCR. Chips were clustered based on their expression and those from patients with CP clustered separately. Significant genes were determined conservatively based on the overlap of three summarization algorithms (n = 1,398). Significantly altered genes were analyzed for over-representation among gene ontologies and muscle specific networks.The majority of altered transcripts were related to increased extracellular matrix expression in CP and a decrease in metabolism and ubiquitin ligase activity. The increase in extracellular matrix products was correlated with mechanical measures demonstrating the importance in disability. These data lay a framework for further studies and development of novel therapies.	\N	\N
22958194	Ancestral background, specifically African descent, confers higher risk for development of inhibitory antibodies to factor VIII (FVIII) in haemophilia A. It has been suggested that differences in the distribution of FVIII gene (F8) haplotypes, and mismatch between endogenous F8 haplotypes and those comprising products used for treatment could contribute to risk. Data from the Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort were used to determine the association between F8 haplotype 3 (H3) vs. haplotypes 1 and 2 (H1 + H2) and inhibitor risk among individuals of genetically determined African descent. Other variables known to affect inhibitor risk including type of F8 mutation and human leucocyte antigen (HLA) were included in the analysis. A second research question regarding risk related to mismatch in endogenous F8 haplotype and recombinant FVIII products used for treatment was addressed. Haplotype 3 was associated with higher inhibitor risk among those genetically identified (N = 49) as of African ancestry, but the association did not remain significant after adjustment for F8 mutation type and the HLA variables. Among subjects of all racial ancestries enrolled in HIGS who reported early use of recombinant products (N = 223), mismatch in endogenous haplotype and the FVIII proteins constituting the products used did not confer greater risk for inhibitor development. Haplotype 3 was not an independent predictor of inhibitor risk. Furthermore, our findings did not support a higher risk of inhibitors in the presence of a haplotype mismatch between the FVIII molecule infused and that of the individual.	\N	\N
22964476	Tocopherol, a member of the vitamin E family, consists of four forms designated as α, β, γ, and δ. Several large cancer prevention studies with α-tocopherol have reported no beneficial results, but recent laboratory studies have suggested that δ- and γ-tocopherol may be more effective. In two different animal models of breast cancer, the chemopreventive activities of individual tocopherols were assessed using diets containing 0.3% of tocopherol (α-, δ-, or γ-) or 0.3% of a γ-tocopherol rich mixture (γ-TmT). Although administration of tocopherols did not prevent human epidermal growth factor receptor 2 (HER2/neu)-driven tumorigenesis, δ- and γ-tocopherols inhibited hormone-dependent mammary tumorigenesis in N-methyl-N-nitrosourea (NMU)-treated female Sprague-Dawley rats. NMU-treated rats showed an average tumor burden of 10.6 ± 0.8 g in the control group at 11 weeks, whereas dietary administration of δ- and γ-tocopherols significantly decreased tumor burden to 7.2 ± 0.8 g (P < 0.01) and 7.1 ± 0.7 g (P < 0.01), respectively. Tumor multiplicity was also reduced in δ- and γ-tocopherol treatment groups by 42% (P < 0.001) and 32% (P < 0.01), respectively. In contrast, α-tocopherol did not decrease tumor burden or multiplicity. In mammary tumors, the protein levels of proapoptotic markers (BAX, cleaved caspase-9, cleaved caspase-3, cleaved PARP) were increased, whereas antiapoptotic markers (Bcl-2, XIAP) were inhibited by δ-tocopherol, γ-tocopherol, and γ-TmT. Furthermore, markers of cell proliferation (PCNA, PKCα), survival (PPAR-γ, PTEN, phospho-Akt), and cell cycle (p53, p21) were affected by δ- and γ-tocopherols. Both δ- and γ-tocopherols, but not α-tocopherol, seem to be promising agents for the prevention of hormone-dependent breast cancer.	\N	\N
22980951	The role of non-complement activating antibodies (ncAbs) to mismatched donor human leukocyte antigen (HLA) in the pathogenesis of chronic lung rejection is not known. We used a murine model of obliterative airway disease (OAD) induced by Abs to major histocompatibility major histocompatibility complex (MHC) class I and serum from donor-specific Abs developed in human lung transplant (LTx) recipients to test the role of ncAbs in the development of OAD and bronchiolitis obliterans syndrome (BOS). Anti-MHC ncAbs were administered intrabronchially in B.10 mice or in C3 knockout (C3KO) mice. Lungs were analyzed by histopathology. Lymphocytes secreting interleukin (IL)-17, interferon-γ, or IL-10 to collagen V and K-α1 tubulin (Kα1T) were enumerated by enzyme-linked immunospot assay. Serum antibodies to collagen V and Kα1T were determined by enzyme-linked immunosorbent assay. Cytokine and growth factor expression in lungs was determined by real-time polymerase chain reaction. Donor-specific Abs from patients with BOS and control BOS-negative LTx recipients were analyzed by C1q assay. Administration of ncAbs in B.10 mice or C3KO resulted in OAD lesions. There were significant increases in IL-17- and interferon-γ-secreting cells to collagen V and Kα1T, along with serum Abs to these antigens. There was also augmented expression of monocyte chemotactic protein-1, IL-6, IL-1β, vascular endothelial growth factor, transforming growth factor-β, and fibroblastic growth factor in mice administered ncAbs by Day 3. Among 5 LTx recipients with BOS, only 1 had C1q binding donor-specific Abs. Complement activation by Abs to MHC class I is not required for development of OAD and human BOS. Therefore, anti-MHC binding to epithelial and endothelial cells can directly activate pro-fibrotic and pro-inflammatory cascades leading to immune response to self-antigens and chronic rejection.	\N	\N
22981307	The "Cohorte Enfant Scanner", a study designed to investigate the risk of radiation-induced cancer after childhood exposure to CT (computed tomography) examinations, used clinical information contained in the "programme de médicalisation des systèmes d'information" (PMSI) database, the French hospital activities national program based upon diagnosis related groups (DRG). However, the quality and adequacy of the data for the specific needs of the study should be verified. The aim of our work was to estimate the percentage of the cohort's children identified in the PMSI database and to develop an algorithm to individualize the children with a cancer or a disease at risk of cancer from medical diagnoses provided by the DRGs database. Of the 1519 children from the "Cohorte Enfant Scanner", who had had a CT scan in the radiology department of a university hospital in 2002, a cross linkage was performed with the DRGs database. All hospitalizations over the period 2002-2009 were taken into account. An algorithm was constructed for the items "cancer" and "disease at risk for cancer" on a sample of 150 children. The algorithm was then tested on the entire population. Overall, 74% of our population was identified in the DRGs database. The algorithm individualized cancer diagnoses with 91% sensitivity (95% confidence interval [95%CI]: 86%; 97%) and 98% specificity (95%CI: 97%; 99%) and 86% positive predictive value (95%CI: 80%; 93%). For the diagnosis of disease at risk for cancer, the sensitivity, specificity and positive predictive value were respectively 91% (95%CI: 84%; 98%), 94% (95%CI: 92%; 95%) and 52% (95%CI: 43%; 61%). The DRG database identified with excellent sensitivity and specificity children with diagnoses of cancer or disease at risk for cancer. Hence, potential confounding factors related to the disease of the child can be taken into account for analyses performed with the cohort.	\N	\N
22990715	Few studies have explored the epidemiology of beta cell loss in youth with diabetes. This report describes the evolution and major determinants of beta cell function, assessed by fasting C-peptide (FCP), in the SEARCH for Diabetes in Youth study. Participants were 1,277 youth with diabetes (948 positive for diabetes autoantibodies [DAs] and 329 negative for DAs), diagnosed when aged <20 years, who were followed from a median of 8 months post diagnosis, for approximately 30 months. We modelled the relationship between rate of change in log FCP and determinants of interest using repeated measures general linear models. Among DA-positive youth, there was a progressive decline in beta cell function of 4% per month, independent of demographics (age, sex, race/ethnicity), genetic susceptibility to autoimmunity (HLA risk), HbA(1c) and BMI z score, or presence of insulin resistance. Among DA-negative youth, there was marked heterogeneity in beta cell loss, reflecting an aetiologically mixed group. This group likely includes youths with undetected autoimmunity (whose decline is similar to that of DA-positive youth) and youth with non-autoimmune, insulin-resistant diabetes, with limited decline (~0.7% per month). SEARCH provides unique estimates of beta cell function decline in a large sample of youth with diabetes, indicating that autoimmunity is the major contributor. These data contribute to a better understanding of clinical evolution of beta cell function in youth with diabetes, provide strong support for the aetiological classification of diabetes type and may inform tertiary prevention efforts targeted at high-risk groups.	\N	\N
23005903	A tubo-ovarian abscess (TOA) is a common complication of pelvic inflammatory disease in premenopausal women; however, in virginal females, TOAs are an exceedingly rare occurrence. Within this rare subset of patients, there is almost always an underlying condition, such as vaginal voiding, or a concomitant disease process. A virginal adolescent female with no prior medical history presented with a large pelvic mass which proved to be a TOA. An exploratory laparotomy was eventually required to establish the diagnosis. Open drainage and antibiotic therapy successfully treated the patient. With only the organism, Streptococcus viridians, isolated in her cultures, an etiology of direct ascension from the lower genitourinary tract is implicated. We believe this to be the youngest case of a TOA occurring in a virginal adolescent female without a predisposing condition. A TOA should be considered in the differential diagnosis of pelvic masses in previously healthy pediatric patients regardless of their sexual activity.	\N	\N
23008381	Japanese encephalitis (JE) is an epidemic encephalitis characterised by altered sensorium, convulsions, headache, brainstem signs with pyramidal and extrapyramidal features. Immune-mediated manifestation as acute transverse myelitis (ATM) has not been previously reported in JE. We describe a 40-year-old man who presented with an acute onset quadriparesis with urinary retention, which was preceded by fever and headache 3 weeks prior. He had elevated IgM titres against JE virus in serum and cerebrospinal fluid. MRI of cervico-thoracic spine demonstrated signal intensity alterations extending from C1 to D10 spinal segments. The patient was treated with intravenous methyl prednisolone for 5 days. He regained normal power at 6 months follow-up and repeat MRI study demonstrated complete resolution of the lesion. We conclude that in a case of JE, one should be vigilant for early diagnosis of possible complication as ATM, in which an early institution of immunomodulator therapy prevents adverse consequences.	\N	\N
23018067	OBJECTIVES. To evaluate attainment of low-density lipoprotein cholesterol goals among hypercholesterolaemic patients undergoing lipid-lowering drug treatment in Hong Kong and to identify potential determinants of treatment outcomes. DESIGN. Cross-sectional observational study. SETTING. A single site in Hong Kong, as part of the CEPHEUS Pan-Asian survey. PATIENTS. Subjects with hypercholesterolaemia aged 18 years or above, who had been on lipid-lowering drug treatment for at least 3 months with no dose adjustment for at least 6 weeks. RESULTS. A total of 561 such patients (mean age, 65.3; standard deviation, 9.7 years) were evaluated. Most had major cardiovascular risk factors; 534 (95.2%) of 561 patients had coronary heart disease and 534 (95.4%) of 560 patients had low-density lipoprotein cholesterol goals set at lower than 70 mg/dL. In all, 465 (82.9%) patients attained their respective low-density lipoprotein cholesterol goals. Among 75 patients who had coronary heart disease or equivalent risk, and multiple risk factors with a 10-year coronary heart disease risk of over 20%, 62 (82.7%) attained their respective low-density lipoprotein cholesterol goals. Significant predictors of low-density lipoprotein cholesterol goal attainment included the patient's baseline lipid profile (total cholesterol and low-density lipoprotein cholesterol levels), blood pressure, and drugs (statin/non-statin) used for treatment. CONCLUSIONS. Hypercholesterolaemic patients undergoing lipid-lowering drug treatment in the present Hong Kong study were able to achieve a very high attainment rate for the low-density lipoprotein cholesterol goal, despite the fact that most of them had major cardiovascular risk factors.	\N	\N
23020826	A patient with central nervous system involvement of Behçet's disease was refractory to conventional immunosuppressive therapy and showed secondary failure of the anti-TNF agent infliximab. This presented as a progressive weakness of the legs and reduction in walking distance. The cerebrospinal fluid showed signs of inflammation including a vastly elevated IL-6 concentration. Given this result, the anti-IL-6 receptor antibody tocilizumab was administered and a good improvement of inflammatory parameters and a satisfactory increase of the walking distance were achieved.	\N	\N
23028288	The prioritization of candidate disease-causing genes is a fundamental challenge in the post-genomic era. Current state of the art methods exploit a protein-protein interaction (PPI) network for this task. They are based on the observation that genes causing phenotypically-similar diseases tend to lie close to one another in a PPI network. However, to date, these methods have used a static picture of human PPIs, while diseases impact specific tissues in which the PPI networks may be dramatically different. Here, for the first time, we perform a large-scale assessment of the contribution of tissue-specific information to gene prioritization. By integrating tissue-specific gene expression data with PPI information, we construct tissue-specific PPI networks for 60 tissues and investigate their prioritization power. We find that tissue-specific PPI networks considerably improve the prioritization results compared to those obtained using a generic PPI network. Furthermore, they allow predicting novel disease-tissue associations, pointing to sub-clinical tissue effects that may escape early detection.	\N	\N
23028439	Several independent studies have supported the association of DYX1C1 with dyslexia, but its role in general reading development remains unclear. Here, we investigated the contribution of this gene to reading, with a focus on orthographic skills, in a sample of 284 unrelated Chinese children aged 5 to 11 years who were participating in the Chinese Longitudinal Study of Reading Development. We tested this association using a quantitative approach for Chinese character reading, Chinese character dictation, orthographic judgment, and visual skills. Significant or marginally significant associations were observed at the marker rs11629841 with children's orthographic judgments at ages 7 and 8 years (all P values<0.020). Significant associations with Chinese character dictation (all P values<0.013) were also observed for this single-nucleotide polymorphism (SNP) at ages 9, 10, and 11 years. Further analyses revealed that the association with orthographic skills was specific to the processing of specific components of characters (P values<0.046). No association was found at either SNP of rs3743205 or rs57809907. Our findings suggest that DYX1C1 influences reading development in the general Chinese population and supports a universal effect of this gene.	\N	\N
23049998	Although "uremic fetor" has long been felt to be diagnostic of renal failure, the compounds exhaled in uremia remain largely unknown so far. The present work investigates whether breath analysis by ion mobility spectrometry can be used for the identification of volatile organic compounds retained in uremia. Breath analysis was performed in 28 adults with an eGFR ≥ 60 ml/min per 1.73 m(2), 26 adults with chronic renal failure corresponding to an eGFR of 10-59 ml/min per 1.73 m(2), and 28 adults with end-stage renal disease (ESRD) before and after a hemodialysis session. Breath analysis was performed by ion mobility spectrometryafter gas-chromatographic preseparation. Identification of the compounds of interest was performed by thermal desorption gas chromatography/mass spectrometry. Breath analyses revealed significant differences in the spectra of patients with and without renal failure. Thirteen compounds were chosen for further evaluation. Some compounds including hydroxyacetone, 3-hydroxy-2-butanone and ammonia accumulated with decreasing renal function and were eliminated by dialysis. The concentrations of these compounds allowed a significant differentiation between healthy, chronic renal failure with an eGFR of 10-59 ml/min, and ESRD (p<0.05 each). Other compounds including 4-heptanal, 4-heptanone, and 2-heptanone preferentially or exclusively occurred in patients undergoing hemodialysis. Impairment of renal function induces a characteristic fingerprint of volatile compounds in the breath. The technique of ion mobility spectrometry can be used for the identification of lipophilic uremic retention molecules.	\N	\N
23050521	Data from the 2011 Survey of Pathways to Diagnosis and Services The median age when school-aged children with special health care needs (CSHCN) and autism spectrum disorder (ASD) were first identified as having ASD was 5 years. School-aged CSHCN identified as having ASD at a younger age (under age 5 years) were identified most often by generalists and psychologists, while those identified later (aged 5 years and over) were identified primarily by psychologists and psychiatrists. Nine out of 10 school-aged CSHCN with ASD use one or more services to meet their developmental needs. Social skills training and speech or language therapy are the most common, each used by almost three-fifths of these children. More than one-half of school-aged CSHCN with ASD use psychotropic medication.	\N	\N
23058984	Mast cells (MCs) are well known for their detrimental effects in the context of allergic disorders. Strategies that limit MC function can therefore have a therapeutic value. Previous studies have shown that siramesine, a sigma-2 receptor agonist originally developed as an anti-depressant, can induce cell death in transformed cells through a mechanism involving lysosomal destabilization. Since MCs are remarkably rich in lysosome-like secretory granules we reasoned that MCs might be sensitive to siramesine. Here we show that murine and human MCs are highly sensitive to siramesine. Cell death was accompanied by secretory granule permeabilization, as shown by reduced acridine orange staining and leakage of granule proteases into the cytosol. Wild type siramesine-treated MCs underwent cell death with typical signs of apoptosis but MCs lacking serglycin, a proteoglycan crucial for promoting the storage of proteases within MC secretory granules, died predominantly by necrosis. A dissection of the underlying mechanism suggested that the necrotic phenotype of serglycin(-/-) cells was linked to defective Poly(ADP-ribose) polymerase-1 degradation. In vivo, siramesine treatment of mice caused a depletion of the MC populations of the peritoneum and skin. The present study shows for the first time that MCs are highly sensitive to apoptosis induced by siramesine and introduces the possibility of using siramesine as a therapeutic agent for treatment of MC-dependent disease.	\N	\N
23061325	A paradox exists in health disparities research where African-American cigarette smokers consume fewer cigarettes per day, yet experience higher rates of tobacco-related disease compared to White American smokers. In this study we conducted focus group interviews among alternative high school youth (N = 78; age 18-19 years old) in an urban area in Southwest Texas to investigate if African-American youth smoke cigarettes differently than their White-American and Hispanic-American counterparts. The majority of African-American participants reported inhaling deeper and smoking their cigarettes "to the filter" because of their concern over wasting any part of an expensive cigarette. White and Hispanic respondents most often put out their cigarettes closer to the middle, and did not express concern about wasting cigarettes. The implication from this qualitative study is that because African Americans smoke differently they are exposed to a higher level of harmful particulate per cigarette. Further research on smoking topography is warranted.	\N	\N
23063289	A meta-analysis of publicly available gene expression changes in A549 cells upon treatment with anti-cancer drugs is reported. To reduce false positives, both fold-change and significance level cutoffs were used. Simulated datasets and permutation analysis were used to guide choice of ratio cutoff. Of the genes identified, FDXR is the only gene differentially expressed in six of the seven drug treatments. Though FDXR has been reported to be differentially expressed upon treatment with 5-fluorouracil and its expression correlated to long term disease survival, to our knowledge this is a first study implicating a wide effect of anti-cancer drug treatment on FDXR expression. The other genes identified which are differentially expressed in four out of the seven drug treatments are CDKN1A and PARVB which are upregulated and MYC, HBP1, LDLR, SIM2, ALX1 and GPHN which are downregulated.	\N	\N
23063663	Liver cancer is one of most deadly cancers worldwide. Hepatocellular carcinoma (HCC) represents a major histological subtype of liver cancers. As cancer is a genetic disease, genetic lesions play a major role in HCC tumorigenesis and progression. Although significant progress has been made to uncover genetic alterations in HCCs, our understanding of genetics involved in the initiation and progression of HCC is far from complete. Next generation sequencing (NGS) has provided a new paradigm in biomedical research to delineate the genetic basis of human diseases. While identification of cancer somatic mutations has been serendipitous, genome sequencing has provided an unbiased approach to systematically catalog somatic mutations and elucidate the mechanisms of tumourigenesis. A number of recently published NGS studies on HCCs have not only confirmed previously known mutations in CTNNB1 and TP53 in HCC, but also identified novel genetic alterations in HCC including mutations in genes involved in epigenetic regulation. WNT, cell cycle and chromatin remodeling pathways have emerged as key oncogenic drivers in HCCs. The frequently altered genes and pathways in HCC reflect classical cancer hallmarks. These findings have started to depict a genetic landscape in HCC and will facilitate development of novel therapeutics for the treatment of this deadly disease.	\N	\N
23063979	Vascular calcification is a hallmark of cardiovascular disease. Interleukin-24 (IL-24) has been known to suppress tumor progression in a variety of human cancers. However, the role of IL-24 in the pathophysiology of diseases other than cancer is unclear. We investigated the role of IL-24 in vascular calcification. IL-24 was applied to a β-glycerophosphate (β-GP)-induced rat vascular smooth muscle cell (VSMC) calcification model. In this study, IL-24 significantly inhibited β-GP-induced VSMC calcification, as determined by von Kossa staining and calcium content. The inhibitory effect of IL-24 on VSMC calcification was due to the suppression of β-GP-induced apoptosis and expression of calcification and osteoblastic markers. In addition, IL-24 abrogated β-GP-induced activation of the Wnt/β-catenin pathway, which plays a key role in the pathogenesis of vascular calcification. The specificity of IL-24 for the inhibition of VSMC calcification was confirmed by using a neutralizing antibody to IL-24. Our results suggest that IL-24 inhibits β-GP-induced VSMC calcification by inhibiting apoptosis, the expression of calcification and osteoblastic markers, and the Wnt/ β-catenin pathway. Our study may provide a novel mechanism of action of IL-24 in cardiovascular disease and indicates that IL-24 is a potential therapeutic agent in VSMC calcification.	\N	\N
23070622	Multivisceral transplantation includes the simultaneous transplantation of multiple abdominal viscera including the stomach, duodenum, pancreas, and small intestine, with (multivisceral transplant, MVT) or without the liver (modified MVT, MMVT). This study reviews the changing indications and outcomes for this procedure over a 7-year period at a university medical center. This study is a retrospective case review of MVTs performed between 2004 and 2010 at a single center. All cases were either MVT or MMVT and included a simultaneous kidney transplant, if indicated. Graft failure was defined as loss of the graft or complete loss of function. Graft function was monitored by clinical function, laboratory values, and serial endoscopy with biopsy. During the study period, 95 patients received 100 transplants including 84 MVT and 16 MMVT. There were 19 patients who received a simultaneous kidney graft. There were 24 pediatric and 76 adult recipients (range 7 months to 66 years). Indications included intestinal failure alone, intestinal failure with cirrhosis, complete portal mesenteric thrombosis, slow-growing central abdominal tumors, intestinal pseudoobstruction, and frozen abdomen. All patients received antibody-based induction immunosuppression with calcineurin inhibitor-based maintenance immunosuppression. At a median mortality adjusted follow-up of 25 months, 1- and 3-year patient survival is 72 % and 57 %. There was a learning curve with this complex procedure resulting in a 48 % patient survival during the period from 2004 to 2007, followed by a 70 % patient survival during the period from 2008 to 2010. Post-transplant complications included rejection (50 % MMVT and 17 % MVT), infection (>90 % first year), graft versus host disease (13 %), and post-transplant lymphoproliferative disorder (5 %). Indications for MVT and MMVT have broadened to include patients with terminal conditions not amenable to other medical therapies such as slow-growing tumors of the mesenteric root, complete portomesenteric thrombosis, and abdominal catastrophes/frozen abdomen. Outcomes have improved over time with many patients returning to full functional status and enjoying long-term survival.	\N	\N
23079185	Elevated serum levels of the proinflammatory cytokine tumor necrosis factor alpha (TNFα) correlate with an increased risk for atherothrombotic events and TNFα is known to induce prothrombotic molecules in endothelial cells. Based on the preexisting evidence for the impact of TNFα in the pathogenesis of autoimmune disorders and their known association with an acquired hypercoagulability, we investigated the effects of TNFα and the role of the TNF receptor subtypes TNFR1 and TNFR2 for arteriolar thrombosis in vivo. Arteriolar thrombosis and platelet-rolling in vivo were investigated in wildtype, TNFR1-/-, TNFR2-/- and TNFR1-/R2-/- C57BL/6 mice using intravital microscopy in the dorsal skinfold chamber microcirculation model. In vitro, expression of prothrombotic molecules was assessed in human endothelial cells by real-time PCR and flow cytometry. In wildtype mice, stimulation with TNFα significantly accelerated thrombotic vessel occlusion in vivo upon ferric chloride injury. Arteriolar thrombosis was much more pronounced in TNFR1-/- animals, where TNFα additionally led to increased platelet-endothelium-interaction. TNFα dependent prothrombotic effects were not observed in TNFR2-/- and TNFR1-/R2- mice. In vitro, stimulation of human platelet rich plasma with TNFα did not influence aggregation properties. In human endothelial cells, TNFα induced superoxide production, p-selectin, tissue factor and PAI-1, and suppressed thrombomodulin, resulting in an accelerated endothelial dependent blood clotting in vitro. Additionally, TNFα caused the release of soluble mediators by endothelial cells which induced prothrombotic and suppressed anticoagulant genes comparable to direct TNFα effects. TNFα accelerates thrombus formation in an in vivo model of arteriolar thrombosis. Its prothrombotic effects in vivo require TNFR2 and are partly compensated by TNFR1. In vitro studies indicate endothelial mechanisms to be responsible for prothrombotic TNFα effects. Our results support a more selective therapeutic approach in anticytokine therapy favouring TNFR2 specific antagonists.	\N	\N
23083013	Atopic dermatitis (AD) is a chronic and relapsing inflammatory skin disease affecting > 10% of children and 1-3% of adults, and can cause significant morbidity. The incidence of AD seems to be increasing. Omalizumab, a monoclonal antibody, has recently been suggested as a potential new systemic treatment for patients with recalcitrant AD with elevated IgE levels, based on its efficacy in treating asthma and allergic rhinitis. We report a study of 10 patients with AD (aged 19-35 years) who received anti-IgE treatment for persistent asthma. All patients, regardless of IgE value, were treated with a fixed schedule of eight cycles of omalizumab 300 mg administered subcutaneously at intervals of 2 weeks. Eczema symptoms were scored at baseline and after 2, 4 and 6 months of treatment. There was a steady improvement in the objective SCORAD (SCORing Atopic Dermatitis), with significantly lower scores observed at the 6-month evaluation. At 2 months after the end of treatment, two patients had a very good result (SCORAD reduction of > 50%), five patients had a satisfactory result (reduction of 25-50%), and three patients had no clinically relevant result (reduction of 25-50%). No patient had worsening of the AD (increase of > 25% in SCORAD), and once a clinical improvement occurred, none of the patients experienced worsening of their eczema symptoms while on omalizumab. With the caveats of the financial expense and unknown long-term risks of malignancy associated with omalizumab, this drug should be considered for treatment-resistant patients with AD, particularly patients with high IgE level whose symptoms are not controlled by routine therapies. Omalizumab has proven useful in treating asthma, but it may also prove valuable for other conditions, such as allergic rhinitis, food allergies, chronic urticaria, and AD, as shown by the present study.	\N	\N
23087412	We recently proposed two novel criteria to assess the usefulness of risk prediction models for public health applications. The proportion of cases followed, PCF(p), is the proportion of individuals who will develop disease who are included in the proportion p of individuals in the population at highest risk. The proportion needed to follow-up, PNF(q), is the proportion of the general population at highest risk that one needs to follow in order that a proportion q of those destined to become cases will be followed (Pfeiffer, R.M. and Gail, M.H., 2011. Two criteria for evaluating risk prediction models. Biometrics 67, 1057-1065). Here, we extend these criteria in two ways. First, we introduce two new criteria by integrating PCF and PNF over a range of values of q or p to obtain iPCF, the integrated PCF, and iPNF, the integrated PNF. A key assumption in the previous work was that the risk model is well calibrated. This assumption also underlies novel estimates of iPCF and iPNF based on observed risks in a population alone. The second extension is to propose and study estimates of PCF, PNF, iPCF, and iPNF that are consistent even if the risk models are not well calibrated. These new estimates are obtained from case-control data when the outcome prevalence in the population is known, and from cohort data, with baseline covariates and observed health outcomes. We study the efficiency of the various estimates and propose and compare tests for comparing two risk models, both of which were evaluated in the same validation data.	\N	\N
23089926	Lipoprotein lipase (LPL) is a key enzyme in lipid metabolism and is associated with obesity, dyslipidemias, hypertension (HTN) and type 2 diabetes mellitus (T2DM). LPL gene polymorphisms can be related with the development of cardiovascular risk factors. The present study was conducted to analyze the relationship of the HindIII and S447X polymorphisms in LPL gene with cardiovascular risk factors in Mexican families. The study population comprised ninety members of 30 Mexican families, in which an index case had obesity, were included in the study. We evaluated the body composition by bioelectrical impedance. Peripheral blood samples were collected to determine biochemical parameters. Screening for both polymorphisms was made by PCR-RFLPs. In the parents, both polymorphisms were in Hardy-Weinberg's equilibrium. We found that the genotype T/T of HindIII was associated with diastolic blood pressure ≥ 85 mmHg (OR=1.1; p=0.011), whereas the genotype C/C of S447X was associated with systolic blood pressure ≥ 130 mmHg (OR=1.2; p<0.001), diastolic blood pressure ≥ 85 mmHg (OR = 1.3; p< 0.001), T2DM (OR=1.3; p< 0.001) and with increase of total cholesterol (β =23.6 mg/mL; p=0.03). These data suggest that the HindIII and S447X LPL gene polymorphisms can confer susceptibility for the development of hypertension and T2DM in Mexican families.	\N	\N
23092312	Many coronary heart disease (CHD) events occur in individuals classified as intermediate risk by commonly used assessment tools. Over half the individuals presenting with a severe cardiac event, such as myocardial infarction (MI), have at most one risk factor as included in the widely used Framingham risk assessment. Individuals classified as intermediate risk, who are actually at high risk, may not receive guideline recommended treatments. A clinically useful method for accurately predicting 5-year CHD risk among intermediate risk patients remains an unmet medical need. This study sought to develop a CHD Risk Assessment (CHDRA) model that improves 5-year risk stratification among intermediate risk individuals. Assay panels for biomarkers associated with atherosclerosis biology (inflammation, angiogenesis, apoptosis, chemotaxis, etc.) were optimized for measuring baseline serum samples from 1084 initially CHD-free Marshfield Clinic Personalized Medicine Research Project (PMRP) individuals. A multivariable Cox regression model was fit using the most powerful risk predictors within the clinical and protein variables identified by repeated cross-validation. The resulting CHDRA algorithm was validated in a Multiple-Ethnic Study of Atherosclerosis (MESA) case-cohort sample. A CHDRA algorithm of age, sex, diabetes, and family history of MI, combined with serum levels of seven biomarkers (CTACK, Eotaxin, Fas Ligand, HGF, IL-16, MCP-3, and sFas) yielded a clinical net reclassification index of 42.7% (p < 0.001) for MESA patients with a recalibrated Framingham 5-year intermediate risk level. Across all patients, the model predicted acute coronary events (hazard ratio = 2.17, p < 0.001), and remained an independent predictor after Framingham risk factor adjustments. These include the slightly different event definition with the MESA samples and inability to include PMRP fatal CHD events. A novel risk score of serum protein levels plus clinical risk factors, developed and validated in independent cohorts, demonstrated clinical utility for assessing the true risk of CHD events in intermediate risk patients. Improved accuracy in cardiovascular risk classification could lead to improved preventive care and fewer deaths.	\N	\N
23097963	This work, partial pressure of the respiratory gases in the capillary blood (pH, PaO2, PaCO2) was studied, following the protective action of the beta2-drenergic stimulator-Hexoprenaline and alpha2-adrenergic blocker-Tolazoline in the bronchoconstriction caused by a beta-blocker-Propranolol. in patients with increased bronchial reactibility. pH, oxygen partial pressure (PaO2), dioxide carbon partial pressure (PaCO2) in the arterial blood, with the assistance of the analyzer IL, following some minutes of sample taking were defined in all patients. As a standard to verify the accuracy of the measurement, ampoule solutions of pH, PaO2 and PaCO2 were utilized (Acidobasel, Berlin). Following the inhalation of the beta-blocker-Propranolol (20 mg/ml-aerosol), there was an evident decrease (p < 0.05) of pO2 and a non-significant increase (p > 0.1) of pCO2. Beta2-adrenergcic stimulator-Hexoprenaline (2 inh x 0.2 mg), shows an protective effect in the decrease of pO2 (p < 0.05) following the bronchoconstriction being provoked by Propranolol. Alpha2-adrenergic blocker-Tolazoline (20 mg/ml-aerosol), has not shown a protective action in the bronchoconstriction caused with propranolol, therefore significant decrease (p < 0.05) of pO2 and a non-significant increase (p > 0.1) of pCO2 appeared. This shows that stimulation of beta2-adrenergic receptor has protective action in changes of the respiratory gases. Meantime, blocker of the alpha2-adrenergic receptor (Tolazoline) has not shown a protective action in changes of the respiratory gases.	\N	\N
23101267	CD200 and its receptor were recognized as having the multiple immunoregulatory functions. Their immunoregulatory, suppressive, and tolerogenic potentials could be very effectively exploited in the treatment of many diseases, e.g. Alzheimer disease, rheumatoid arthritis, and allergy to name only some. Many research projects are aimed to develop clinically valuable methods being based on the structure and function of these paired molecules. In this review, we would like to introduce CD200/CD200R functions in a clinical context.	\N	\N
23114434	Surveillance of nosocomial infections is meanwhile a cornerstone of infection prevention activities in hospitals. The objective of this article is to compare healthcare-associated infection rates in intensive care patients, neonatal intensive care patients and operated patients (ICU-KISS, OP-KISS, NEO-KISS) of the German nosocomial infection surveillance system (KISS) with the corresponding data of the US American National Healthcare Safety Network (NHSN) and the European Centre for Disease Prevention and Control (ECDC). In general, the methodological differences among the three surveillance systems are minor but there are some exceptions. Therefore, differences between countries have to be interpreted very carefully as they may be due to differences in diagnostics, patient mix, types of interventions, length of stay, selection of participating hospitals, post-discharge surveillance activities and interpretation of case definitions. Organizational aspects, such as mandatory participation with public disclosure on infection rates may also have an impact.	\N	\N
23117745	Arterial calcification is the result of the same highly organized processes as seen in bone, which rely on a delicate balance between osteoblasts and osteoclasts. Although previously understood as passive precipitation, evidence has accumulated to suggest that arterial calcification is the result of organized, regulated processes bearing many similarities to osteogenesis in bone, including the presence of subpopulations of arterial wall cells that retain osteoblastic lineage potential. These cells have the potential to form mineralized nodules and express osteoblast markers, including bone morphogenetic protein-2, osteocalcin, osteopontin, and alkaline phosphatase. By contrast, osteoclast-like cells mediate the catabolic process of mineral resorption. Recent data shows that cells positive for tartrate-resistant acid phosphatase, a major marker for osteoclasts, have been histologically identified in atherosclerotic lesions and are referred to as osteoclast-like cells. Evidence has accumulated to suggest that initial arterial calcification through passive precipitation of calcium phosphate initiates balanced mineralization regulated by osteoclast-like and osteoblast-like cells. Subsequently, various pathogenic conditions may trigger an imbalance between osteoblastogenesis and osteoclastogenesis, leading to either calcification in stenotic/occlusive disease or destruction of the extracellular matrix in aneurysmal disease. Further elucidation of these newly emerging concepts could lead to a novel therapeutic approach to arterial stenotic/occlusive disease and/or abdominal aortic aneurysm.	\N	\N
23126056	Amyloidosis is a clinical entity that results from deposition of an extracellular protein material that causes disruption in normal architecture and impairs function of multiple organs and tissues. Secondary amyloidosis (AA) is a rare but serious complication that appears in the context of cancer, chronic inflammation, and chronic infectious disease, including rheumatoid arthritis. Renal failure is the most common clinical presentation of AA, ranging from nephrotic syndrome and impaired renal function to renal failure, with a potential for high morbidity. We present a case of a 52-year-old female patient diagnosed with rheumatoid arthritis at age 27. She was hospitalized due to worsening clinical condition. Physical examination revealed marked peripheral edema in both lower extremities. Laboratory tests showed an increase of inflammatory reactants, anemia, electrolyte disbalance, and severe hypoalbuminemia and hypoproteinemia. She had proteinuria 15.4 g/24 h and renal function estimated by creatinine clearance was 78 mL/min, within the second degree of chronic kidney disease. Renal biopsy was performed for evaluation of renal insufficiency with nephrotic range proteinuria. Congo red staining showed the presence of characteristic amyloid deposits that immunoreacted with the antibody against amyloid A protein, thus confirming the diagnosis of secondary amyloidosis.	\N	\N
23132831	Development of effective therapeutic strategies to eliminate cancer stem cells, which play a major role in drug resistance and disease recurrence, is critical to improve cancer treatment outcomes. Our study showed that glioblastoma stem cells (GSCs) exhibited low mitochondrial respiration and high glycolytic activity. These GSCs were highly resistant to standard drugs such as carmustine and temozolomide (TMZ), but showed high sensitivity to a glycolytic inhibitor 3-bromo-2-oxopropionate-1-propyl ester (3-BrOP), especially under hypoxic conditions. We further showed that combination of 3-BrOP with carmustine but not with TMZ achieved a striking synergistic effect and effectively killed GSCs through a rapid depletion of cellular ATP and inhibition of carmustine-induced DNA repair. This drug combination significantly impaired the sphere-forming ability of GSCs in vitro and tumor formation in vivo, leading to increase in the overall survival of mice bearing orthotopic inoculation of GSCs. Further mechanistic study showed that 3-BrOP and carmustine inhibited glyceraldehyde-3-phosphate dehydrogenase and caused a severe energy crisis in GSCs. Our study suggests that GSCs are highly glycolytic and that certain drug combination strategies can be used to effectively overcome their drug resistance based on their metabolic properties.	\N	\N
23133607	Functional genetic variations play important roles in shaping phenotypic differences among individuals through affecting gene expression, and thus, very likely to influence disease susceptibility, such as cancer susceptibility. One critical question in this era of post-genome wide association studies (GWAS) is how to assess the functional significance of the genetic variations identified from GWAS. In the current study, with lymphoblastoid cell lines (LCLs) from 74 non-related women with familial ovarian cancer and 47 unrelated controls matched on gender and race, we explored the associations between seven ovarian cancer risk variants identified from GWAS (rs3814113 on 9p22.2, rs2072590 on 2q31, rs2665390 on 3q25, rs10088218, rs1516982, rs10098821 on 8q24.21, and rs2363956 on 19p13) and whole genome mRNA expression profiles. We observed 95 significant trans-associations at a permutation level of 0.001. Compared to the other risk variants, rs10088218, rs1516982, and rs10098821 on 8q24.21 had the greatest number of significant associations (25, 16, and 38, respectively). Two possible cis-associations were observed between rs10098821 and c-Myc, and rs2072590 and HS.565379 (Permutated P = 0.0198 and 0.0399, respectively). Pathway enrichment analysis showed that several key biological pathways, such as cell cycle (P = 2.59×10(-06)), etc, were significantly overrepresented. Further characterization of significant associations between mRNAs and risk alleles might facilitate understanding the functions of GWAS discovered risk alleles in the genetic etiology of ovarian cancer.	\N	\N
23136226	A combination of bortezomib (1.3 mg/m(2)), melphalan (5 mg/m(2)), and dexamethasone (40 mg) (BMD), with all three drugs given as a contemporary intravenous administration, was retrospectively evaluated. Fifty previously treated (median 2 previous lines) patients with myeloma (33 relapsed and 17 refractory) were assessed. The first 19 patients were treated with a twice-a-week (days 1, 4, 8, 11, 'base' schedule) administration while, in the remaining 31 patients, the three drugs were administered once a week (days 1, 8, 15, 22, 'weekly' schedule). Side-effects were predictable and manageable, with prominent haematological toxicity, and a better toxic profile in 'weekly' schedule (36% versus 66% in 'base' schedule). The overall response rate was 62%. After median follow-up of 24.5 months (range 2.7-50 months), the median progression-free survival (PFS) was 21.6 with no difference between the two schedules and the median overall survival (OS) was 33.8 months. Independently from the adopted schedule, we found that also in a cohort of relapsed/refractory patients achieving at least partial remission improved PFS (35.2 versus 9 months) and OS (unreached median versus 18 months). Taken together, our observations suggest that BMD is an effective regimen in advanced myeloma patients with acceptable toxicity.	\N	\N
23137772	Molecular cytogenetic evaluation of human osteosarcoma (OS) has revealed the characteristically high degree of genomic reorganization that is the hallmark of this cancer. The extent of genomic disorder in OS has hindered identification of the genomic aberrations driving disease progression. With pathophysiological similarities to its human counterpart, canine OS represents an ideal model for comparison of conserved regions of genomic instability that may be disease-associated rather than genomic passengers. This study used high-resolution oligonucleotide array comparative genomic hybridization and a variety of informatics tools to aid in the identification of disease-associated genome-wide DNA copy number aberrations in canine and human OS. Our findings support and build upon the high level of cytogenetic complexity, through the identification of shared regions of microaberration (<500 kb) and functional analysis of possible orthologous OS-associated genes to pinpoint the cellular processes most commonly affected by aberration in human and canine OS. Aberrant regions contained previously reported genes such as CDC5L, MYC, RUNX2, and CDKN2A/CDKN2B, while expanding the gene of interest list to include ADAM15, CTC1, MEN1, CDK7, and others. Such regions of instability may thus have functional significance in the etiology of OS, the most common primary bone tumor in both species.	\N	\N
23143555	The objective of the study is to investigate the mechanisms of cyclophosphamide sequential therapy for patient with primary Sjögren's syndrome-associated interstitial lung disease (PSS-ILD). This was a retrospective review of 15 patients (2005-2008) with PSS-ILD who underwent cyclophosphamide sequential therapy. Peripheral blood and bronchoalveolar lavage (BALF) were obtained before and 3, 6, 12 and 24 months after the treatment. The TNF-α and TGF-β1 mRNA levels in peripheral blood were measured using reverse transcription polymerase chain reaction. Serum and BALF TNF-α, TGF-β1 and MMP-9 levels were measured using sandwich enzyme-linked immunosorbent assay. The average levels of serum TNF-α (0.39 ± 0.22) and TGF-β1 (0.31 ± 0.18) mRNA in patients with PSS-ILD were higher compared with that in patients with PSS without ILD. TNF-α level (0.23 ± 0.19) was significantly decreased 3 months after cyclophosphamide treatment (t = 2.533, p < 0.05), and TGF-β1 (0.31 ± 0.18) level markedly decreased after 6 months of treatment (t = 2.617, p < 0.05). The levels of serum TNF-α (11.2 ± 2.6) μg/L, TGF-β1 (72 ± 19) μg/L and MMP-9 (38 ± 9) μg/L in patients with PSS-ILD were higher than that in patients with PSS without ILD. TGF-β1 (36 ± 12) μg/L level decreased significantly after 3 months of treatment (t = 2.526, p < 0.05), and TNF-α level (7.1 ± 1.3) μg/L markedly decreased after 6 months of therapy (t = 2.578, p < 0.05). MMP-9 level (18 ± 4) μg/L decreased significantly after 12-month treatment (t = 2.329, p < 0.05). The levels of BALF TNF-α (17.1 ± 3.5) μg/L, TGF-β1 (36 ± 17) μg/L and MMP-9 (27 ± 10) μg/L in patients with PSS-ILD were higher than that in patients with PSS without ILD. TGF-β1 (21 ± 14) μg/L level decreased significantly after 3-month treatment, and TNF-α level (9.4 ± 1.7) μg/L was decreased after 6 months of cyclophosphamide treatment that may be associated with its inhabitation on production of TNF-α, TGF-β1 and MMP-9.	\N	\N
23144854	The Glutathione S-transferase P1 (GSTP1) polymorphism have been considered a risk modifier for developing head and neck cancer (HNC) in many studies; however, the results of such studies are inconsistent. The aim of this study was to evaluate the possible association between the GSTP1 Ile105Val polymorphism and risk of HNC. We performed a search in the relevant electronic database and a meta-analysis based on 28 published case-control studies that included 6,404 cases and 6,523 controls. To take into account the possibility of heterogeneity across the studies, a Chi-square based I(2)-statistic test was performed. Crude pooled odds ratios (ORs) with 95% confidence intervals (CIs) were assessed using both fixed-effects and random-effects models. The results of this meta-analysis showed that the GSTP1 Ile105Val polymorphism was not significantly associated with risk of HNC in the overall study population (pooled OR 1.00, 95% CI 0.92-1.09) or in subgroup analyses stratified by ethnicity, sample size, tumor site or publication year. Moreover, substantial evidence of heterogeneity among the studies was observed. Publication year was identified as the main cause of heterogeneity. This meta-analysis does not support a significant association between the GSTP1 Ile105Val polymorphism and risk of HNC.	\N	\N
23145068	Electrode implantation into the subthalamic nucleus for deep brain stimulation in Parkinson's disease (PD) is associated with a temporary motor improvement occurring prior to neurostimulation. We studied this phenomenon by functional magnetic resonance imaging (fMRI) when considering the Unified Parkinson's Disease Rating Scale (UPDRS-III) and collateral oedema. Twelve patients with PD (age 55.9± (SD)6.8 years, PD duration 9-15 years) underwent bilateral electrode implantation into the subthalamic nucleus. The fMRI was carried out after an overnight withdrawal of levodopa (OFF condition): (i) before and (ii) within three days after surgery in absence of neurostimulation. The motor task involved visually triggered finger tapping. The OFF/UPDRS-III score dropped from 33.8±8.7 before to 23.3±4.8 after the surgery (p<0.001), correlating with the postoperative oedema score (p<0.05). During the motor task, bilateral activation of the thalamus and basal ganglia, motor cortex and insula were preoperatively higher than after surgery (p<0.001). The results became more enhanced after compensation for the oedema and UPDRS-III scores. In addition, the rigidity and axial symptoms score correlated inversely with activation of the putamen and globus pallidus (p<0.0001). One month later, the OFF/UPDRS-III score had returned to the preoperative level (35.8±7.0, p = 0.4).In conclusion, motor improvement induced by insertion of an inactive electrode into the subthalamic nucleus caused an acute microlesion which was at least partially related to the collateral oedema and associated with extensive impact on the motor network. This was postoperatively manifested as lowered movement-related activation at the cortical and subcortical levels and differed from the known effects of neurostimulation or levodopa. The motor system finally adapted to the microlesion within one month as suggested by loss of motor improvement and good efficacy of deep brain stimulation.	\N	\N
23146629	We report a 14-year-old-boy with markedly elevated serum creatine kinase (CK) levels, in whom massive triglyceride storage was found in peripheral blood leukocytes and in muscle biopsy. Sequencing PNPLA2, the gene encoding the adipose triglyceride lipase (ATGL) and responsible for the neutral lipid storage disease with myopathy (NLSDM), we identified two heterozygous mutations, including a previously reported nonsense and a novel missense mutation in the patatin domain of the gene. Lipid storage myopathy can be clinically silent in childhood and presenting only with hyperCKemia.	\N	\N
23154328	Trismus is a common problem among oral cancer patients. This report aimed to study the inciting factors of trismus and to find out the rationale of trismus release. Between 1996 and 2008, 61 oral cancer patients with retrievable records of interincisor distance (IID) were analyzed by retrospective chart review. The IID decreased from 31.4 (12.4) to 24.9 (12.0) mm in 36 patients undergoing cancer ablation only (P = 0.001). Other variables prompting trismus include buccal cancer (P = 0.017), radiotherapy (P = 0.008), and recurrence (P = 0.001). In contrast, the IID improved from 11.7 (7.1) to 22.7 (11.9) mm in 25 patients receiving cancer ablative and trismus releasing surgeries (P = 0.000). The improvement fared better in individuals with IID less than 15 mm than the others (P = 0.037). In conclusion, involvement of buccal region, ablative surgery, radiotherapy, and recurrence are provocative factors of trismus. Patients with IID less than 15 mm will benefit from releasing surgery significantly. Others may better be handled with conservative managements firstly, and enrolled as candidates of surgical release only until the patients entertained a 28-month period of disease-free interval, by which time the risk of recurrence would be markedly reduced.	\N	\N
23159635	Activin, a member of the transforming growth factor-β family, has been known to be a growth and differentiating factor. Despite its pluripotent effects, the roles of activin signaling in prostate cancer pathogenesis are still unclear. In this study, we established several cell lines that express a constitutive active form of activin type IB receptor (ActRIBCA) in human prostate cancer cells, ALVA41 (ALVA-ActRIBCA). There was no apparent change in the proliferation of ALVA-ActRIBCA cells in vitro; however, their migratory ability was significantly enhanced. In a xenograft model, histological analysis revealed that the expression of Snail, a cell-adhesion-suppressing transcription factor, was dramatically increased in ALVA-ActRIBCA tumors, indicating epithelial mesenchymal transition (EMT). Finally, mice bearing ALVA-ActRIBCA cells developed multiple lymph node metastases. In this study, we demonstrated that ActRIBCA signaling can promote cell migration in prostate cancer cells via a network of signaling molecules that work together to trigger the process of EMT, and thereby aid in the aggressiveness and progression of prostate cancers.	\N	\N
23167225	In this study, we hypothesized that subclinical impairment of left ventricular (LV) mechanical function in bicuspid aortic valve (BAV) patients is independent of valvular hemodynamics represented by valvuloarterial impedance and aortic elastic characteristics. Therefore, we aimed to test left ventricular mechanics in cases of isolated non-stenotic BAV with non-dilated aorta. Thirty-three patients with isolated BAV exhibiting non-dilated aorta, and 25 age-and gender-matched healthy subjects were included in the study. Patients with aortic valve velocity > 1.5 m/s and mild-to-moderate aortic regurgitation or ascending aorta diameter > 3.5 cm were excluded from the study. Aortic elasticity parameters and valvulo-arterial impedance were calculated. Strain measurements were reported as the peak longitudinal strain (LS) for four chamber (4C), long axis (LAX) and two chamber (2C) views. Strain rate (Sr) measurements were reported as the peak systolic strain rate (Sr-sm), early diastolic strain rate (Sr-em) and late diastolic strain rate (Sr-am) for 4C, LAX and 2C views. Systolic and diastolic diameters of the ascending aorta, aortic elastic properties (aortic strain, aortic distensibility, aortic stiffness and aortic elastic modulus), and valvulo-arterial impedances were found to be comparable between the BAV and control groups. BAV group was observed to have statistically significantly lower 4C (18.9 +/- 1.7 vs. 17.8 +/- 1.5, p = 0.02), LAX (19.7 +/- 1.7 vs. 17.7 +/- 1.3, p = 0.001) and 2C (20.1 +/- 1.8 vs. 17.7 +/- 1.2, p < 0.001) peak longitudinal strain values compared with the control group. Moreover, LV-GS values were found to be significantly lower in the BAV group than in the control group (19.6 +/- 1.1 vs. 17.7 +/- 0.9, p < 0.001). However, there was no statistically significant difference between the groups in terms of Sr-sm, Sr-em ve Sr-am values in the 4C, LAX, and 2C views. BAV might affect LV systolic functions, assessed by 2D strain imaging, in a fashion independent from the valvular dynamics and aortic elasticity. This might show that BAV is not only a valvular disease, but possibly a ventricular disease as well.	\N	\N
23168153	Allergic rhinitis (AR) is a highly prevalent allergic disease and also counts among the 10 most frequent reasons for medical consultation. Its impact on quality of life (QoL) and work productivity has been established but comparisons with other diseases are rare in the literature. The aim of this study was to evaluate the impact of AR in health-related QoL (HRQoL) and work productivity in primary care patients, compared with other prevalent diseases such as hypertension, diabetes mellitus (DM) type II, and symptomatic depression. Six hundred sixteen patients were included in a multicenter cross-sectional observational study. A generic HRQoL questionnaire, 36-item Short Form, and a specific questionnaire, "Work Productivity and Activity Impairment" were handed out to measure QoL and work productivity impact of the diseases. To assess clinical severity with a comparable scale between diseases Clinical Global Impression (CGI) had been used. Symptomatic depression was found to produce the greatest impairment on work productivity with a decrease of 59.5%, with significant differences compared with AR, hypertension, and DM type II (p < 0.05). Symptomatic depression was found to produce the highest negative impact on daily activities with a statistically significant reduction of 59.4% (p < 0.05) compared with AR (26.6% decrease), hypertension (8.8% decrease), and DM (16.7% decrease) patients. Differences between AR and DM or hypertension were also significant (p < 0.05). Restriction on daily activities for AR was 27.8%, which is significantly higher (p < 0.05) than hypertension (19.8% decrease) but not DM (25.7% decrease). Depression had the highest impairment on daily activities (59.4%), compared with the remaining three groups (p < 0.05). AR impairs work productivity in a greater magnitude than hypertension and DM type II.	\N	\N
23174870	Head and neck cancer is the fifth most common type of cancer worldwide. The objective of this study was to evaluate the clinical and epidemiological parameters in a head and neck surgery service. Cross-sectional study using patients' records, developed in otolaryngology and head and neck department of a university hospital in the northwest of the state of São Paulo. A total of 995 patients in the head and neck surgery service between January 2000 and May 2010 were evaluated. The variables analyzed included: age, gender, skin color, tobacco and alcohol consumption, primary site, staging and histological tumor type, treatment and number of deaths. The disease was more frequent among men (79.70%), smokers (75.15%) and alcohol abusers (58.25%). The most representative sites were oral cavity (29.65%) and larynx (24.12%) for the primary site; squamous cell carcinoma (84.92%) was the most frequent histological type, and surgery (29.04%) and radiotherapy (14.19%) were the most common treatments. The cancer that affects patients assisted by the head and neck surgery service occurs mainly men, smokers and alcohol abusers, and the oral cavity and larynx are the sites with the highest incidence. The high rate of patients with stages III and IV indicates late diagnosis by the treatment centers, which reflects the need for prevention education campaigns for early diagnosis of the disease.	\N	\N
23178050	Antidepressants might increase compliance with cardiovascular disease risk reduction interventions. However, antidepressants have been linked to deleterious metabolic effects. In the present multicenter study, we sought to determine whether patients who take antidepressants derive the expected benefits from cardiac rehabilitation in terms of improvements in multiple atherosclerotic risk factors. A cohort of 26,957 patients who had completed a baseline assessment before participating in an exercise-based cardiac rehabilitation program constituted the study population. The patients were stratified into 3 cohorts (i.e., nondepressed, depressed unmedicated, and depressed medicated) at baseline according to a self-reported history of depression and the current use of antidepressants. Risk factors were assessed at baseline and after ∼12 weeks of program participation. A self-reported history of depression was present at baseline in 5,172 patients (19.2%). Of these patients, 2,147 (41.5%) were taking antidepressants. Patients in the nondepressed cohort (49.4% completion) were more likely (p <0.001) to complete the exit assessment than patients in the depressed unmedicated (44.5% completion) or depressed medicated (43.5% completion) cohorts. Patients in all 3 cohorts who completed the exit assessment showed significant improvement in multiple risk factors. Moreover, the magnitude of improvement in blood pressure, serum lipids and lipoproteins, fasting glucose, weight, and body mass index was similar (p >0.05) in patients taking antidepressants and those who were not. In conclusion, our study is the first to show that antidepressants do not offset the average magnitude of improvement in multiple atherosclerotic risk factors that occurs with completion of a cardiac rehabilitation program.	\N	\N
23179223	Exposomic studies of the rapidly changing environment of the Three Gorges Reservoir (TGR) after its impounding is elaborated as a novel field of human and environmental research. Molecular exposomics is focused on the measure of all exposures to molecules and especially persistent organic pollutants-like compounds are of emerging interest due to their lifetime existence in the environment and humans. Theoretical considerations in general and particular for the TGR are deduced and presented using quantitative approaches for this research field. Since exposomics is strongly time-dependent, a theory is presented to link extension of exposure, time, and related effects. Similarity to the first law of thermodynamics is outlined. On top of this, the integrated use of biomarkers is presented employing chemical analysis for biomarkers of exposure and effects, biomarkers in vivo, in vitro approaches and the link between chemical mixtures, and the onset of disease and lethality. Besides real organisms, also virtual organisms are favored to act as well-defined sub-compartments such as fat of biota and with respect to time of exposure. Exposomics is the perspective of risk evaluation and chronic exposures in the running century. It needs novel theories, approaches, and integrated action between medical and environmental disciplines. The existing knowledge about molecular stressors has to be assembled and put into a context especially with respect not only to time resp. lifetime exposure of humans but also eco-toxicological findings by using highly conserved phylogenetic mechanisms to enable links between human and risks of environmental biota. The TGR is a good example not only to employ biomonitoring of real but also virtual organisms due to the lack of established ecotopes in this changing environment so far. Progress in understanding long-term risks requires a proper theory as well as novel tools such as virtual organisms. On top, multidisciplinary approaches and the utilization of existing knowledge about the exposure of the environment and humans have to be merged and directed into mutual concepts. Effect-oriented and chemical analysis must be designed time-oriented to determine lifetime exposures of mankind and nature. Perspectively, a first attempt about exposomic theory and concepts is proposed and has to be developed experimentally further enclosing virtual besides of real organisms and compartments. Environmental and human exposomics have to be considered as a unified global issue in order to effectively utilize their mutual existing knowledge most effectively. The TGR is a challenging model system aiming this objective.	\N	\N
23179576	In this study of 100,949 new users of oral bisphosphonates age ≥ 35 years, "early quitters" were found to differ from others with poor refill compliance in terms of socioeconomic, demographic, and treatment-related characteristics. New risk factors for poor compliance and persistence were identified. Poor compliance with anti-osteoporotic therapy is an on-going worldwide challenge. In this study, we hypothesized that "early quitters" differ in socioeconomics, demographics, co-medications, and comorbid conditions from other patients with low compliance. The study was a register-based nationwide cohort study of anti-osteoporotic therapy comprising 100,949 men and women. Statistical analysis including backward stepwise logistic regression analysis was used to explain causes of treatment failure and Kaplan-Meier survival analysis to estimate persistence of treatment. It was noted that 56.6 % of the patients were persistent and compliant, 4.7 % of the patients were persistent but "low compliant" while 38.7 % of the patients were "early quitters". "Early quitters" were found to differ in socioeconomics from "low compliant" patients. Differences concerning increased risk of "early quitters" were associated with high household income, subjects' age 71.9-79 years, living in the countryside or village, prior treatment with analgesics and anti-parkinson drugs, and dementia. Differences concerning decreased risk of "early quitters" were associated with male, living in an apartment, children living at home, living close to a university hospital, anti-osteoporotic therapy other than alendronate, number of drugs especially above three, pulmonary disease, collagen disease. The results suggest a need for improved support for patients to facilitate the interpretation of the disease and the perception of the benefits and risks of treatment-to reduce the risk of "early quitters". We were able to identify new risk groups that may be candidates for targeted actions.	\N	\N
23198711	To examine the long-term relationships between costs, utilization, and patient-centered medical home (PCMH) clinical practice systems. Clinical practice systems were evaluated at baseline by the Physician Practice Connections-Research Survey (PPC-RS). Annual costs and utilization of a retrospectively constructed cohort of 58,391 persons receiving primary care at 1 of 22 medical groups over a 5-year period (2005-2009) were compared. Multivariate regressions adjusting for patient demographics, health status, and autoregressive errors compared PPC-RS scores and study outcomes for the entire cohort and 3 subcohorts defined by medical complexity (medication count 0-2 [n = 29,657], 2-6 [n = 19,505], >7 [n = 9229]). Outcomes (adjusted to 2005 dollars) were total costs, outpatient costs, inpatient costs, inpatient days, and emergency department (ED) use. For the entire cohort, a 10% increase in PPC-RS scores was associated with 3.9 (medication count: 0-2), 6 (3-6), and 11.6 (>7) fewer ED visits per 1000 in 2005; and 5.1, 7.6, and 13.6 fewer ED visits in 2009. That 10% increase was not associated with the 0-2 medication subcohort's total (-$22/person in 2005; $184/person in 2009), outpatient (-$11/person in 2005; $42/person in 2009), or inpatient ($26/person in 2005; $29/person in 2009) costs. However, it was associated with significantly decreased total (-$446/person in 2005; -$184/person in 2009) and outpatient (-$241/person in 2005; -$54/person in 2009) costs for the most medically complex subcohort (>7 medications). Association of PCMH clinical practice systems with reduced costs appears limited to the most medically complex patients.	\N	\N
23199744	Due to their unique electric, magnetic, and optical properties, engineered nanostructures have been applied to provide diagnostic, therapeutic, as well as prognostic information about the status of disease. In this study, we report a multifunctional nanoprobe based on PEGylated Gd(2)O(3):Yb(3+), Er(3+) nanorods (denoted as PEG-UCNPs) for in vivo up-conversion luminescence (UCL), T(1)-enhanced magnetic resonance (MR), and X-ray computed tomography (CT) multi-modality imaging. A facile and large-scale hydrothermal system combining the merits of an in situ thermal decomposition method and a surface-modified approach is introduced to construct high-quality PEG-UCNPs. By grafting PEG molecules on the surface of PEG-UCNPs, the nanostructures possess excellent stability against in vivo environment and hold long blood circulation time. Cell-cytotoxicity assay, hemolyticity, as well as post-injection histology, hematology, and inflammation analysis further demonstrate their non-cytotoxic character and indicate further in vivo application. In detail, the capability of PEG-UCNPs as high-performance contrast agents for UCL/MR/CT imaging is evaluated successfully through small-animal experiments. Additionally, pharmacokinetics, biodistribution, and clearance route are studied after intravenous injection in a mouse model, reflecting their overall safety.	\N	\N
23208668	The surgical lesion of different brain structures has been used as a treatment for Parkinson's disease (PD) for several decades. More recently, the favored therapeutic approach has involved the administration of levodopa and the use of DBS. These two major therapeutic advances have greatly modified both the clinical condition of patients and the history of the disease. With the introduction of L-dopa in 1967, patients could regain mobility, because their akinesia, tremor, and rigidity were greatly improved, with consequent significant improvement in quality of life and increased life expectancy. However, after the so-called "honeymoon" period in which the disease seemed to be controlled, motor fluctuations and L-dopa-induced dyskinesias mitigated the initial enthusiasm. In the 1990s, unilateral pallidotomy and DBS of the globus palllidus internus and STN reduced these motor fluctuations and dyskinesias remarkably, thereby inaugurating a new era in the surgical treatment of PD. Short- and medium-term follow-up studies of patients who underwent surgery have documented sustained, significant motor benefits. However, given the progressive nature of PD and the purely symptomatic effects of pallidotomy and DBS, the long-term clinical evolution of these surgical patients currently seems to be associated with a new PD phenotype, mainly characterized by axial motor problems and cognitive impairment. Here, we analyze the long-term clinical outcomes of surgical PD patients with at least 5-year follow-up, focusing on the long-term motor symptoms that were initially responsive to surgery.	\N	\N
23216270	Although associations between autoimmune disorders (AIs) and the development of myeloid neoplasms have been described, the pathologic features and natural history of these malignancies have not been well characterized. We evaluated whether patients with AIs with acute myeloid leukemia (AML) were similar in nature to patients traditionally considered to have therapy-related AML (t-AML). Twenty-three patients with AML with a documented prior AI were included in our analysis. Median age at AML diagnosis was 59 years (range 32-78 years), and four patients were men (17%). Median latency between AI diagnosis and AML was 7.0 years. Ten patients (43%) had normal cytogenetics and six patients (26%) had favorable risk disease. In patients older than 65, all four patients had a normal karyotype. Median follow-up for all patients was 19.8 months (range 1.8-100.4 months), with 12 patients alive at last follow-up and median overall survival for all patients of 68.1 months. The encouraging survival data lend support to the notion that AML in patients with AIs appears to have characteristics and outcome more analogous to de novo than t-AML.	\N	\N
23217354	MicroRNAs are endogenously expressed small noncoding RNAs that regulate gene expression at the post-transcriptional level. MicroRNAs have emerged as key regulators of several physiological and pathophysiological processes in the cardiovascular system. Aberrant expression of microRNAs has been implicated in the pathophysiological processes underlying the development of atherosclerosis and cardiovascular disease, including change in endothelial function, vascular smooth muscle cell proliferation and migration, macrophage function, and foam cell formation. In this review, we summarize the recent data showing the roles of microRNAs in cell studies, studies on atherosclerotic mice, and human studies.	\N	\N
23219418	The appearance of liver metastases during the follow-up of a patient with a skin melanoma has classically been considered a sign of a very poor prognosis. There are limited therapeutic options, since these lesions are non-resectable and form part of a disseminated disease in several organs. In certain cases, in those where the disease is restricted to the liver or accompanied by a resectable extra-hepatic disease, hepatectomy can be useful, obtaining acceptable survivals of about 25% at 5 years, although hepatic or skin recurrence is usually early. The limited number of patient cases published, the absence of randomised studies, and the heterogeneity of the series, makes it difficult to reach conclusions to be able to recommend which patients may benefit from liver resection, with an acceptable level of scientific evidence, and thus define its real usefulness. There are also no action plans defined as to when and what type of adjuvant therapy we should use.	\N	\N
23222568	The rarity of conjunctival melanoma has impeded progress in the management of patients with this cancer; however, much progress has occurred in recent years. Primary acquired melanosis is now differentiated histologically into hypermelanosis and conjunctival melanocytic intra-epithelial neoplasia, for which an objective reproducible scoring system has been developed. Mapping and clinical staging of conjunctival disease has improved. Adjunctive radiotherapy and topical chemotherapy have made tumour control more successful, with reduced morbidity. Genetic analyses have identified BRAF and other mutations, which may predict responsiveness to new chemotherapeutic agents, for example Vemurafenib, should metastatic disease develop. Multicentre studies are under way to enhance survival prediction by integrating clinical stage of disease with histological grade of malignancy and genetic abnormalities. Such improved prognostication would not only be more relevant to individual patients, but would also provide greater opportunities for basic science research.	\N	\N
23222982	The study aimed to assess the efficacy of the adopted principles of the treatment of lung abscess without sequestration on the example of 2397 patients. Treatment led to the complete recovery in 1731 (72,2%) patients. The 614 (25,6%) patients showed the chronization of the process and 52 (2,2%) died. The surgical treatment of lung abscess without sequestration (performed in cases of uneffective conservative treatment) led to the complete recovery on 45.7% more often and the chronization of the process was registered on 26.8% more seldom, whereas the lethality rate was higher than by conservative treatment on 8%.	\N	\N
23226290	MiRNAs are key regulators of tumorigenesis that are aberrantly expressed in the circulation and tissue of patients with cancer. The aim of this study was to determine whether miRNA dysregulation in the circulation reflected similar changes in tumour tissue. Athymic nude mice (n = 20) received either a mammary fat pad (n = 8, MFP), or subcutaneous (n = 7, SC) injection of MDA-MB-231 cells. Controls received no tumour cells (n = 5). Tumour volume was monitored weekly and blood sampling performed at weeks 1, 3 and 6 following tumour induction (total n = 60). Animals were sacrificed at week 6 and tumour tissue (n = 15), lungs (n = 20) and enlarged lymph nodes (n = 3) harvested. MicroRNAs were extracted from all samples (n = 98) and relative expression quantified using RQ-PCR. MiR-221 expression was significantly increased in tumour compared to healthy tissue (p<0.001). MiR-10b expression was significantly higher in MFP compared to SC tumours (p<0.05), with the highest levels detected in diseased lymph nodes (p<0.05). MiR-10b was undetectable in the circulation, with no significant change in circulating miR-221 expression detected during disease progression. MiR-195 and miR-497 were significantly decreased in tumour tissue (p<0.05), and also in the circulation of animals 3 weeks following tumour induction (p<0.05). At both tissue and circulating level, a positive correlation was observed between miR-497 and miR-195 (r = 0.61, p<0.001; r = 0.41, p<0.01 respectively). This study highlights the distinct roles of miRNAs in circulation and tissue. It also implicates miRNAs in disease dissemination and progression, which may be important in systemic therapy and biomarker development.	\N	\N
23227561	We reviewed the tuberculosis (TB) surveillance database to determine the mode of detection, delays in achieving a TB diagnosis, and patients' occupational status upon registration. Of the 23,261 TB patients who were newly notified in 2010, 81.7% were diagnosed at medical institutions. Of these, 12.0% were diagnosed during hospitalisation with a disease other than TB, and 9.9% were diagnosed during outpatient visits with diseases other than TB. The overall proportion of TB cases detected by contact examination was only 2.8%, but this mode of detection was higher (56.1%) among younger TB patients aged 0-14 years. Of the 18,328 pulmonary TB patients, 27.3% had only respiratory symptoms, 31.0% had both respiratory and other symptoms, and 16.4% had only non-respiratory symptoms. Approximately one-quarter of elderly patients aged > or = 80 years with symptomatic pulmonary TB had only non-respiratory symptoms. pulmonary TB tended to have long total delays (the amount of time between the onset of symptoms and diagnosis). Among elderly patients, patient delays tended to be short, whereas doctor delays tended to be long. Of the 2,785 female pulmonary TB patients aged 20-59 years, 14.5% were medical workers and 10.4% of these were nurses.	\N	\N
23251076	NK cells exhibit the highest cytotoxic capacity within the immune system. Alteration of their number or functionality may have a deep impact on overall immunity. This is of particular relevance in aging where the elderly population becomes more susceptible to infection, cancer, autoimmune diseases, and neurodegenerative diseases amongst others. As the fraction of elderly increases worldwide, it becomes urgent to better understand the aging of the immune system to prevent and cure the elderly population. For this, a better understanding of the function and phenotype of the different immune cells and their subsets is necessary. We review here NK cell functions and phenotype in healthy aging as well as in various age-associated diseases.	\N	\N
23254356	Similar to T-helper (Th) cells, CD8(+) T cells also differentiate into distinct subpopulations. However, the existence of IL-9-producing CD8(+) T (Tc9) cells has not been elucidated so far. We show that murine CD8(+) T cells activated in the presence of IL-4 plus TGF-β develop into transient IL-9 producers characterized by specific IFN-γ and IL-10 expression patterns as well as by low cytotoxic function along with diminished expression of the CTL-associated transcription factors T-bet and Eomesodermin. Similarly to the CD4(+) counterpart, Tc9 cells required for their differentiation STAT6 and IRF4. Tc9 cells deficient for these master regulators displayed increased levels of Foxp3 that in turn suppressed IL-9 production. In an allergic airway disease model, Tc9 cells promoted the onset of airway inflammation, mediated by subpathogenic numbers of Th2 cells. This support was specific for Tc9 cells because CTLs failed to exert this function. We detected increased Tc9 frequency in the periphery in mice and humans with atopic dermatitis, a Th2-associated skin disease that often precedes asthma. Thus, our data point to the existence of Tc9 cells and to their supportive function in Th2-dependent airway inflammation, suggesting that these cells might be a therapeutic target in allergic disorders.	\N	\N
23254704	Organ transplantation and other major surgeries are impacted by ischemia-reperfusion injury (IRI). Mesenchymal stromal cells (MSCs) recently became an attractive alternative therapeutic tool to combat IRI. The present review highlights the effects of MSCs in the preclinical animal models of IRI and clinical trials, and explains their potential modes of action based on the pathophysiological IRI cascade. The application of MSCs in animal models of IRI show anti-inflammatory and anti-apoptotic effects, particularly for damage to the kidneys, heart and lungs. The mechanism of MSC action remains unclear, but may involve paracrine factors which could include the transfer of microvesicles, RNA or mitochondria. Although few clinical trials have reached completion, adverse effects appear minimal. MSCs show promise in protecting against IRI-induced damage. They appear to help recovery mainly by affecting the levels of inflammation and apoptosis during the organ repair process. In addition, they may mediate immunomodulatory effects on the innate and adaptive immune processes triggered during reperfusion and reduce fibrosis. Success in preclinical animal models has led to the initiation of ongoing clinical trials.	\N	\N
23265076	Diabetes is an important contributor to the burden of disease in South Africa and prevalence rates as high as 33% have been recorded in Cape Town. Previous studies show that quality of care and health outcomes are poor. The development of an effective education programme should impact on self-care, lifestyle change and adherence to medication; and lead to better control of diabetes, fewer complications and better quality of life. Pragmatic cluster randomized controlled trialParticipants: Type 2 diabetic patients attending 45 public sector community health centres in Cape TownInterventions: The intervention group will receive 4 sessions of group diabetes education delivered by a health promotion officer in a guiding style. The control group will receive usual care which consists of ad hoc advice during consultations and occasional educational talks in the waiting room. To evaluate the effectiveness of the group diabetes education programmeOutcomes: diabetes self-care activities, 5% weight loss, 1% reduction in HbA1c. self-efficacy, locus of control, mean blood pressure, mean weight loss, mean waist circumference, mean HbA1c, mean total cholesterol, quality of lifeRandomisation: Computer generated random numbersBlinding: Patients, health promoters and research assistants could not be blinded to the health centre's allocationNumbers randomized: Seventeen health centres (34 in total) will be randomly assigned to either control or intervention groups. A sample size of 1360 patients in 34 clusters of 40 patients will give a power of 80% to detect the primary outcomes with 5% precision. Altogether 720 patients were recruited in the intervention arm and 850 in the control arm giving a total of 1570. The study will inform policy makers and managers of the district health system, particularly in low to middle income countries, if this programme can be implemented more widely. Pan African Clinical Trial Registry PACTR201205000380384.	\N	\N
23268170	Kawasaki disease is a common paediatric vasculitide. It is usually diagnosed by its classical constellation of mucocutaneous signs. Recurrent Kawasaki disease is a rare phenomenon that occurs in approximately 3% of all patients diagnosed with Kawasaki disease. Its presentation is usually similar to the first episode of Kawasaki disease, and early diagnosis with prompt treatment is key in preventing associated cardiovascular morbidities. Recurrent Kawasaki disease is not well reported, and atypical presentations have not been previously reported in medical literature. Here, we report the case of a young girl with recurrent Kawasaki disease who presented atypically with acute airway obstruction secondary to retropharyngeal phlegmon.	\N	\N
23275389	To determine the longitudinal effects of TNF inhibitors on BMD and radiographic progression in patients with AS and to assess independent factors associated with increased BMD in the lumbar spine. Sixty-three patients with AS were included. Twenty-six patients were treated with TNF inhibitors and 37 were not. BMD in the lumbar spine and right femur was measured by DXA at baseline and 1 and 2 years later. Lumbar spine radiography was performed at baseline and after 2 years. Radiographic progression was scored using the Stoke AS Spinal Score (SASSS) and the modified SASSS. Univariate and multivariate linear regression analyses were performed to identify factors independently associated with spinal BMD increase. BMD in the lumbar spine and total proximal femur of patients receiving TNF inhibitors increased consistently over 2 years compared with that in patients not receiving TNF inhibitors (P < 0.01 and P = 0.02), and treated patients showed increased SASSS scores (P = 0.05); however, syndesmophyte development was no different between the two groups. There was a significant difference in the change of SASSS in patients treated with both TNF inhibitors and bisphosphonates compared with those treated with TNF inhibitors alone (P < 0.01). TNF inhibitor therapy and the increase in SASSS were independently associated with increased lumbar spine BMD (P = 0.009 and P < 0.001). TNF inhibitors appear to be associated with increased SASSS scores and improvements in BMD. Further prospective studies with larger subject numbers are needed to validate this paradoxical role of TNF inhibitors.	\N	\N
23278140	In contrast to adolescent acne, infantile acne (IA) is a rare condition with only a limited body of available literature. In this descriptive, retrospective study, we reviewed six cases from 2002 to 2010 treated with oral isotretinoin. The average age of onset was 6.16 months (range 0-21 mos). Consistent with the previous, limited literature, we found predominantly boys are affected, a predilection for the cheeks, and a polymorphic inflammatory morphology. Two patients had a family history of acne. All cases were successfully and safely treated with oral isotretinoin. The suggested treatment of childhood acne is similar to that of adolescents (graded according to the severity of the skin disease and risk of scarring). Oral isotretinoin appears to be an effective and safe treatment for severe IA.	\N	\N
23280098	Influenza A viruses circulating in pigs in Brazil are still not characterized, and only limited data are available about swine influenza epidemiology in the country. Therefore, we characterized the hemagglutinin (HA) and neuraminidase (NA) genes of influenza viruses isolated from Brazilian pigs. We also evaluated one case of probable swine-to-human transmission. Twenty influenza viruses isolated from pigs during 2009-2010 in five Brazilian states (Minas Gerais, Sao Paulo, Parana, Rio Grande do Sul, and Mato Grosso) were used. One human isolate, from a technician who became ill after visiting a swineherd going through a respiratory disease outbreak, was also used in the study. Phylogenetic analysis for the HA and NA genes and hemagglutinin amino acid sequence alignment were performed. All isolates clustered with pandemic H1N1 2009 (pH1N1) viruses and appeared to have a common ancestor. Genetic diversity was higher in the HA than in the NA gene, and the amino acid substitution S203T in one of HA's antigenic sites was found in most of the samples. The human isolate was more related to swine isolates from the same herd visited by the technician than to other human isolates, suggesting swine-to-human transmission. Our results show that pH1N1 was disseminated and the predominant subtype in Brazilian pigs in 2009-2010.	\N	\N
23284040	Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is one of the two established Hodgkin lymphoma (HL) subtypes. The risk factors of NLPHL are largely unknown. In general, genetic factors are known to have a modest effect on the risk of HL; however, familial risk in NLPHL has not been previously examined. We conducted a population-based study by using the Finnish registries and evaluated the familial risk in NLPHL. We launched a population-based search to identify patients with NLPHL and their relatives by examining the records of the Finnish Cancer Registry, established in 1953, and the official Finnish population registries. We collected a data set of 692 patients with NLPHL, identified their 4,280 first-degree relatives, and calculated the registry-based standardized incidence ratios (SIRs) for different cancers in the first-degree relatives. In addition, the primary tumor biopsies of HL-affected relatives were collected when possible, the HL diagnoses were re-reviewed by a hematopathologist, and the SIR for NLPHL was calculated on the basis of confirmed NLPHL diagnoses. On the basis of confirmed NLPHL diagnoses, the SIR for NLPHL was 19 (95% CI, 8.8 to 36) in the first-degree relatives. The risk was most prominent in female relatives of young patients. The registry-based SIR for classical HL was 5.3 (95% CI, 3.0 to 8.8), and for non-Hodgkin lymphoma, it was 1.9 (95% CI, 1.3 to 2.6). Our results implicate an unexpectedly high familial component in the development of NLPHL. Research is warranted to identify the putative genetic and environmental factors underlying this finding and to develop strategies for better management of patients with NLPHL and their relatives.	\N	\N
23293016	Kawasaki disease (KD) is a systemic inflammatory illness of childhood that particularly affects the coronary arteries. It can lead to coronary artery aneurysms, myocardial infarction, and sudden death. Clinical and epidemiologic data support an infectious cause, and the etiology remains unknown, but recent data support infection with a 'new' virus. Genetic factors influence KD susceptibility; the incidence is 10-fold higher in children of Asian when compared with Caucasian ethnicity. Recent research has identified genes affecting immune response that are associated with KD susceptibility and outcome. A re-examination of the pathologic features of KD has yielded a three process model of KD vasculopathy, providing a framework for understanding the KD arterial immune response and the damage it inflicts and for identifying new therapeutic targets for KD patients with coronary artery abnormalities. The researcher is faced with many challenges in determining the pathogenesis of KD. A systems biology approach incorporating genomics, proteomics, transcriptomics, and microbial bioinformatics analysis of high-throughput sequence data from KD tissues could provide the keys to unlocking the mysteries of this potentially fatal illness of childhood.	\N	\N
23295556	To describe the course and management of a protracted outbreak after intercontinental transfer of 2 patients colonized with multidrug-resistant Acinetobacter baumannii (MDRAB). An 18-month outbreak investigation. An 860-bed university hospital in France. Case patients (ie, carriers) were those colonized or infected with an MDRAB isolate. During the epidemic period, all intensive care unit (ICU) patients and contacts of carriers who were transferred to wards were screened for MDRAB carriage. Contact precautions, environmental screening, and auditing of healthcare worker (HCW) practices were implemented; rooms were cleaned with hydrogen peroxide mist disinfection. One ICU, in which most of the cases occurred, was closed on 4 occasions for thorough cleaning and disinfection. The 2 index case patients were identified as 2 patients who carried the same MDRAB strain and who were admitted to the hospital after repatriation from Tahiti 5 months apart. During an 18-month period, a total of 84 secondary cases occurred. Reintroduction of MDRAB into the ICUs occurred from patients previously colonized or from healthcare personnel. Termination of the outbreak was only achieved when all carriers from wards or the ICU were cohorted to an isolation unit with dedicated healthcare personnel. Intercontinental transfer of carriers of MDRAB can result in extensive outbreaks and serious disruption of the hospital's organization. Transmission from carriers most likely occurred via the hands of HCWs, poor cleaning protocols, airborne spread, and contaminated water from sink traps. This protracted outbreak was controlled only after implementation of an extensive control program and eventual cohorting of all carriers in an isolation unit with dedicated healthcare personnel.	\N	\N
23296696	Previously, most dengue cases in Singapore were hospitalized despite low incidence of dengue hemorrhagic fever (DHF) or death. To minimize hospitalization, the Communicable Disease Centre at Tan Tock Seng Hospital (TTSH) in Singapore implemented new admission criteria which included clinical, laboratory, and DHF predictive parameters in 2007. All laboratory-confirmed dengue patients seen at TTSH during 2006-2008 were retrospectively reviewed for clinical data. Disease outcome and clinical parameters were compared over the 3 years. There was a 33.0% mean decrease in inpatients after the new criteria were implemented compared with the period before (p < 0.001). The proportion of inpatients with DHF increased significantly from 31.7% in 2006 to 34.4% in 2008 (p = 0.008); 68 DHF cases were managed safely on an outpatient basis after compared with none before implementation. DHF inpatients had more serious signs such as clinical fluid accumulation (15.5% vs 2.9% of outpatients), while most DHF outpatients had hypoproteinemia (92.7% vs 81.3% of inpatients). The eight intensive care unit admissions and five deaths during this time period all occurred among inpatients. The new criteria resulted in a median cost saving of US$1.4 million to patients in 2008. The new dengue admission criteria were effective in sustainably reducing length of hospitalization, yielding considerable cost savings. A minority of DHF patients with mild symptoms recovered uneventfully through outpatient management.	\N	\N
23301916	Wiskott-Aldrich syndrome (WAS) is a rare X-linked recessive disease characterized by eczema, thrombocytopenia and immune deficiency. WAS gene mutations impair WAS protein function which cause WAS. The WAS-related disorders of X-linked thrombocytopenia (XLT) and X-linked congenital neutropenia (XLN) may have similar but less severe symptoms those are also caused by mutations of the same gene. We present two cases of WAS in neonates with WAS gene mutations. Early genetic diagnosis can help to the treatment and prevention this disease.	\N	\N
23313927	Mexican Americans are the fastest aging segment of the U.S. population, yet little scientific literature exists regarding the Alzheimer's disease (AD) among this segment of the population. The extant literature suggests that biomarkers of AD will vary according to race/ethnicity though no prior work has explicitly studied this possibility. The aim of this study was to create a serum-based biomarker profile of AD among Mexican American. Data were analyzed from 363 Mexican American participants (49 AD and 314 normal controls) enrolled in the Texas Alzheimer's Research & Care Consortium (TARCC). Non-fasting serum samples were analyzed using a luminex-based multi-plex platform. A biomarker profile was generated using random forest analyses. The biomarker profile of AD among Mexican Americans was different from prior work from non-Hispanic populations with regards to the variable importance plots. In fact, many of the top markers were related to metabolic factors (e.g., FABP, GLP-1, CD40, pancreatic polypeptide, insulin-like-growth factor, and insulin). The biomarker profile was a significant classifier of AD status yielding an area under the receiver operating characteristic curve, sensitivity, and specificity of 0.77, 0.92, and 0.64, respectively. Combining biomarkers with clinical variables yielded a better balance of sensitivity and specificity. The biomarker profile for AD among Mexican American cases is significantly different from that previously identified among non-Hispanic cases from many large-scale studies. This is the first study to explicitly examine and provide support for blood-based biomarkers of AD among Mexican Americans. Areas for future research are highlighted.	\N	\N
23316660	Polyarteritis nodosa (PAN) is a multi-system disease, characterized by necrotizing vasculitis of medium-sized arteries that may affect any organ system. Cutaneous PAN is the cutaneous limited form of PAN. It affects 10% of all cases of PAN and usually demonstrates a benign and chronic course. We hereby describe a 47-year-old female with diabetes mellitus who presented with painful ulcers on both legs. The clinical and histological findings were consistent with PAN. A thorough investigation ruled out systemic PAN and cutaneous PAN was determined. Despite intensive therapies including corticosteroids and azathioprine, marked progression of the ulcers was noted and large areas of necrosis appeared. The patient underwent above-knee amputation of both legs and eventually died in less than three years. Although cutaneous PAN is known to have a benign and chronic course, we have presented an unusual progressive and severe course that resulted in the death of the patient.	\N	\N
23324593	An under-appreciated clue about pathogenesis in Parkinson disease (PD) is the distribution of pathology in the early and middle stages of the disease. This pathological 'roadmap' shows that in addition to dopaminergic neurons in the substantia nigra pars compacta (SNc), a significant number of other central and peripheral neuronal populations exhibit Lewy pathology, phenotypic dysregulation or frank degeneration in PD patients. This spatially distributed, at-risk population of neurons shares a number of features, including autonomously generated activity, broad action potentials, low intrinsic calcium buffering capacity and long, poorly myelinated, highly branched axons. Many, and perhaps all, of these traits add to the metabolic burden in these neurons, suggesting that mitochondrial deficits could drive pathogenesis in PD-in agreement with a large segment of the literature. What is less clear is how this neuronal phenotype might shape the susceptibility to proteostatic dysfunction or to the spread of α-synuclein fibrils deposited in the extracellular space. The review explores the literature on these issues and their translational implications.	\N	\N
23327371	Over the past few decades a large number of new and emerging infectious diseases have been recognised in humans, partly because of improved diagnostic technologies and increased awareness and also, partly because of dynamic ecological changes between human hosts and their exposure to animals and the environment (Coker et al. 2011). Some 177 new pathogenic organisms have been recognised to be 'emerging', that is, have newly arisen or been newly introduced into human populations; almost three quarters of these, 130 (73%), have come from zoonotic origins (Cascio et al. 2011; Cutler, Fooks &amp; Van Der Poel 2010; Taylor, Latham &amp; Woolhouse 2001; Woolhouse &amp; Gowtage-Sequeria 2005). One of the most prevalent and important human infectious disease is influenza, a disease responsible globally for a quarter million deaths annually. In the USA alone the toll from influenza is estimated at 36 000 deaths and 226 000 hospitalisations, and it ranks as the most important cause of vaccine preventable mortality in that country (CDC 2010). The epidemiological behaviour of human influenza clearly defines it as an emerging infectious disease and the recent understanding of its zoonotic origins has contributed much to the understanding of its behaviour in humans (Fauci 2006).	\N	\N
23330027	Acute rheumatic fever (ARF) and rheumatic heart disease (RHD) constitute important public health problems in developing countries. Children with ARF and RHD seen at Children's Hospital-Sudan from May 2008-2009 were examined clinically and by echocardiography. Blood cytokines (interleukin 10 (IL10), Tumor necrosis factor alpha (TNF- alpha) and interferon gamma (IFN-gamma) were done. Thirty six children were enrolled; 63% had established RHD, and 37% ARF. Mitral regurgitation (MR) was the most common lesion (94%).Ninety five percent of the valve lesions were severe. The serum interleukin IL10 level ranged between 3-6 pg/ml. TNF alpha levels were 9- 100 pg/ml in 12 patients (40%), 101-1000 pg/ml in 10 patients (33%), more than 1000 in 8 patients (26%). The level of IFN gamma ranged between 2-7 pg/m in all patients except 2 (84 and 135 pg/ml). RHD is manifested with severe valvular lesions and a high TNF alpha indicating and ongoing inflammation.	\N	\N
23330952	The authors present 1-year results in 60 patients with cervical radiculopathy due to spondylosis and stenosis that was treated with a bilateral percutaneous facet implant. The implant consists of a screw and washer that distracts and immobilizes the cervical facet for root decompression and fusion. Clinical and radiological results are analyzed. Between 2009 and 2011, 60 patients were treated with the DTRAX Facet System in a multicenter prospective single-arm study. All patients had symptomatic clinical radiculopathy, and conservative management had failed. The majority of patients had multilevel radiographically confirmed disease. Only patients with single-level radiculopathy confirmed by history, physical examination, and in some cases confirmatory nerve blocks were included. Patients were assessed preoperatively with Neck Disability Index, visual analog scale, quality of life questionnaire (Short Form-12 version 2), CT scans, MRI, and dynamic radiographs. Surgery was percutaneous posterior bilateral facet implants consisting of a screw and expandable washer and iliac crest bone aspirate. Patients underwent postoperative assessments at 2 weeks, 6 weeks, 3 months, 6 months, and 1 year with validated outcome questionnaires. Alterations of segmental and overall cervical lordosis, foraminal dimensions, device retention and fusion criteria were assessed for up to 1 year with CT reconstructions and radiographs. Fusion criteria were defined as bridging trabecular bone between the facets, translational motion < 2 mm, and angular motion < 5°. All patients were followed to 1 year postoperatively. Ages in this cohort ranged from 40 to 75 years, with a mean of 53 years. Forty-two patients were treated at C5-6, 8 at C6-7, 7 at C4-5, and 3 at C3-4. Fifty-six had bilateral implants; 4 had unilateral implants due to intraoperative facet fracture (2 patients) and inability to access the facet (2 patients). The Neck Disability Index, Short Form-12 version 2, and visual analog scale scores were significantly improved at 2 weeks and remained significantly improved up to 1 year. At the treated level, 93% had intrafacet bridging trabecular bone on CT scans, translational motion was < 2 mm in 100% and angular movement was < 5° in 83% at the 1-year follow-up. There was no significant change in overall cervical lordosis. There was a 1.6° loss of segmental lordosis at the treated level at 1 year that was significant. Foraminal width, volume, and posterior disc height was significantly increased at 6 months and returned to baseline levels at 1 year. There was no significant decrease in foraminal width and height at adjacent levels. There were no reoperations or surgery- or device-related complications, including implant failure or retained hardware. Results indicate that the DTRAX Facet System is safe and effective for treatment of cervical radiculopathy.	\N	\N
23336917	The use of ventricular assist devices in patients with complex congenital heart disease has not been well described. We present a case of successful ventricular assist device support in a 38-year-old man with congenitally corrected transposition of the great arteries and severe secondary pulmonary hypertension.	\N	\N
23338998	The aim of this study was to verify if genetic factors influence the short- and long-term therapeutic responses to oestroprogestagen (OP) therapy, implemented in girls with functional hypothalamic amenorrhoea (FHA) in order to improve their bone mineral density (BMD). The study included 78 FHA girls who underwent a four-year sequential OP therapy with 17-beta oestradiol and didrogesterone. Changes in the lumbar spine BMD were determined at the end of the therapy and six years after its discontinuation, and analysed in regards to PvuII and XbaI polymorphisms of oestrogen receptor-alpha gene, BsmI polymorphism of vitamin D3 receptor gene, and Sp1 polymorphism of the type-1 collagen gene. After four years of OP therapy, a significant increase in BMD was documented in the studied group. Follow-up densitometry performed six years after completing the therapy revealed a significant decrease in BMD level; nonetheless, the values of this parameter were still significantly higher compared to pretreatment level. Neither the particular polymorphisms nor their combinations influenced the relative change in BMD at the end of the therapy and after a six-year follow-up. Variability of genes involved in oestrogen, vitamin D3 and collagen metabolism does not influence the short- and long-term results of OP therapy in girls with FHA.	\N	\N
23344286	Preeclampsia complicates approximately 3-5% of pregnancies and remains one of the major causes of maternal and neonatal morbidity. It shares pathogenic similarities with adult cardiovascular disease as well as many risk factors. Attempts at prevention of preeclampsia using various supplements and classes of medications have failed or had limited success, and they were not convincing enough to lead to widespread adoption of any particular strategy. Contrary to the experience with preeclampsia, prevention of cardiovascular mortality and other cardiovascular events in nonpregnant patients using 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors, or statins, is widely accepted. Pravastatin and other statins have been shown to reverse various pathophysiologic pathways associated with preeclampsia, such as angiogenic imbalance, endothelial injury, inflammation, and oxidative stress. These beneficial effects are likely to contribute substantially to preventing preeclampsia and provide biological plausibility for the use of pravastatin in this setting. Pravastatin has favorable safety and pharmacokinetic profiles. In addition, animal studies and human pregnancy exposure data do not support teratogenicity claims for pravastatin. Therefore, the Eunice Kennedy Shriver National Institute of Child Health and Human Development Obstetric--Fetal Pharmacology Research Units Network started a pilot trial to collect maternal--fetal safety data and to evaluate pravastatin pharmacokinetics when used as a prophylactic daily treatment in high-risk pregnant women (identifier NCT01717586, clinicaltrials.gov).	\N	\N
23346802	The purpose of this article was to describe the phenomena related to the mechanisms regulating alterations of vascular blood flow in ophthalmic and retrobulbar circulation. In this review, various indirect and direct methods of evaluating retinal blood flow have been discussed. Laser, contrast and ultrasonographic techniques, including color Doppler ultrasonography, electroretinography, electroencephalography, calorimetric investigations, with the radiographic entities and registering changes in tunica vasculosa circulation were described. Additionally, radiographic investigations, isometric measurements and studies with the use of pharmacological agents, evaluation of partial pressure of oxygen or carbon dioxide in both inhaled and exhaled air, and in daylight as well as in darkness were presented. Although there are many control methods of regulating mechanisms of bulbar circulation, none of those techniques used presently and in the past is ideal, hence the only investigations widely applied for this purpose have been both Doppler ultrasonography and laser methods. In the review influence of myogenic and neurogenic mechanisms on blood flow in eyeball was described. Moreover, the part of vessels coarcting and dilating substances in these hemodynamic phenomena has been included. In the course of various ophthalmic disease entities of vascular origin, different substances take part in general and local regulation of ocular and retrobulbar circulation, whose action mechanism might be the cause of hemodynamic disorders. Color Doppler ultrasonography remains one of the more frequently used methods which could indirectly register alterations of vascular blood flow in retrobulbar arteries.	\N	\N
23347399	Methcathinone abuse is a new cause of manganism. The psychostimulant is prepared from pseudoephedrine using potassium permanganate as an oxidant. We describe the clinical, biological, neuroimaging characteristics and follow-up results in a large Estonian cohort of intravenous methcathinone users. During 2006-2012 we studied 38 methcathinone abusers with a mean age of 33 years. Subjects were rated by the Unified Parkinson's Disease Rating Scale (UPDRS), Hoehn and Yahr (HY), and Schwab and England (SE) rating scales. Twenty-four cases were reassessed 9-70 (20 ± 15) months after the initial evaluation. Manganese (Mn) in plasma and hair was analysed by inductively coupled plasma-atom emission spectrometry. Magnetic resonance imaging (MRI) was performed in 11, and single-photon emission computed tomography (SPECT) with iodobenzamide (IBZM) in eight subjects. The average total UPDRS score was 43 ± 21. The most severely affected domains in UPDRS Part III were speech and postural stability, the least affected domain was resting tremor. At follow-up there was worsening of HY and SE rating scales. Subjects had a higher mean level of Mn in hair (2.9 ± 3.8 ppm) than controls (0.82 ± 1.02 ppm), P = 0.02. Plasma Mn concentrations were higher (11.5 ± 6.2 ppb) in active than in former users (5.6 ± 1.8 ppb), P = 0.006. Active methcathinone users had increased MRI T1-signal intensity in the globus pallidus, substantia nigra and periaquaductal gray matter. IBZM-SPECT showed normal symmetric tracer uptake in striatum. Methcathinone abusers develop a distinctive hypokinetic syndrome. Though the biomarkers of Mn exposure are characteristic only of recent abuse, the syndrome is not reversible.	\N	\N
23347458	We compared values of baseline serum cystatin C (SCysC), serum creatinine (SCr), and measured glomerular filtration rate (mGFR) for predicting end-stage renal disease (ESRD) in patients with type 2 diabetes and elevated albuminuria. Observational longitudinal study. Pima Indians with type 2 diabetes and elevated albumin-creatinine ratio (ACR ≥30 mg/g). Baseline SCysC, SCr, and mGFR. Individuals were followed up from their first examination with diabetes and ACR ≥30 mg/g until December 2010, onset of ESRD, or death, whichever came first. Incidence rates adjusted for age and sex were computed by Mantel-Haenszel stratification. The abilities of SCysC, SCr, and mGFR values to predict ESRD were compared with receiver operating characteristic curves. Of 234 Pima Indians with a mean age of 42.8 years who were followed up for a median of 10.7 (range, 0.6-21.3) years, 68 (29%) developed ESRD. The incidence of ESRD was significantly higher in patients in the lowest versus highest tertile of 1/SCysC (incidence rate ratio, 2.43; 95% CI, 1.31-4.50). By contrast, mGFR and 1/SCr had J-shaped associations with ESRD. In unadjusted analyses, 1/SCysC had the highest area under the receiver operating characteristic curve (AUROC; 0.719 ± 0.035) and mGFR had the lowest (0.585 ± 0.042; P < 0.001); the AUROC for 1/SCr was intermediate (0.672 ± 0.040; P = 0.1 and P = 0.03 vs 1/SCysC and mGFR, respectively). In analyses adjusted for age, sex, diabetes duration, height, weight, hemoglobin A1c level, and ACR, 1/SCysC had the highest AUROC (0.845 ± 0.026). Models with mGFR or 1/SCr alone had similar AUROCs (P = 0.9) and both were lower than the model with 1/SCysC alone (P = 0.02 and P = 0.03, respectively). The predictive values of the filtration markers are limited to the extent that their precision is based on a single measurement. SCysC level was a better predictor of ESRD than mGFR or SCr level in Pima Indians with type 2 diabetes and elevated albuminuria.	\N	\N
23354259	The surgical treatment of acute colonic diverticulitis is associated with significant morbidity and mortality. However, patient and operative characteristics associated with mortality in this patient population are unclear. We hypothesize that demographic and perioperative variables can be used to predict postoperative mortality.The purpose of this study was to identify perioperative variables predictive of postoperative mortality after emergent surgery for acute diverticulitis. Patients with diverticulitis undergoing colostomy and/or partial colectomy with or without primary anastomosis were retrieved from the American College of Surgeons National Surgical Quality Improvement Program database for years 2005 to 2008 inclusive. Only patients undergoing emergent surgery for acute diverticulitis were included. Univariate analyses were performed to compare demographic characteristics, preoperative laboratory values, comorbidities, and intraoperative variables. Variables with a significant (p < 0.10) difference between survivors and nonsurvivors were included in a stepwise logistic regression model to determine predictors of 30-day mortality. Concordance indices (c indices) for postoperative mortality were calculated using 2005 to 2008 data to determine predictive accuracy and validated on 2009 data. A total of 2,214 patients met inclusion criteria. Mean age was 61 years, and 50% of patients were male. Thirty-day mortality was 5.1%. Nine preoperative variables were significantly associated with postoperative mortality on multivariable analysis. The c index of this nine-variable model was 0.901. Renal dysfunction, hypoalbuminemia, American Society of Anesthesiologists class, and age were chosen to create a simpler model, with a c index of 0.886 for 2005 to 2008 data and 0.893 for 2009 data. Four readily available perioperative variables can be used to predict 30-day mortality after emergent surgery for acute diverticulitis. Prognostic study, level II.	\N	\N
23379818	MicroRNAs (miRNAs) are small noncoding RNAs that not only regulate gene expression during normal development but can also be active players in several diseases. To date, several studies have demonstrated a possible role for specific miRNAs in the regulation of pulmonary vascular homeostasis suggesting that novel therapeutic agents which target these modulators of gene expression could serve to treat pulmonary arterial hypertension (PAH). The characterization of miRNA-mediated gene modulation in the pulmonary circulation is expanding very rapidly. This review summarizes current relevant findings on the role of miRNAs in the pathogenesis of PAH and expands on the potential use of agents that target these molecules as future disease-modifying therapies. Further understanding of miRNA biology and function in the pulmonary circulation will serve to further enhance our understanding of their contribution to the pathogenesis of PAH. The implementation of a systems biology approach will help accelerate the discovery of miRNAs that influence angiogenesis and cellular responses to vascular injury. Experimental characterization of these miRNAs using in vitro and in vivo methods will be required to validate the biological roles of these miRNAs prior to the consideration of their use as therapeutic targets in future clinical trials.	\N	\N
23382786	CXCR4 is a G-protein-coupled receptor involved in a number of physiological processes in the hematopoietic and immune systems. The SDF-1/CXCR4 axis is significantly associated with several diseases, such as HIV, cancer, WHIM syndrome, rheumatoid arthritis, pulmonary fibrosis and lupus. For example, CXCR4 is one of the major co-receptors for HIV entry into target cells, while in cancer it plays an important role in tumor cell metastasis. Several promising CXCR4 antagonists have been developed to block SDF-1/CXCR4 interactions that are currently under different stages of development. The first in class CXCR4 antagonist, plerixafor, was approved by the FDA in 2008 for the mobilization of hematopoietic stem cells and several other drugs are currently in clinical trials for cancer, HIV, and WHIM syndrome. While the long-term safety data for the first generation CXCR4 antagonists are not yet available, several new compounds are under preclinical development in an attempt to provide safer and more efficient treatment options for HIV and cancer patients.	\N	\N
23389330	Childhood tuberculosis (TB) accounts for a significant proportion of the global tuberculosis disease burden. However, current and previous efforts to develop better diagnostic, therapeutic, and preventive interventions have focused on TB in adults, and childhood TB has been relatively neglected. The purpose of this review is to provide an update on the diagnostic and therapeutic recommendations for childhood TB with an emphasis on intrathoracic disease. The literature from a range of sources was reviewed and synthesized to provide an overview of the contemporary approaches for the diagnosis and treatment of childhood TB. This review summarizes the clinical, radiological, bacteriological, and immunological approaches to diagnose TB infection and disease in children. In addition, we summarize the updated guidelines for the treatment of TB in children. The development of better diagnostic and therapeutic methods for childhood TB remains a significant challenge. As the strategies for diagnosis and treatment of childhood TB continue to improve and the knowledge base increases, the implementation of these strategies will be crucial.	\N	\N
23393912	The most common autosomal form of Chronic Granulomatous Disease, p47-phox deficient CGD, generally features a GT (deltaGT) deletion in the GTGT sequence at the start of exon 2 on the NCF-1 gene. This consistency is due to the coexistence of and the recombination between 2 homologous pseudogenes (psi s) and NCF-1. The GTGT: deltaGT ratio mirrors the NCF-I: NCF-1 psi ratio and is 2:4 in normal individuals. To determine the molecular basis of the Autosomal-CGD in a family with 2 children, a male and female, affected by the disease. The female patient suffered recurrent infection, retinitis pigmentosa and discoid lupus. Chemiluminescence (CL) was used to study the respiratory burst, while genetic analysis was done by RT-PCR, PCR, deltaGT and the 20bp gene scans. The CL response of the patient was profoundly low. The patient's p47-phox band was absent in the RT-PCR for NADPH-oxidase component mRNAs. The deltaGT scan showed that the patient's GTGT: deltaGT ratio was 0:6, the parents' and the younger brother's was 1:5 and the younger sister's was 2:4. Examination of other NCF-1/ NCF-1 psi s differences showed that the father had a compound deltaGT allele ie. deltaGT-20bp, inherited by the patient, and that both parents had compound GTGT alleles with a single 30bp segment in intron 1. The patient was a classic, homozygous deltaGT p47-phox deficient CGD with one allele harbouring a compound deltaGT-20bp gene. The deltaGT and 20bp gene scans offer a relatively simple and efficient means of defining a p47-phox deficient CGD patient.	\N	\N
23394360	Acute kidney injury (AKI) is common in hospitalized human immunodeficiency virus (HIV)-infected patients and is associated with hospital mortality. We aimed to evaluate the impact of AKI on long-term mortality of hospitalized HIV-infected patients. Retrospective analysis of a cohort of 433 hospitalized HIV-infected patients who were discharged alive from the hospital. AKI was defined according to 'Risk Injury Failure Loss of kidney function End-stage kidney disease' creatinine criteria, as an increase of baseline serum creatinine (SCr) X 1.5 or in patients with baseline SCr > 4 mg/dL if there was an acute rise in SCr of at least 0.5 mg/dL. Cumulative mortality curves were determined by the Kaplan-Meier method, and log-rank test was employed to analyze statistically significant differences between curves. Cox regression method was used to determine independent predictors of mortality. Risk factors were assessed with univariate analysis, and variables that were statistically significant (P < 0.05) in the univariate analysis were included in the multivariate analysis. Sixty-four patients (14.8%) had AKI. Median follow-up was 37 months. At follow-up 81 patients (18.7%) died. At 1, 2 and 5 years of follow-up, the cumulative probability of death of patients with AKI was 21.2, 25 and 31.3%, respectively, as compared with 10, 13.3 and 16.5% in patients without AKI (log-rank, P = 0.011). In multivariate analysis AKI was associated with increased mortality (adjusted HR 1.7, 95% CI 1.1-3; P = 0.049). AKI was independently associated with long-term mortality of hospitalized HIV-infected patients.	\N	\N
23394995	Maintenance of an adequate and properly regulated immune system is essential for health and well-being. Components in food may modulate immune responses in a positive way (immunonutrition), and some of these components are present in kiwifruit. Kiwifruit contains vitamin C, carotenoids, polyphenols, and dietary fiber, and these are all potentially beneficial to the immune system. Research that has contributed to our understanding of the beneficial effects that kiwifruit may have on immune responses spans from in vitro studies using cell lines and human blood cells, to using animal models targeting both mucosal and systemic immunity. Some limited human intervention trials have been undertaken and are described, in which kiwifruit has been shown to influence a number of biomarkers of oxidative stress and beneficial immune responses, to reduce the incidence and severity of symptoms of upper respiratory tract infections and potentially be more beneficial than supplementation with vitamin C alone.	\N	\N
23395237	To investigate the expression and possible roles of Twist1 and Y-box-binding protein-1 (YB-1) in bladder cancer tissue. Twist1 belongs to the family of basic helix-loop-helix transcription factors. A functional link between Twist1 and YB-1 has recently been determined to play an important role in bladder cancer cell lines. Frozen samples from 75 patients with bladder cancer were analyzed by quantitative real-time polymerase chain reaction (PCR). Formalin-fixed and paraffin-embedded tissues from 53 patients with bladder cancer were examined by immunohistochemistry. Twist1 transcript levels were positively correlated with YB-1 transcript levels (coefficient of correlation = 0.42, P<0.001), tumor grade (low grade vs. high grade; P<0.001), invasiveness (non-muscle-invasive bladder cancer vs. muscle invasive bladder cancer; P = 0.0018), and metastasis (meta- vs. meta+; P<0.001). YB-1 transcript level was also correlated with grade (P = 0.029) and invasiveness (P = 0.006). By immunohistochemistry, Twist1 expression was also correlated with YB-1 expression (P<0.001). Further, both Twist1 and YB-1 expression were positively correlated with invasiveness (P = 0.007 and P = 0.002, respectively). Patients with high Twist1 expression and high YB-1 expression had lower overall survival rates, compared with patients with low expression (log-rank test, P = 0.040 and P<0.001, respectively). These results suggest a functional link between Twist1 and YB-1, and they indicate that Twist1 and YB-1 promote bladder cancer progression.	\N	\N
23396208	Regulatory T (Treg) cells suppress autoimmune disease, and impaired Treg cell function is associated with rheumatoid arthritis. Here we demonstrate that forkhead box P3 (FOXP3) transcriptional activity and, consequently, Treg cell suppressive function are regulated by phosphorylation at Ser418 in the C-terminal DNA-binding domain. In rheumatoid arthritis-derived Treg cells, the Ser418 site was specifically dephosphorylated by protein phosphatase 1 (PP1), whose expression and enzymatic activity were induced in the inflamed synovium by tumor necrosis factor α (TNF-α), leading to impaired Treg cell function. Moreover, TNF-α-induced Treg cell dysfunction correlated with increased numbers of interleukin-17 (IL-17)(+) and interferon-γ (IFN-γ)(+)CD4(+) T cells within the inflamed synovium in rheumatoid arthritis. Treatment with a TNF-α-specific antibody restored Treg cell function in subjects with rheumatoid arthritis, which was associated with decreased PP1 expression and increased FOXP3 phosphorylation in Treg cells. Thus, TNF-α controls the balance between Treg cells and pathogenic TH17 and TH1 cells in the synovium of individuals with rheumatoid arthritis through FOXP3 dephosphorylation.	\N	\N
23399616	Tyrosine kinase inhibitors (TKIs) are increasingly common treatments for cancer; however, their effective use is hampered by unwanted side effects. One of the most common of these is TKI-induced diarrhea, although so far very little is known about its mechanisms and the best management approaches. As such, this review will briefly cover the extent of the problem, models for researching the problem and touch on future directions for management approaches to the problem. As there is a paucity of knowledge regarding the mechanisms of TKI-induced diarrhea in humans, this review will discuss the rodent models that have been used in the investigation of TKI-induced gut injury. This will be put into context with the pharmacological targets of TKIs and how this new information might help to better tailor treatment and management of patients on these drugs. The recognition of TKI-induced diarrhea as a significant treatment side effect has prompted efforts into uncovering the pathogenesis of this complication. This will enable future patients to be better managed throughout their treatment with these highly effective cancer drugs.	\N	\N
23399972	Blood pressure (BP) is characterized by marked short-term fluctuations occurring within a 24 h period (beat-to-beat, minute-to-minute, hour-to-hour, and day-to-night changes) and also by long-term fluctuations occurring over more-prolonged periods of time (days, weeks, months, seasons, and even years). Rather than representing 'background noise' or a randomly occurring phenomenon, these variations have been shown to be the result of complex interactions between extrinsic environmental and behavioural factors and intrinsic cardiovascular regulatory mechanisms. Although the adverse cardiovascular consequences of hypertension largely depend on absolute BP values, evidence from observational studies and post-hoc analyses of data from clinical trials have indicated that these outcomes might also depend on increased BP variability (BPV). Increased short-term and long-term BPV are associated with the development, progression, and severity of cardiac, vascular, and renal damage and with an increased risk of cardiovascular events and mortality. Of particular interest are the findings from post-hoc analyses of large intervention trials in hypertension, showing that within-patient visit-to-visit BPV is strongly prognostic for cardiovascular morbidity and mortality. This result has prompted discussion on whether antihypertensive treatment should be targeted not only towards reducing mean BP levels but also to stabilizing BPV with the aim of achieving consistent BP control over time, which might favour cardiovascular protection.	\N	\N
23404743	In 2010, guidelines published by the National Institute for Clinical Excellence (NICE) suggested a change in the way patients with stable chest pain of suspected cardiac origin were investigated. These guidelines removed exercise treadmill testing from routine use and introduced cardiac CT to regular use. To investigate whether these guidelines had improved our service provision by reducing the number of further investigations required to make a diagnosis, and to see if our costs had increased now that the less expensive exercise treadmill tests were not recommended. Clinic letters were used to assess patients pretest likelihood of coronary artery disease for two six-month cohorts of consecutive patients seen in the rapid access chest pain clinic (January-June 2010 and July-December 2011) using NICE published methodology, and to ascertain which investigations patients had. Using NICE modelled costs, we generated comparative hypothetical costs for each cohort and an average cost per patient. In the January-June 2010 cohort, 435 patients with chest pain were seen, and in July-December 2011, 334 patients were seen. In the pre-NICE guidelines cohort, 23% of patients required two investigations as compared with 11.4% in the post-NICE guidelines cohort, with no patient requiring three investigations as compared with 3% in the original cohort. There was no significant increase in costs per patient in the post-NICE guidance group. Implementing NICE guidance reduced the number of investigations needed per patient, and did not prove more expensive for our department in the short term.	\N	\N
23406712	The Centers for Medicare and Medicaid Services (CMS) require high-risk (HR) criteria for carotid artery stenting (CAS) reimbursement. The impact of these criteria on outcomes after carotid endarterectomy (CEA) and CAS remains uncertain. Additionally, if these HR criteria are associated with more adverse events after CAS, then existing comparative effectiveness analysis of CEA vs CAS may be biased. We sought to elucidate this using data from the SVS Vascular Registry. We analyzed 10,107 patients undergoing CEA (6370) and CAS (3737), stratified by CMS HR criteria. The primary endpoint was composite death, stroke, and myocardial infarction (MI) (major adverse cardiovascular event [MACE]) at 30 days. We compared baseline characteristics and outcomes using univariate and multivariable analyses. CAS patients were more likely to have preoperative stroke (26% vs 21%) or transient ischemic attack (23% vs 19%) than CEA. Although age ≥ 80 years was similar, CAS patients were more likely to have all other HR criteria. For CEA, HR patients had higher MACEs than normal risk in both symptomatic (7.3% vs 4.6%; P < .01) and asymptomatic patients (5% vs 2.2%; P < .0001). For CAS, HR status was not associated with a significant increase in MACE for symptomatic (9.1% vs 6.2%; P = .24) or asymptomatic patients (5.4% vs 4.2%; P = .61). All CAS patients had MACE rates similar to HR CEA. After multivariable risk adjustment, CAS had higher rates than CEA for MACE (odds ratio [OR], 1.2; 95% confidence interval [CI], 1.0-1.5), death (OR, 1.5; 95% CI, 1.0-2.2), and stroke (OR, 1.3; 95% CI,1.0-1.7), whereas there was no difference in MI (OR, 0.8; 95% CI, 0.6-1.3). Among CEA patients, age ≥ 80 (OR, 1.4; 95% CI, 1.02-1.8), congestive heart failure (OR, 1.7; 95% CI, 1.03-2.8), EF <30% (OR, 3.5; 95% CI, 1.6-7.7), angina (OR, 3.9; 95% CI, 1.6-9.9), contralateral occlusion (OR, 3.2; 95% CI, 2.1-4.7), and high anatomic lesion (OR, 2.7; 95% CI, 1.33-5.6) predicted MACE. Among CAS patients, recent MI (OR, 3.2; 95% CI, 1.5-7.0) was predictive, and radiation (OR, 0.6; 95% CI, 0.4-0.8) and restenosis (OR, 0.5; 95% CI, 0.3-0.96) were protective for MACE. Although CMS HR criteria can successfully discriminate a group of patients at HR for adverse events after CEA, certain CMS HR criteria are more important than others. However, CEA appears safer for the majority of patients with carotid disease. Among patients undergoing CAS, non-HR status may be limited to restenosis and radiation.	\N	\N
23408511	Intellectual disability is a condition characterized by significant limitations in cognitive abilities and social/behavioral adaptive skills and is an important reason for pediatric, neurologic, and genetic referrals. Approximately 10% of protein-encoding genes on the X chromosome are implicated in intellectual disability, and the corresponding intellectual disability is termed X-linked ID (XLID). Although few mutations and a small number of families have been identified and XLID is rare, collectively the impact of XLID is significant because patients usually are unable to fully participate in society. To reveal the molecular mechanisms of various intellectual disabilities and to suggest small molecules which by binding to the malfunctioning protein can reduce unwanted effects. Using various in silico methods we reveal the molecular mechanism of XLID in cases involving proteins with known 3D structure. The 3D structures were used to predict the effect of disease-causing missense mutations on the folding free energy, conformational dynamics, hydrogen bond network and, if appropriate, protein-protein binding free energy. It is shown that the vast majority of XLID mutation sites are outside the active pocket and are accessible from the water phase, thus providing the opportunity to alter their effect by binding appropriate small molecules in the vicinity of the mutation site. This observation is used to demonstrate, computationally and experimentally, that a particular condition, Snyder-Robinson syndrome caused by the G56S spermine synthase mutation, might be ameliorated by small molecule binding.	\N	\N
23409482	Although cutaneous amebiasis (CA) is a rare disease, it is a public health concern worldwide, particularly in developing nations. It gains importance because of its severe clinical course, which can be confused with other disorders. Therefore, knowledge of its clinical features, histopathology, and pathogenesis is essential. We present a retrospective analysis over 50 years of 26 patients with CA who were diagnosed and treated at 2 Mexican institutions. Our main focus was to draw clinical information to identify mechanisms by which amebae reach the skin, occurring in a relatively small percentage of infected individuals. The recorded data included age and sex of the patients, form of presentation, any associated illnesses and/or factors, and methods for diagnosis. Histologic slides were reviewed in all cases; cytologic preparations also were available for 6 cases. Most patients were male (overall male to female ratio, 1.9 to 1). The disease always presented as painful ulcers containing varying amounts of amebae microscopically; the amebae were fairly easy to identify with routine stains, particularly when examination of tissue or smears was prepared from the edges of the ulcer instead of the necrotic centers. Erythrophagocytosis by the trophozoites was found and represented an unequivocal sign of its pathogenicity. We review the 2 mechanisms by which the organisms reach the skin. Most cases resolve with the use of specific antiamebic drugs; however, if left untreated, progression is rapid and unrelenting, sometimes with massive destruction of skin and subcutaneous tissues. Therefore, CA is a particularly virulent form of amebiasis.	\N	\N
23412808	The use of natural remedies and pharmacological mineral supplements for liver disease treatment has a long history. In present study, the levels of selenium (Se) and zinc (Zn) were determined in biological samples (serum and whole blood) of female hepatitis C patients (n = 132), age ranged 30-45 years, before and after 30 days treatment with herbal/pharmaceutical supplements. For comparative study, 128 age-matched female subjects, residing in the same residential areas and have socioeconomic status, were selected as referents. The Se and Zn in supplements, blood, and sera were determined by atomic absorption spectrometry. It was observed that Zn and Se in blood and serum samples of viral hepatitis C (HCV) patients were reduced in the range of 28.6-39 % and 24-36 %, respectively, as compared to those of referents. After herbal/pharmaceutical supplementations, 20.6-25.0 and 9.15-13.2 % of Zn and 10.6-12.1 and 19.6-21.4 % of Se were enhanced in sera and blood samples of HCV patients, respectively. The resulted data indicated that the levels of Se and Zn in addition to some biochemical parameters were improved in HCV patients after herbal/pharmaceutical supplementation. The effects of both supplements were not significantly different (p > 0.05).	\N	\N
23412860	We report 20 infants aged between 1 month and 6 months found to have subdural bleeding and also multiple unexplained fractures in a pattern similar to that described earlier as temporary brittle bone disease. Child abuse seemed unlikely as a cause of the fractures as in no case was there clinical evidence of injury commensurate with the fracturing, as some patients had fractures while in hospital and as metaphyseal lesions, when present, were often symmetrical in distribution. Abuse seemed unlikely to have been the cause of the subdural bleeding in several patients; three had clear histories of accidental injury and five had evidence that the initial bleeding was likely to have taken place at birth. Abuse also seemed unlikely as the cause of the syndrome; the nine patients who were returned to their parents had no subsequent allegations of abuse with a mean follow-up period of 15.8 years. The finding of hypermobile joints in the parents of eight of the children is an additional pointer to a natural cause for this condition. The cause of this combination of fractures and subdural bleeding is not yet clear but it is important to be aware that it can result from natural disease.	\N	\N
23423257	Antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) is a group of vasculitides characterized by small-to-medium-sized blood vessel vasculitis and the presence of ANCA. Although our understanding of the causes of AAV remains limited, new information supporting an autoimmune basis is emerging. This review highlights recent progresses in etiology, pathogenesis, classification, and treatment. A genome-wide association study has confirmed a role for genetic susceptibility in AAV, and links between environmental factors and AAV induction through abnormal neutrophil extracellular traps has been demonstrated. Ongoing international consensus initiatives have revised approaches to the classification of vasculitis that has been enhanced by the analysis of large-scale prospective clinical data sets. New autoantibodies to human lysosome-associated membrane protein-2 antibody, moesin, and plasminogen have been detected in AAV sera and a prognostic classification of renal biopsies developed. Clinical trial networks have extended the evidence base for the treatment of AAV, and rituximab has emerged as an alternative to cyclophosphamide for remission induction. Long-term outcomes following current treatment strategies have been determined and increased risks for cardiovascular and malignant disease reported.	\N	\N
23425809	Liver diseases are responsible for metabolic disturbances and the loss of muscle mass and function. This study aims to correlate maximal oxygen uptake (VO2max) with the Model for End Stage Liver Disease (MELD) severity score and associate VO2max with mortality in patients with alcoholic cirrhosis. This prospective study included 27 patients who had a diagnosis of alcoholic liver cirrhosis. All subjects were followed for 3 years and performed an exercise test to determine VO2max. The study included 18 men and 9 women. We observed a strong inverse correlation between VO2max and MELD (r=-0.91, p<0.001). In a survival analysis, individuals who had a VO2max less than 14mL/kg showed 60% mortality when compared with those who had a VO2max greater than 14mL/kg (p<0.0001; OR: 3.29; 95% CI: 1.44-5.25). The VO2max is directly associated with the survival of patients with alcoholic cirrhosis and demonstrates a strong inverse correlation with the MELD severity score.	\N	\N
23440103	We hereby report two patients with parathyroid carcinoma presenting extremely high calcium and PTH levels, severe bone disease, and palpable neck mass at diagnosis. They both underwent parathyroidectomy, and one of them evolved to lung metastasis. Important hypocalcemia was observed after surgery in both: after parathyroidectomy in one patient, and only after surgical removal of the metastasis in the other. Both required intravenous calcium replacement, thus revealing hungry bone syndrome (HBS). HBS usually reflects rapid mineralization after correction of hyperparathyroidism. The more severe the bone disease before surgery, the more prone the patient is to HBS after surgery. Despite being an unfavorable outcome, HBS state suggests that surgical removal of hypersecretory parathyroid tissue was accomplished. In this study, HBS was observed in both patients, who presented severe bone disease prior to surgery. HBS would be expected post-operatively in successful parathyroid carcinoma removal.	\N	\N
23442763	The relationship between cytomegalovirus (CMV) infection and mortality among immunocompetent individuals is uncertain. We aimed to examine whether seropositivity for CMV and the level of CMV immunoglobulin G (IgG) antibody are associated with all-cause and cause-specific mortality. We used data from a random sample of 13 090 participants aged 40-79 years at recruitment in 1993-1997 to the European Prospective Investigation of Cancer-Norfolk population-based cohort study. We measured baseline IgG antibody levels against CMV. Death certificates were obtained for all participants who died before 31 March 2011. Codes for the underlying cause of death were used to investigate cause-specific mortality. A total of 2514 deaths occurred during a mean follow-up of 14.3 years (SD, 3.3 years). Compared to seronegative participants (age- and sex-adjusted mortality rate, 12.4 [95% confidence interval {CI}, 11.3-13.2] per 1000 person-years at risk), rates increased across thirds of IgG antibody levels (score test of trend P < .0001). CMV seropositivity (prevalence 59%) was associated with increased all-cause mortality (age- and sex-adjusted hazard ratio [HR], 1.16 [95% CI, 1.07-1.26]), similarly in men and women (P for interaction = .52). The association persisted after additionally adjusting for measures of socioeconomic status and possible confounders. Cause-specific analyses suggested that increased mortality from cardiovascular disease (HR, 1.06 [95% CI, .91-1.24]), cancer (HR, 1.13 [95% CI, .98-1.31]), and other causes (HR, 1.23 [95% CI, 1.04-1.47) all appeared to contribute to the overall associations. Seropositivity and higher IgG antibody levels against CMV are associated with increased mortality and after adjustment for a range of potential confounders in the general population.	\N	\N
23443955	Radioiodine (RAI) is used in the treatment of hyperthyroidism and differentiated thyroid cancer. Radioiodine therapy is associated with dry eyes and some side effects are seen especially due to beta rays. In this study, the functional and cytological status of lacrimal glands after RAI therapy was evaluated. Twenty-five patients with a mean age of 55.16 years with planned low-dose RAI therapy were evaluated. Just before and 6 months after the treatment, the lacrimal glands were evaluated with tear break-up time (BUT), Schirmer's test, impression cytology and "Ocular Surface Disease Index (OSDI)" questionnaire. The mean value of Schirmer's test was 16.20 ± 3.61 pre-treatment and 11.28 ± 4.39 post-treatment for the right eye, and 15.76 ± 3.27 and 10.60 ± 4.42 for the left eye, respectively. The mean value of Schirmer's test decreased significantly post-treatment in both eyes (p = 0.0001). The BUT score also decreased significantly post-treatment (p = 0.001). The mean value of OSDI score was 27.5 ± 8.02 pre-treatment and 46.36 ± 10.27 post-treatment. The mean value of OSDI score increased post-treatment (p = 0.0001). The impression scores also increased post-treatment in both eyes (p = 0.0001). Even low-dose (≤30 mci) RAI treatment affects lacrimal gland functions. Low-dose RAI causes a decrease in the value of Schirmer's test and the BUT test, and an increase in the value of OSDI score and impression scores.	\N	\N
23444587	In this paper, we explore the benefits of storytelling in health communication and, in particular, immunization education. During the mid-20th century polio epidemic, both personal stories and scientific information abounded in the media. However, as rates of vaccine-preventable diseases declined, narratives about the dangers of such diseases faded as did the public fear of them. Meanwhile, anti-vaccine advocates flooded the media and Internet with stories of injured children and tied those injuries, such as autism, to vaccines. Medical experts often counter anti-vaccine concerns with scientific information which can fail to persuade parents. Furthermore, evidence suggests that many people misunderstand quantitative information resulting in a misinterpretation of risk. Compared to scientific information, stories relate life lessons and values. They are effective because they are memorable and relatable. Evidence also suggests that storytelling can effectively improve health knowledge and behaviors. Inspired by In Harm's Way--True Stories of Uninsured Texas Children by the Children's Defense Fund and Faces of Influenza by the American Lung Association, we published Vaccine-Preventable Disease: The Forgotten Story, a collection of photographs and personal stories of families affected by vaccine-preventable diseases. We have found that the stories included in our booklet capture all the benefits of storytelling. Given the many benefits of storytelling, providers should strive to include stories along with medical facts in their daily practice.	\N	\N
23446227	Neuroendocrine tumors (NET) are malignant solid tumors that arise in hormone-secreting tissue of the diffuse neuroendocrine system or endocrine glands. Although traditionally understood to be a rare disease, the incidence and prevalence of NET have increased greatly in the past 3 decades. However, during this time, progress in diagnosis and outcome of NET has generally been modest. In order to achieve improved outcome in NET, a better understanding of NET biology combined with more reliable serum markers and better techniques to identify tumor localization and small lesions are needed. Although some NET biomarkers exist, sensitive and specific markers that predict tumor growth and behavior are generally lacking. In addition, the integration of new molecular imaging technologies in patient diagnosis and follow-up has the potential to enhance care. To discuss developments and issues required to improve diagnostics and management of NET patients, with specific focus on the latest advances in molecular imaging and biomarker science, 17 global leaders in the fields of NET, molecular imaging and biomarker technology gathered to participate in a 2-day meeting hosted by Prof. Kjell Öberg at the University of Uppsala in Sweden. During this time, findings were presented regarding methods with potential prognostic and treatment applications in NET or other types of cancers. This paper describes the symposium presentations and resulting discussions.	\N	\N
23447119	Erdheim-Chester disease (ECD) is a rare, non-Langerhans form of histiocytosis of unknown origin with distinct clinicopathologic and radiographic features. Reports detailing the cytology of ECD are rare. We describe a case of ECD with pericardial effusion. Cytologic examination revealed a hypercellular specimen composed of clusters and singly dispersed foamy macrophages with round nuclei and inconspicuous nucleoli, admixed with lymphocytes, eosinophils, and Touton-type multinucleated giant cells. Immunostains for CD68 were strongly positive in the foamy macrophages while S100 and CD1a were negative. The presence of foamy histiocytes, multinucleated giant cells, lymphocytes and eosinophils are also features of other systemic histiocytic disorders, including Langerhans cell histiocytosis (LCH), Rosai-Dorfman disease (RDD) and sarcoidosis. To the best of out knowledge, this is the first report describing the cytological features of ECD in a pericardial effusion.	\N	\N
23449087	Single cell genomics has made increasingly significant contributions to our understanding of the role that somatic genome variations play in human neuronal diversity and brain diseases. Studying intercellular genome and epigenome variations has provided new clues to the delineation of molecular mechanisms that regulate development, function and plasticity of the human central nervous system (CNS). It has been shown that changes of genomic content and epigenetic profiling at single cell level are involved in the pathogenesis of neuropsychiatric diseases (schizophrenia, mental retardation (intellectual/leaning disability), autism, Alzheimer's disease etc.). Additionally, several brain diseases were found to be associated with genome and chromosome instability (copy number variations, aneuploidy) variably affecting cell populations of the human CNS. The present review focuses on the latest advances of single cell genomics, which have led to a better understanding of molecular mechanisms of neuronal diversity and neuropsychiatric diseases, in the light of dynamically developing fields of systems biology and "omics".	\N	\N
23451796	Lowering blood glucose with insulin therapy towards beneficial target levels while also avoiding hypoglycaemia is a challenging task. An important confounding factor, which might be under-appreciated in this scenario, is that of variable glucose readings causing difficulties with dose adjustment. Furthermore, this glucose variability is, to some extent, a reflection of variability in the glucose-lowering action of the insulin therapy itself. Not only is glucose variability a major confounding factor in disease management but it is possibly also of direct prognostic consequence and is increasingly recognized as an informative measurement in diabetes management. The scope for insulin-induced glucose variability is particularly great with basal insulins because of their prolonged absorption from high-dose depots. Pharmacodynamic (PD) variability manifests as both fluctuations in the level of glucose-lowering effect over time, and as inconsistencies in the response from one injection to another. Well-controlled pharmacokinetic (PK)/PD studies using repeated isoglycaemic clamp methodology clearly how that many injected basal insulin products have high variable absorption with correspondingly variable action. Incomplete resuspension and precipitation appear to be important issues with regard to unpredictability in this action, while an inadequate duration of action relative to the dosing interval results in a fluctuating action profile. There are some ultra-long-acting basal insulins with novel protraction mechanisms currently in clinical development for which clamp studies show markedly improved PK/PD profiles.	\N	\N
23456185	The temporal lobe is of importance for visuospatial orientation. Intracranial arachnoid cysts have a predilection for the temporal fossa, and might therefore affect visuospatial orientation. The aim was to find out whether temporal cysts affect maze learning and if surgical cyst decompression improves maze performance. Forty-five patients with a temporal arachnoid cyst and 17 control patients with cervical disc disease were tested in a labyrinth route in the hospital corridors the day before surgery and at least 3 months postoperatively. Thirty-five cyst patients (78 %) experienced postoperative improvement of their preoperative complaints. The cyst patients spent significantly longer time than the controls navigating through the maze in the preoperative test, 161 s and 127 s, respectively, but there was no difference in number of errors between the two groups. However, the cyst patients improved significantly in the postoperative test, both with regards to number of errors they made and time spent, contrary to the control patients, whose postoperative performance equalled that of the preoperative test. For the cyst patients, postoperative improvement in the labyrinth test correlated with the clinical outcome-but not the neuroradiological outcome-after the operation. Thus, temporal arachnoid cysts may affect visuospatial orientation and learning in a reversible manner.	\N	\N
23459906	this paper reports the results of a nursing-administered theory-based intervention, the "Moving Heart Program", based on the implementation intention theory and pointed at improving physical activity adherence among coronary heart disease outpatients in Brazil. this experimental study applied assessments at baseline, 1 and 2 months after baseline. The Consolidated Standards of Reporting Trials statement was followed. Participants were randomly assigned to intervention, comprising action and coping plans on how to deal with anticipated barriers (n=69), or a standard-care control group (n=67). participants submitted to the intervention showed significant higher levels of physical activity 2 months after baseline and were significantly more active than the control group. the results indicate that the intervention is feasible for patients with coronary heart disease and can be a useful tool to facilitate intended lifestyle changes. This study brings relevant contributions to the Nursing field and other health-related areas, once the intervention presents low cost to health services and can be applied in cardiac rehabilitation programs, showing significant benefits to participants.	\N	\N
23462063	To assess the effectiveness of flow reversal as an alternative means of cerebral protection by using transcranial Doppler recordings and diffusion-weighted imaging (DWI) as surrogate markers of brain injury. Eighteen patients with symptomatic carotid artery disease were recruited. Magnetic resonance imaging was performed before the intervention and at 3 and 24 hours and 30 days after the intervention to detect new ischemic lesions with DWI. Transcranial Doppler recordings were made during the procedure to assess for microembolic signals (MESs). Data were compared against data from a historical control cohort of patients who underwent CAS placement with or without filter protection (n = 15 each) under the same protocol in a different study. There were fewer periprocedural new lesions on DWI in the reverse-flow cohort compared with the historical control cohort with filter protection (P = .084). Reverse flow revealed significantly fewer MESs during the whole procedure compared with the filter-protected group (P = .01) but not the unprotected group (P = .55). There was a marked decrease in MES counts for reverse flow protection during the embologenic stages of the procedure (P = .004). Use of the reverse flow device was associated with fewer overall lesions on DWI and proportionately fewer positive scans compared with the use of filter-type devices (P = .08, not significant). Transcranial Doppler recordings demonstrated a significant reduction in embolization to the brain during carotid artery stent placement with the use of reverse-flow cerebral protection.	\N	\N
23462484	Patients suffering from Parkinson's disease (PD) frequently experience painful sensations that may be due to central modification of nociception in PD. We compared pain thresholds and cerebral activity in nociceptive areas using Positron Emission Tomography (PET) during nociceptive stimulation before (OFF condition) and after (ON condition) levodopa challenge between nine PD patients with and nine PD patients without neuropathic pain. Pain thresholds were determined using a cold pressor test in the two conditions. We used H2(15)O PET to study the regional cerebral blood flow changes in subjects while they received alternate randomized noxious and innocuous cold stimuli during OFF and ON periods. Pain thresholds were not significantly different between PD patients with and without pain in either condition (OFF and ON). In both groups of PD patients, levodopa significantly raised pain threshold (F1,16 = 26.71; p < 0.0001) with a mean variation of -2.7 (±2.3 °C). In the OFF condition, PD patients with pain had a lower pain activation in the right prefrontal cortex and posterior insula and a higher pain activation in the right anterior cingulate cortex (BA32/8) than pain-free patients. Levodopa significantly reduced pain-induced-activation in the right insula and in the anterior cingulate cortex in both groups. Levodopa decreased nociceptive perception in both PD patients with and without pain. In PD patients with neuropathic pain the medial affective pathway was preferentially recruited whereas pain-free PD patients exhibited a greater activation in lateral discriminative nociceptive areas.	\N	\N
23462618	The objective of this study was to compare the toxicological effects of different source-related ambient PM10 samples in regard to their chemical composition. In this context we investigated airborne PM from different sites in Aachen, Germany. For the toxicological investigation human alveolar epithelial cells (A549) and murine macrophages (RAW264.7) were exposed from 0 to 96 h to increasing PM concentrations (0-100 μg/ml) followed by analyses of cell viability, pro-inflammatory and oxidative stress responses. The chemical analysis of these particles indicated the presence of 21 elements, water-soluble ions and PAHs. The toxicological investigations of the PM10 samples demonstrated a concentration- and time-dependent decrease in cell viability and an increase in pro-inflammatory and oxidative stress markers.	\N	\N
23470563	The IGF-I receptor (IGF-IR) has an important role in malignant disease and is the target of several drugs presently in clinical trials. Gene therapy has been explored as cancer treatment, mainly for delivery of genes that induce cell death or enhance the immunological response to cancer. Previously, we have shown that the implantation of autologous bone-marrow stromal cells producing a soluble form of IGF-IR (sIGFIR) inhibited experimental liver metastasis of several tumor types in mice. Here, we evaluated the utility of adenovirus-based gene delivery for generating therapeutically effective plasma levels of this decoy. We constructed a third generation gutless adenovirus expressing sIGFIR and found that HEK-293 cells transduced by this, but not control adenoviruses, secreted soluble receptor protein that blocked IGF-I-induced tumor cell migration, proliferation and survival in vitro. Following virus injection in vivo, viral DNA was detectable by PCR in several host organs, particularly the liver, and this resulted in the production of measurable sIGFIR plasma levels for up to 21 days post injection. In mice producing virus-encoded sIGFIR, experimental liver metastasis was inhibited, indicating that sIGFIR levels were therapeutically effective. The results show that adenovirus-based delivery of inhibitory soluble proteins can provide an effective anticancer strategy.	\N	\N
23475581	Tissue oxidative stress is a common hallmark of atherosclerosis and non-alcoholic steatohepatitis (NASH), 2 conditions linked epidemiologically and pathophysiologically. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the master regulator of inducible antioxidant responses, that can attenuate cellular injury from oxidative stress induced by obesity and other redox insults. Nrf2 expression and activation is reduced in mouse and human vessels that harbor accelerated atherosclerosis and in livers with histologic criteria of NASH. Systemic antioxidants have thus been attractive therapeutic targets, but clinical trials have been largely unsuccessful in improving cardiovascular health. Macrophage-selective Nrf2 activation may, however, provide an approach to reduce vascular and hepatocyte injury without the complications of systemic antioxidants, since macrophages play key roles in the development and progression of both atherosclerosis and NASH. In this article, we review the common mechanisms of oxidative stress and inflammation in atherosclerosis and NASH, and discuss the role of Nrf2 in vascular and hepatocyte protection.	\N	\N
23478151	Primary carcinoid tumors of the kidney are very rare, malignant tumors consisting of neuroendocrine cells. The pathogenesis of renal carcinoid is unclear because neuroendocrine cells are not normally found in adult renal parenchyma. Electron microscopy, immunohistochemistry, octreotide scan, positron emission tomography along with conventional radiographic imaging techniques are used in diagnosis and follow-up. Presenting symptoms usually include flank pain and haematuria. Early stage disease is treated with surgery only. However, randomized trials are lacking because of the very low number of reported cases. Thus, the role of debulking surgery, chemotherapy, radiotherapy, octreotide and targeted therapy in the management of advanced disease remains an open question. In this article the clinicopathologic features and prognosis of this very rare disease along with treatment outcomes of the reported cases are reviewed. In addition, we report a new case of a metastatic primary renal atypical carcinoid tumor treated with octreotide therapy.	\N	\N
23479135	Platinum-based chemotherapy is the most common treatment for patients with advanced non-small cell lung cancer (NSCLC). Genetic polymorphisms in the base excision repair (BER) pathway are suspected to influence the response of patients to this type of therapy. In this study, we investigated whether nonsynonymous single nucleotide polymorphisms (SNPs) in the BER pathway were associated with the response, progression-free survival (PFS) and overall survival (OS) of NSCLC patients following platinum-based chemotherapy. We used TaqMan to genotype four SNPs (APE1 Asp148Glu, PARP1 Va1762Ala, XRCC1 Arg194Trp and XRCC1 Arg399Gln) in 147 patients with advanced NSCLC who had undergone routine platinum-based chemotherapy. Logistic regression analysis showed that subjects with the XRCC1-399 A allele had a significantly better response to platinum-based chemotherapy than those with the XRCC1-399 GG genotype (AA/AG vs. GG: adjusted OR = 2.35, 95 % CI = 1.11-5.00). Furthermore, multivariate Cox proportional hazard regression analysis showed that the PARP1-762 CC genotype was a significantly unfavorable prognostic factor for PFS (CC vs. CT/TT: adjusted HR = 1.90, 95 % CI = 1.02-3.52). In contrast, the APE1-148 GG genotype was a significantly protective prognostic factor for OS (GG vs. TT: adjusted HR = 0.33, 95 % CI = 0.12-0.92). We found that XRCC1 Arg399Gln, PARP1 Va1762Ala and APE1 Asp148Glu SNPs in the BER pathway may influence the prognosis of advanced NSCLC patients following platinum-based chemotherapy.	\N	\N
23484318	To increase the death rate of fatal anaphylaxis in guinea pigs and the detectahie level of the tryptase of mast cell in hlood serum. Seventy-four guinea pigs were randomly divided into five groups: original model group, original model control group, improved model group, improved model control group, improved model with non-anaphylaxis group. Using mixed human serum as the allergen, the way of injection, sensitization and induction were improved. ELISA was used to detect the serum mast cell tryptase and total IgE in guinea pigs of each group. The death rate of fatal anaphylaxis in original model group was 54.2% with the different degree of hemopericardium. The severe pericardial tamponade appeared in 9 guinea pigs in original model group and original model control group. The death rate of fatal anaphylaxis in improved model group was 75% without pericardial tamponade. The concentration of the serum total IgE showed no statistically difference hetween original model group and original model control group (P > 0.05), hut the serum mast cell tryptase level was higher in the original model group than that in the original model control group (P > 0.05). The concentration of the serum total IgE and the serum mast cell tryptase level were significantly higher in improved model group than that in the improved model control group (P < 0.05). The death rate of the improved model significantly increases, which can provide effective animal model for the study of serum total IgE and mast cell tryptase.	\N	\N
23484512	An increasing number of people with mild cognitive impairment (MCI) visits a memory clinic to find out whether their symptoms indicate Alzheimer's disease (AD). Markers in cerebrospinal fluid are increasingly used for the diagnosis of Alzheimer's disease. In the short term, CSF biomarkers are more accurate in ruling out progression to AD-type dementia than demonstrating progression. The predictive value of the CSF biomarkers increases with longer-duration follow-up and declines with age. The added value of CSF biomarkers is not yet clear in MCI patients in whom extensive clinical, neuropsychological examination or imaging have already been performed.	\N	\N
23485507	An optimal prostate biopsy in clinical practice is based on a balance among adequate detection of clinically significant prostate cancers (sensitivity), assuredness regarding the accuracy of negative sampling (negative predictive value), limited detection of clinically insignificant cancers and good concordance with whole gland surgical pathology results to allow accurate risk stratification and disease localization for treatment selection. Inherent within this optimization is variation of the core number, location, labeling and processing for pathological evaluation. To date, there is no consensus in this regard. The purpose of this review is to 1) define the optimal number and location of biopsy cores during primary prostate biopsy among men with suspected prostate cancer, 2) define the optimal method of labeling prostate biopsy cores for pathological processing which will provide relevant and necessary clinical information for all potential clinical scenarios, and 3) determine the maximal number of prostate biopsy cores allowable within a specimen jar which would not preclude accurate histological evaluation of the tissue. A bibliographic search using PubMed® covering the period up to July 2012 yielded approximately 550 articles. Articles were reviewed and categorized based on which of the 3 objectives of this review was addressed. Data were extracted, analyzed and summarized. Recommendations are provided based on this literature review and our clinical experience. The use of 10 to 12-core extended sampling protocols increases cancer detection rates compared to traditional sextant sampling methods and reduces the likelihood of repeat biopsy by increasing negative predictive value, ultimately allowing more accurate risk stratification without increasing the likelihood of detecting insignificant cancers. As the number of cores increases above 12, the increase in diagnostic yield becomes marginal. Only limited evidence supports the use of initial biopsy schemes involving more than 12 cores or saturation. Apical and laterally directed sampling of the peripheral zone increases cancer detection rate, reduces the need for repeat biopsies and predicts pathological features on prostatectomy while transition zone biopsies do not. There are little data to suggest that knowing the exact site of an individual positive biopsy core provides meaningful clinical information. However, determining laterality of cancer on biopsy may be helpful for predicting sites of extracapsular extension and therapeutic planning. Placement of multiple biopsy cores in a single container (greater than 2) appears to compromise pathological evaluation, which can reduce cancer detection rate and increase the likelihood of equivocal diagnoses. A 12-core systematic biopsy that incorporates apical and far-lateral cores in the template distribution allows maximal cancer detection, avoids repeat biopsy, and provides information adequate for identifying men who need therapy and planning that therapy while minimizing the detection of occult, indolent prostate cancers. This literature review does not provide compelling evidence that individual site specific labeling of cores benefits clinical decision making regarding the management of prostate cancer. Based on the available literature, we recommend packaging no more than 2 cores in each jar to avoid reduction of the cancer detection rate through inadequate tissue sampling.	\N	\N
23494361	Disseminated intravascular coagulation (DIC) is a life-threatening complication, and its control is essential for therapeutic success. Recombinant human soluble thrombomodulin alfa (rTM) is a novel therapeutic agent for DIC. The efficacy of rTM in the treatment of DIC is reportedly superior to that of conventional anti-DIC treatments, such as unfractionated heparin or low molecular weight heparin, but hemorrhagic events occasionally interfere with the therapeutic benefits of rTM. We assessed the clinical features of 20 consecutive patients who were given rTM for DIC associated with various hematologic disorders. Eight patients achieved remission of both primary disease and DIC, eight died due to progression of the primary disease, and four died of various hemorrhagic complications. Assessment of 16 biomarkers for coagulation showed that the four patients who died of hemorrhagic complications despite remission of their primary disease showed lower ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin Type 1 motif, member 13) plasma activity than other patients (P = 0.016). The optimal cut-off level of ADAMTS-13 for predicting risk of hemorrhagic complications was 42 % (P = 0.007). Plasma ADAMTS-13 activity determined at diagnosis of DIC may help predict the risk of hemorrhagic events during and/or following DIC treatment with hematologic disorders.	\N	\N
23494513	The use of self-expandable metal stents (SEMS) for the treatment of malignant colorectal obstruction is increasing. However, results of risk factors for its complications are inconsistent. This study aimed to examine the clinical effectiveness of the procedure as well as the complications and risk factors associated with the complications. Medical records of patients with malignant colorectal obstruction who underwent endoscopic placement of covered or uncovered SEMS were reviewed retrospectively. The procedure was performed by two endoscopists with experience in pancreatobiliary endoscopy. A total of 152 patients were included (102 men; mean age, 70 ± 12.5 years). The procedure was performed for palliative management in 83 patients and performed as a bridge to surgery in 69 patients. There were 111 uncovered stents and 41 covered stents. The technical success rate was 100% and the clinical success rate 94.1%. Overall complications were observed in 49 patients (32.2%) during the follow-up period (median, 98 days; interquartile range, 19-302 days). Obstruction (17.1%), migration (7.9%), perforation (5.2%), bleeding (1.3%), and tenesmus (0.7%) were the causes of the complications. Stage IV disease, carcinomatosis peritonei, complete obstruction of the colon, palliative intention, and covered stents increased the complications based on the univariate analysis. Multivariate analysis revealed that complete obstruction of the colon and covered stents were significantly independent risk factors for complications. In the palliative group, Kaplan-Meier analysis showed significantly shorter median duration to the onset of complications in the covered stent group than in the uncovered stent group. Although SEMS in patients with malignant colorectal obstruction is effective both as palliative therapy and as a bridge to surgery, one-third of patients experienced complications. Severity of obstruction and stent type can influence outcomes.	\N	\N
23510013	Children with disabilities are two to three times more likely to become overweight or obese than typically developing children. Children with spina bifida (SB) are at particular risk, yet obesity prevalence and weight management with this population are under-researched. This retrospective chart review explored how weight is assessed and discussed in a children's SB outpatient clinic. Height/weight data were extracted from records of children aged 2-18 with a diagnosis of SB attending an outpatient clinic at least once between June 2009-2011. Body mass index was calculated and classified using Centers for Disease Control and Prevention cut-offs. Notes around weight, diet and physical/sedentary activities were transcribed verbatim and analysed using descriptive thematic analysis. Of 180 eligible patients identified, only 63 records had sufficient data to calculate BMI; 15 patients were overweight (23.81%) and 11 obese (17.46%). Weight and physical activity discussions were typically related to function (e.g. mobility, pain). Diet discussions focused on bowel and bladder function and dietary challenges. Anthropometrics were infrequently recorded, leaving an incomplete picture of weight status in children with SB and suggesting that weight is not prioritised. Bowel/bladder function was highlighted over other benefits of a healthy body weight, indicating that health promotion opportunities are being missed. Implications for Rehabilitation It is important to assess, categorise and record anthropometric data for children and youth with spina bifida as they may be at particular risk of excess weight. Information around weight categorisation should be discussed openly and non-judgmentally with children and their families. Health promotion opportunities may be missed by focusing solely on symptom management or function. Healthcare professionals should emphasise the broad benefits of healthy eating and physical activity, offering strategies to enable the child to incorporate healthy lifestyle behaviours appropriate to their level of ability.	\N	\N
23511908	Corticostriatal projections are essential components of forebrain circuits and are widely involved in motivated behaviour. These axonal projections are formed by two distinct classes of cortical neurons, intratelencephalic (IT) and pyramidal tract (PT) neurons. Convergent evidence points to IT versus PT differentiation of the corticostriatal system at all levels of functional organization, from cellular signalling mechanisms to circuit topology. There is also growing evidence for IT/PT imbalance as an aetiological factor in neurodevelopmental, neuropsychiatric and movement disorders - autism, amyotrophic lateral sclerosis, obsessive-compulsive disorder, schizophrenia, Huntington's and Parkinson's diseases and major depression are highlighted here.	\N	\N
23515578	Disturbances in proteostasis are observed in many neurodegenerative diseases. This leads to activation of protein quality control to restore proteostasis, with a key role for the removal of aberrant proteins by proteolysis. The unfolded protein response (UPR) is a protein quality control mechanism of the endoplasmic reticulum (ER) that is activated in several neurodegenerative diseases. Recently we showed that the major proteolytic pathway during UPR activation is via the autophagy/lysosomal system. Here we investigate UPR induction if the other major proteolytic pathway of the ER -ER associated degradation (ERAD)-is inhibited. Surprisingly, impairment of ERAD results in decreased UPR activation and protects against ER stress toxicity. Autophagy induction is not affected under these conditions, however, a striking relocalization of the lysosomes is observed. Our data suggest that a protective UPR-modulating mechanism is activated if ERAD is inhibited, which involves lysosomes. Our data provide insight in the cross-talk between proteolytic pathways involved in ER proteostasis. This has implications for neurodegenerative diseases like Alzheimer's disease where disturbed ER proteostasis and proteolytic impairment are early phenomena in the pathology.	\N	\N
23523498	Unicompartmental knee arthroplasty (UKA) is a less invasive treatment for medial gonarthrosis. However, registry data have demonstrated higher revision and early failure rates. The purpose of this study is to report the early survivorship and failure modes in a series of 1000 consecutive medial mobile bearing UKA. UKA patients with a minimum of 2 year follow-up or those meeting the study endpoint (UKA failure or death) were included. Demographic variables, pre and post-operative clinical variables, and mode of failure were analyzed. Eight hundred and thirty-nine knees were included in the analysis. Forty revisions were performed at an average of 23.1 months (range, 2.3-74.2) following UKA for a survivorship of 95.2%. Indications for revision were aseptic loosening (15), tibial collapse (7), mobile bearing dislocation (2), persistent pain (12), progression of disease (2), infection (1), and tibiofemoral instability (1). These results are from a single center and may not be comparable to those of larger reports such as national registries.	\N	\N
23526950	Transformation is a complex process, involving many changes in the cell. In this work, we investigated the transcriptional changes that arose during the development of squamous cell carcinoma (SCC) in mice. Using microarray analysis, we looked at gene expression during different stages in cancer progression in 31 mice. By analyzing tumor progression in each mouse separately, we were able to define the global changes that were common to all 31 mice, as well as significant changes that occurred in fewer individuals. We found that different genes can contribute to the tumorigenic process in different mice, and that there are many ways to acquire the malignant properties defined by Hanahan and Weinberg as "hallmarks of cancer". Eventually, however, all these changes lead to a very similar cancerous phenotype. The finding that gene expression is strongly heterogeneous in tumors that were induced by a standardized protocol in closely related mice underscores the need for molecular characterization of human tumors and personalized therapy.	\N	\N
23528171	Surgical resection of lung metastases of epithelial and mesenchymal tumors has an irreplaceable position in the complex treatment of advanced stages of these malignancies. Among the most significant prognostic factors affecting longterm survival of these patients are: parameter of complete resection, number and size of metastases, histological type of primary tumor, lymph node involvement, DFI (Disease Free Interval) and biological aggressiveness of the tumor or TDT (Tumor Doubling Time). retrospective analysis of patients with lung metastases of epithelial and mesenchymal tumors operated on at the I. Department of Surgery from 2005 to 2011. The authors present a set of 50 patients and evaluation of their age, gender, type of primary tumor, number of metastases, occurrence of bilateral metastases, repeat metastasectomies, duration of DFI, type of operation and selected approach and performance of mediastinal lymphadenectomy. The probability of five-year survival, relationship between survival on DFI, difference in survival between metastases of colorectal cancer versus renal cancer and the influence of repeated metastasectomies and number of metastases on survival were statistically analyzed. Sixty operations were performed on a set of 50 patients (average age 61.2 years). Forty-two procedures were performed by thoracotomic approach. A solitary metastasis was discovered in 43 patients; in 8 patients, more than 3 metastases were resected. Repeated metastasectomies were performed 10 times. Mediastinal lymphadenectomy was performed in 21 cases. The most frequent procedure was extraanatomic resection (28×). Fourteen patients had DFI < 12 months, 19 patients had DFI 12-36 months and 17 patients had DFI > 36 months. Average survival was 66.9 months; the probability of five-year survival was 0.549 (54.9%). A relationship between DFI and survival was not discovered. There was no statistically significant difference in survival after metastasectomy for colorectal cancer and renal cancer. A relationship between survival interval and number of metastases and repeated metastasectomies was not discovered. Surgical resection of lung metastases plays an important role in multidisciplinary care, assuming a precise selection of patients indicated for this treatment. When properly adhering to the indication criteria, very positive results of long-term survival may be expected.	\N	\N
23537409	Nitric oxide (NO) is involved in the regulation of several physiological processes such as vascular homeostasis. Exogenous NO supply offers major therapeutic interest, especially in the treatment of coronary artery disease, ischemic syndromes and other cardiovascular pathologies. Nevertheless, the administration of NO itself is limited by its short half-life. NO prodrugs have been marketed for decades, e.g. organic nitrates for angina pectoris. These prodrugs display undeniable advantages such as angina crisis relief and preconditioning effect. Nevertheless, they suffer from several drawbacks: toxicity, tolerance, endothelial dysfunction exacerbation. These negative effects are related to massive production of reactive species derived from oxygen or nitrogen, which trigger oxidative and nitrosative stress. New NO donors are under development to overcome those disadvantages, among which the S-nitrosothiols family seems especially promising.	\N	\N
23539255	Laparoscopy-assisted total gastrectomy (LATG) has been used more frequently despite the associated technical difficulty and concerns over oncological safety. This study was undertaken to compare the short- and long-term surgical outcomes following either LATG or open total gastrectomy (OTG) for gastric cancer. A total of 120 LATG and 228 OTG were retrospectively matched with respect to sex, age (±5 years), and pathological tumor-node-metastasis stage for comparison of the clinical outcomes. The total complication rate among 120 LATG and 228 OTG was 18.3 % (22/120) and 16.2 % (37/228), respectively. The most common complication after LATG was anastomotic-related complication (6.7 %); five anastomotic leakages (4.2 %) and three anastomotic strictures were reported (2.5 %). That after OTG was wound complication (3.5 %), including seroma or infection. Matched patients analysis: Time to first gas passing and time to the resumption of a soft diet were significantly shorter in the LATG group than in the OTG group. The postoperative hospital stay of LATG was shorter in the LATG group (9.3 ± 4.2 days) than in the OTG group (11.7 ± 7.3 days; p = 0.057). Among matched patients, there was no significant difference between complication rate (24 vs. 32 %; p = 0.504) or leakage rate (6 vs. 4 %). During median follow-up of 50 (range, 10-92) months, there was no significant difference in the disease-free survival rate between the matched groups, respectively (94.5 vs. 87.1 %: p = 0.148). As for patients with TNM stage I gastric cancer, the disease-free survival rate (100 vs. 90.9 %; p = 0.5) and the cumulative survival rate (91.5 vs. 95.2 %; p = 0.618) did not differ significantly between the LATG and OTG groups. LATG for gastric cancer has the advantage over an OTG in terms of better short-term outcomes and similar long-term outcome. LATG is an acceptable alternative to OTG for the treatment of gastric cancer.	\N	\N
23541879	This consensus document was prepared by an expert panel of the Grupo de Estudio de Sida (GESIDA [Spanish AIDS Study Group]) and the Plan Nacional sobre el Sida (PNS [Spanish National AIDS Plan]). The document updates current guidelines on the treatment of tuberculosis (TB) in HIV-infected individuals contained in the guidelines on the treatment of opportunistic infections published by GESIDA and PNS in 2008. The document aims to facilitate the management and treatment of HIV-infected patients with TB in Spain, and includes specific sections and recommendations on the treatment of drug-sensitive TB, multidrug-resistant TB, and extensively drug-resistant TB, in this population. The consensus guidelines also make recommendations on the treatment of HIV-infected patients with TB in special situations, such as chronic liver disease, pregnancy, kidney failure, and transplantation. Recommendations are made on the timing and initial regimens of antiretroviral therapy in patients with TB, and on immune reconstitution syndrome in HIV-infected patients with TB who are receiving antiretroviral therapy. The document does not cover the diagnosis of TB, diagnosis/treatment of latent TB, or treatment of TB in children. The quality of the evidence was evaluated and the recommendations graded using the approach of the Grading of Recommendations Assessment, Development and Evaluation Working Group.	\N	\N
23542225	BM failure (BMF) is a major and frequent complication of dyskeratosis congenita (DKC). Allogeneic hematopoietic SCT (allo-HSCT) represents the only curative treatment for BMF associated with this condition. Transplant-related morbidity/mortality is common especially after myeloablative conditioning regimens. Herein, we report nine cases of patients with DKC who received an allo-SCT at five different member centers within the Eastern Mediterranean Blood and Marrow Transplantation Registry. Between October 1992 and February 2011, nine DKC patients (male, 7 and female, 2), with a median age at transplantation of 19.1 (4.9-31.1) years, underwent an allo-HSCT from HLA-matched, morphologically normal-related donors (100%). Preparative regimens varied according to different centers, but was reduced intensity conditioning (RIC) in eight patients. Graft source was unstimulated BM in five cases (56%) and G-CSF-mobilized PBSCs in four (44%) cases. The median stem cell dose was 6.79 (2.06-12.4) × 10(6) cells/kg body weight. GVHD prophylaxis consisted of CsA in all nine cases; MTX or mycophenolate mofetil were added in five (56%) and two (22%) cases, respectively. Anti-thymocyte globulin was administered at various doses and scheduled in four (44%) cases. Median time-to-neutrophil engraftment was 21 (17-27) days. In one case, late graft failure was noted at 10.4 months post allo-HSCT. Only one patient developed grade II acute GVHD (11%). Extensive chronic GVHD was reported in one case, whereas limited chronic GVHD occurred in another four cases. At a median follow-up of 61 (0.8-212) months, seven (78%) patients were still alive and transfusion independent. One patient died of metastatic gastric adenocarcinoma and graft failure was the cause of death in another patient. This study suggests that RIC preparative regimens are successful in inducing hematopoietic cell engraftment in patients with BMF from DKC. Owing to the limited sample size, the use of registry data and heterogeneity of preparative as well as GVHD prophylaxis regimens reported in this series, we are unable to recommend a particular regimen to be considered as the standard for patients with this disease.	\N	\N
23544766	To evaluate chemotherapy regimen utilization in patients with non-small cell lung cancer (NSCLC) treated in US community oncology practices, to examine the relationship between evidence-based guideline adherence and the follow-up monitoring period (FUMP) over 1.5 years, and to understand the relative costs of commonly administered chemotherapy regimens. Retrospective data analysis. Using a large US medical oncology clinical database derived from a proprietary web-based drug dispensing technology, we identified adult patients with NSCLC who started adjuvant therapy for early-stage disease or first-line therapy for advanced and metastatic disease from July 1, 2009, through June 30, 2010. Adjuvant or first-line regimen utilization and the FUMP within 1.5 years were analyzed with respect to national evidence-based guideline adherence. Costs for commonly administered regimens based on 2010 Medicare reimbursement were compared. A total of 3505 patient treatment regimens were included in this study. Rates of guideline adherence were 75.0% and 61.3% for the first-line and the adjuvant treatment groups, respectively (P < .0001). Treatment with guidelinebased regimens correlated with a significantly longer FUMP in the first-line treatment groupcompared with non-guideline-based regimens (P = .005). Regimen costs for the top 11 regimens in the adjuvant and first-line treatment settings varied greatly. Low-cost regimens were prescribed more commonly. Rates of guideline adherence were significantly higher in the first-line than in the adjuvant NSCLC treatment group. First-line treatment with guideline-based regimens correlated with an extended FUMP for advanced NSCLC patients.	\N	\N
23544828	Osteoporosis is a systemic disease that affects millions of people worldwide. It is estimated that 50% of women and approximately 20% of men more than 50 years of age will sustain a fragility fracture. The cause of nonunion in patients with osteoporosis is likely multifactorial, and includes age-related changes in fracture repair as well as challenges in achieving stable internal fixation. This article discusses fracture healing in patients with osteoporosis and the principles of fixation. Pharmacotherapy for the patient with osteoporosis is also discussed.	\N	\N
23547660	Tiotropium bromide is an effective therapy for COPD patients. Comparing across programs tiotropium Respimat Soft Mist inhaler was at least as efficacious as tiotropium HandiHaler, however, concerns have been raised about tiotropium's safety when given via Respimat. The TIOSPIR trial (NCT01126437) compares the safety and efficacy of tiotropium Respimat 5 μg once daily (marketed) and 2.5 μg once daily (investigational) with tiotropium HandiHaler 18 μ once daily (marketed). The hypotheses to be tested are 1). that tiotropium Respimat 5 μg once daily and Respimat 2.5 μg once daily are non-inferior to HandiHaler in terms of all-cause mortality, and 2). that tiotropium Respimat 5 μg once daily is superior to HandiHaler in terms of time to first exacerbation. A spirometry substudy evaluates the bronchodilator efficacy. The trial is a randomized, double-blind, double dummy, event-driven, parallel group study. Participants can use any background treatment for COPD except inhaled anticholinergic agents. The study encompasses a wide range of COPD patients, e.g. patients with stable cardiac diseases including arrhythmia can be included. Clinical sites are international and include both primary care as well as specialists. To date, over 17,000 participants have been randomized from over 1200 sites in 50 countries with an anticipated treatment duration of 2-3 years. TIOSPIR will provide precise estimates of the relative safety and efficacy of the Respimat and HandiHaler formulations of tiotropium, assess potential dose-dependence of important outcomes and provide information on the clinical epidemiology of COPD in a large international patient cohort.	\N	\N
23549020	Metastatic prostate carcinoma commonly involves bones and extrapelvic lymph nodes, with occasional visceral deposits. Central nervous system involvement is unusual and particularly the occurrence of leptomeningeal metastasis (LM) is extremely rare, with few cases described in the medical literature. The clinical presentation is characterized by multifocal neurological deficit and the prognosis is generally dismal, with survival ranging between 3 and 6 months. We report on a patient affected by LM due to prostate cancer who was treated with a combined-modality approach consisting of sequential chemotherapy and radiotherapy. A 70-year-old man was referred to our group for cognitive mental disorder, left-sided frontal headache and nausea; the patient had a previous history of metastatic prostate cancer. LM was diagnosed neuroradiologically with brain MRI and evidence of a detectable level of PSA in the cerebrospinal fluid. He was treated with docetaxel and prednisone for 3 cycles followed by external beam radiotherapy (EBRT) to the whole brain to a total dose of 30 Gy in 10 fractions with a simultaneous integrated boost to the macroscopic disease (total dose of 35 Gy in 10 fractions). No acute toxicity was observed. A substantial clinical response was obtained after EBRT with neurological improvement and radiologically stable disease at post-treatment imaging until 10 weeks after radiation. The patient died of sudden general condition deterioration 3 months after EBRT. Since LM derived from prostate cancer is likely to become a more common clinical event, such patients would need to be included in clinical trials evaluating new therapeutic approaches, considering that the current treatment strategies have been shown to be rather ineffective.	\N	\N
23549631	The prognosis of thrombotic thrombocytopenic purpura (TTP) has considerably improved since the introduction of plasma exchange (PEX) therapy. However, unresponsive thrombotic thrombocytopenic purpura (Un-TTP) still carries high morbidity and mortality rates, indicating a need for early specific treatments. In a retrospective study including consecutive adults with TTP admitted between January 1997 and January 2011 in a teaching hospital intensive care unit (ICU), our objective here is to identify early clinical and laboratory features predicting Un-TTP. Patients who responded to plasma exchange and steroids (N = 49) were compared with patients with unresponsive TTP defined as requirement for other treatments, protracted course, or death (N = 37, 43 %). Hospital mortality was 24.3 % in the Un-TTP group. Variables associated with Un-TTP on univariate logistic regression were older age, cardiac involvement, neurological involvement, higher anti-a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS13) immunoglobulin G (IgG) titer, lower platelet counts starting on day 2, higher Sequential Organ Failure Assessment (SOFA) scores starting on day 3, need for higher plasma volumes to obtain remission, and greater use of adjuvant treatments and life-sustaining interventions. Multivariate logistic regression identified four factors independently associated with Un-TTP: age over 60 years [odds ratio (OR) 7.90; 95 % confidence interval (95 % CI) 1.06-78.34], cardiac (OR 5.17; 95 % CI 1.63-16.39) or neurological (OR 8.04; 95 % CI 1.27-51.03) manifestations at diagnosis, and day 2 platelet count less than 15 G/l (OR 3.88; 95 % CI 1.30-11.62). Therapeutic intensification starting on day 3 or even earlier in patients with the independent risk factors for unresponsive TTP identified in our study deserves evaluation in a multicenter prospective study.	\N	\N
23554958	Intracranial Artery Stenosis (ICAS) is one of the most common causes of ischemic stroke in Asia. Previous studies have shown the number of ideal cardiovascular health (CVH) metrics was associated with lower risk of stroke. This study aimed to investigate the relationship between ideal CVH metrics and prevalence of ICAS. A random sample of 5,412 participants (selected from Kailuan Study as a reference population) aged 40 years or older (40.10% women), free of stroke, transient ischemic attack, and coronary disease, were enrolled in the Asymptomatic Polyvascular Abnormalities Community study from 2010 to 2011. We collected information on the seven CVH metrics (including smoking, body mass index, dietary intake, physical activity, blood pressure, total cholesterol and fasting blood glucose); and assessed ICAS by transcranial Doppler. The relationship between the ideal CVH metrics and prevalence of ICAS was analyzed using the multivariate logistic regression. After adjusting for age, sex, and other potential confounders, the adjusted odds ratios(95% confidence interval) for ICAS were 0.76(0.58-0.99), 0.55(0.43-0.72), 0.49(0.37-0.65), 0.43(0.31-0.61), and 0.36(0.22-0.62), respectively, for those having 2, 3, 4, 5, and 6-7 ideal CVH metrics compared with those having 0-1 ideal metric(p-trend<0.0001). Similar inverse associations were observed in different age and gender groups (all p-trends<0.05). We found a clear gradient relationship between the number of ideal CVH metrics and lower prevalence of ICAS in a Chinese population, which supports the importance of ideal health behaviors and factors in the prevention of ICAS.	\N	\N
23557197	Human leukocyte antigen matching at allelic resolution is proven clinically significant in hematopoietic stem cell transplantation, lowering the risk of graft-versus-host disease and mortality. However, due to the ever growing HLA allele database, tissue typing laboratories face substantial challenges. In light of the complexity and the high degree of allelic diversity, it has become increasingly difficult to define the classical transplantation antigens at high-resolution by using well-tried methods. Thus, next-generation sequencing is entering into diagnostic laboratories at the perfect time and serving as a promising tool to overcome intrinsic HLA typing problems. Therefore, we have developed and validated a scalable automated HLA class I and class II typing approach suitable for diagnostic use. A validation panel of 173 clinical and proficiency testing samples was analysed, demonstrating 100% concordance to the reference method. From a total of 1,273 loci we were able to generate 1,241 (97.3%) initial successful typings. The mean ambiguity reduction for the analysed loci was 93.5%. Allele assignment including intronic sequences showed an improved resolution (99.2%) of non-expressed HLA alleles. We provide a powerful HLA typing protocol offering a short turnaround time of only two days, a fully integrated workflow and most importantly a high degree of typing reliability. The presented automated assay is flexible and can be scaled by specific primer compilations and the use of different 454 sequencing systems. The workflow was successfully validated according to the policies of the European Federation for Immunogenetics. Next-generation sequencing seems to become one of the new methods in the field of Histocompatibility.	\N	\N
23557266	Adhesion molecules play a key role in the pathogenetic mechanisms of inflammatory bowel disease (IBD), both in Crohn's disease (CD) and ulcerative colitis (UC). In the last decade, some progress has been made in understanding their key role in leukocyte trafficking control in terms of basic research, but evidence of clinical efficacy is lacking. In the last 2 years, new molecules directed against integrins and integrin receptors have been developed and investigated in clinical trials, showing that anti-α4β7 integrin agents can be effective and safe for the induction and maintenance of remission in active CD and UC. Preliminary data show that anti-MAdCAM, anti-β7 and anti-integrin receptor agents are not all effective in IBD. Such results open new perspectives on clinical management of IBD, and new directions in understanding the role of adhesion molecules and leukocyte recruitment both in CD and UC.	\N	\N
23578358	Angiogenic stimulation is a promising new strategy for treating patients with arteriosclerotic coronary artery disease. This strategy aims to ameliorate cardiac function by improving myocardial perfusion and lowering the risk of myocardial infarction. However, angiogenesis may contribute to the growth of atherosclerotic lesions. Atherogenesis is also a potential side effect of angiogenic therapy. Early clinical trials were performed using fibroblast growth factor 2 (FGF2) protein, which enhances the formation of new collateral vessels to reduce ischaemic symptoms. Conversely, angiogenic stimulation by FGF2 is a dilemma because it could cause negative angiogenic effects, such as atherosclerosis. Thus far, clinical trials in patients with recombinant FGF2 protein therapy have not yet yielded undisputable beneficial effects. Future trials should determine whether an improvement can be obtained in patients with coronary artery disease using a combination of FGF2 and other growth factors or a combination of the FGF2 gene and stem cell therapy. This review summarises the multiple roles of FGF2 in the progression of atherosclerosis, its effect on pro-angiogenesis and improvement of cardiac function in coronary artery disease, and the potentially unfavourable effect of angiogenesis on the prevention and treatment of atherogenesis.	\N	\N
23581956	To review cases of nosocomial influenza and compare the epidemiology, clinical characteristics and outcomes with community-acquired cases. Prospective case series of adults hospitalised with influenza during April - November of 2010 and 2011 using a hospital-based sentinel surveillance system. A nosocomial case was defined as polymerase chain reaction-confirmed influenza where symptom onset was more than 2 15s after admission or, if this was not known, where the date of the positive test was more than 7 15s after admission. Demographic, clinical and outcome measures for patients with nosocomial influenza compared with patients admitted with community-acquired influenza. In 2010-2011, 598 cases of influenza were detected, of which 26 (4.3%) were nosocomial. All patients with nosocomial influenza had chronic comorbidities, compared with 71.7% of patients (410/572) with community-acquired influenza (P = 0.001). Similar proportions of community-acquired (32.5%) and nosocomial (36.4%) cases occurred in patients vaccinated in the current season. Clinical findings at time of enrollment did not differ between the two groups, with similar rates of fever, cough, chest pain and dyspnoea. Compared with community-acquired cases, a higher proportion of patients with nosocomial influenza received neuraminidase inhibitors within 2 15s of symptom onset (38.5% v 15.9%; P = 0.003). Admission to intensive care took place in 21.3% and 23.1% of community-acquired and nosocomial cases, respectively. One death from nosocomial influenza occurred in a patient with end-stage respiratory disease. Nosocomial influenza is uncommon but may be associated with severe disease. It may be partially preventable as patients frequently have comorbidities for which influenza vaccination is recommended. Patients, particularly those at high risk of complications, and their contacts (including health care workers) should be vaccinated to prevent severe disease.	\N	\N
23591331	Self-expandable metal stents (SEMSs) are used to relieve malignant biliary obstruction. To compare outcomes between covered self-expandable metal stents (CSEMSs) and uncovered self-expandable metal stents (USEMSs) in malignant biliary obstruction. Retrospective cohort study. Tertiary cancer center. Patients with malignant biliary obstruction. Placement of CSEMS or USEMS. Time to recurrent biliary obstruction (TRO), overall survival (OS), and adverse events. From January 2000 to June 2011, 749 patients received SEMSs: 171 CSEMSs and 578 USEMSs. At 1 year, there was no significant difference in the percentage of patients with recurrent obstruction (CSEMSs, 35% vs USEMSs, 38%) and survival (CSEMSs, 45% vs USEMSs, 49%). There was no significant difference in the median OS (CSEMSs, 10.4 months vs USEMSs, 11.8 months; P = .84) and the median TRO (CSEMSs, 15.4 months vs USEMSs, 26.3 months; P = .61). The adverse event rate was 27.5% for the CSEMS group and 27.7% for the USEMS group. Although tumor ingrowth with recurrent obstruction was more common in the USEMS group (76% vs 9%, P < .001), stent migration (36% vs 2%, P < .001) and acute pancreatitis (6% vs 1%, P < .001) were more common in the CSEMS group. Retrospective study. There was no significant difference in the patency rate or overall survival between CSEMSs and USEMSs for malignant distal biliary strictures. The CSEMS group had a significantly higher rate of migration and pancreatitis than the USEMS group. No significant SEMS-related adverse events were observed in patients undergoing neoadjuvant chemoradiation or surgical resection.	\N	\N
23594492	To detect fully penetrant rare recessive variants that could constitute Mendelian subentities of complex diseases, we propose a novel strategy, the HBD-GWAS strategy, which can be applied to genome-wide association study (GWAS) data. This strategy first involves the identification of inbred individuals among cases using the genome-wide SNP data and then focuses on these inbred affected individuals and searches for genomic regions of shared homozygosity by descent that could harbor rare recessive disease-causing variants. In this second step, analogous to homozygosity mapping, a heterogeneity lod-score, HFLOD, is computed to quantify the evidence of linkage provided by the data. In this paper, we evaluate this strategy theoretically under different scenarios and compare its performances with those of linkage analysis using affected sib-pair (ASP) data. If cases affected by these Mendelian subentities are not enriched in the sample of cases, the HBD-GWAS strategy has almost no power to detect them, unless they explain an important part of the disease prevalence. The HBD-GWAS strategy outperforms the ASP linkage strategy only in a very limited number of situations where there exists a strong allelic heterogeneity. When several rare recessive variants within the same gene are involved, the ASP design indeed often fails to detect the gene, whereas, by focusing on inbred individuals using the HBD-GWAS strategy, the gene might be detected provided very large samples of cases are available.	\N	\N
23594728	The presence of baseline proteinuria predicts the outcome in patients with chronic kidney disease and in the general population, independent of renal function. However, the predictive value of proteinuria during an episode of acute illness has not been reported yet. Therefore, we investigated the incidence and predictive value of proteinuria in patients with community-acquired pneumonia. An analysis of prospectively collected data, obtained from patients >18 years of age, was performed. Patients were hospitalized with community-acquired pneumonia in two hospitals in the Netherlands and participated in two consecutive clinical trials. A total protein/creatinine (P/C) ratio was measured in a urine sample from the day of admission. Patients were categorized in quartiles of P/C ratio. Primary outcome was length of hospital stay. 198/319 patients (62%) had a P/C ratio >23 mg/mmol creatinine. In multivariate analysis, proteinuria turned out to be an independent predictor for length of stay and admission to the intensive care unit. The incidence of proteinuria during pneumonia is high and proteinuria is an independent predictor for length of hospital stay and admission to the intensive care unit. Proteinuria is a cheap and easily accessible marker for outcome and might be used to assess the severity of pneumonia.	\N	\N
23602249	Obesity is associated with elevated risk of heart disease. A solid understanding of the safety and potential adverse effects of high-fat, low-carbohydrate diet (HFLCD) similar to that used by humans for weight loss on the heart is crucial. High fat intake is known to promote increases in reactive oxygen species and mitochondrial damage. We hypothesized that there would be adverse effects of HFLCD on myocardial ischemia/reperfusion injury through enhancing oxidative stress injury and impairing mitochondrial biogenesis in a nongenetic, diet-induced rat model of obesity. To test the hypothesis, 250-g male Sprague-Dawley rats were fed an obesity-promoting diet for 7 weeks to induce obesity, then switched to HFLCD or a low-fat control diet for 2 weeks. Isolated hearts underwent global low flow ischemia for 60 minutes and reperfusion for 60 minutes. High-fat, low-carbohydrate diet resulted in greater weight gain and lower myocardial glycogen, plasma adiponectin, and insulin. Myocardial antioxidant gene transcript and protein expression of superoxide dismutase and catalase were reduced in HFLCD, along with increased oxidative gene NADPH oxidase-4 transcript and xanthine oxidase activity, and a 37% increase in nitrated protein (nitrotyrosine) in HFLCD hearts. The cardiac expression of key mitochondrial regulatory factors such as nuclear respiratory factor-1 and transcription factor A-mitochondrial were inhibited and myocardial mitochondrial DNA copy number decreased. The cardiac expression of adiponectin and its receptors was down-regulated in HFLCD. High-fat, low-carbohydrate diet impaired recovery of left ventricular rate-pressure product after ischemia/reperfusion and led to 3.5-fold increased injury as measured by lactate dehydrogenase release. In conclusion, HFLCD leads to increased ischemic myocardial injury and impaired recovery of function after reperfusion and was associated with attenuation of mitochondrial biogenesis and enhanced oxidative stress in obese rats. These findings may have important implications for diet selection in obese patients with ischemic heart disease.	\N	\N
23607333	Genetic polymorphism studies of cytokines may provide an insight into the understanding of acute kidney injury (AKI) and death in intensive care unit (ICU) patients. The aim of this study was to investigate whether the genetic polymorphisms of -308 G < A tumour necrosis factor (TNF)-α, -174 G > C interleukin (IL)-6 and -1082 G > A IL-10 may predispose ICU patients to the development of AKI and/or death. In a prospective nested case-control study, 303 ICU patients and 244 healthy individuals were evaluated. The study group included ICU patients who developed AKI (n = 139) and 164 ICU patients without AKI. The GG genotype of TNF-α (low producer phenotype) was significantly lower in the with AKI than without AKI groups and healthy individuals (55 versus 62 versus 73%, respectively; P = 0·01). When genotypes were stratified into four categories of TNF-α/IL-10 combinations, it was observed that low TNF-α plus low IL-10 producer phenotypes were more prevalent in patients with AKI, renal replacement therapy and death (P < 0·05). In logistic regression analysis, low TNF-α producer plus low IL-10 producer phenotypes remained as independent risk factors for AKI and/or death [odds ratio (OR) = 2·37, 95% confidence interval (CI): 1·16-4·84; P = 0·02] and for renal replacement therapy (RRT) and/or death (OR = 3·82, 95% CI: 1·19-12·23; P = 0·02). In this study, the combination of low TNF-α plus low IL-10 producer phenotypes was an independent risk factor to AKI and/or death and RRT and/or death in critically ill patients. Our results should be validated in a larger prospective study with long-term follow-up to emphasize the combination of these genotypes as potential risk factors to AKI in critically ill patients.	\N	\N
23613224	High-intensity interval training (HIT) as exercise therapy is gradually implemented in cardiac rehabilitation as the cardiovascular benefits from exercise is intensity dependent. However, in previous studies, HIT has been performed with strict supervision. The aim of the study was to assess the feasibility and effectiveness of different modes of HIT in cardiac rehabilitation. a randomized clinical study. Ninety participants with coronary artery disease (80 men/10 women, mean age 57 ± 8 years) were randomly assigned to one of three exercise modes: group exercise (GE), treadmill exercise (TE), or home-based exercise (HE). HIT was performed twice a week for 12 weeks with an exercise intensity of 85-95% of peak heart rate. The primary outcome measure was change in peak oxygen uptake (peak VO2). Eighty-three participants (92%) completed the intervention without any severe adverse events. Peak VO2 increased from 34.7 ± 7.3 to 39.0 ± 8.0 ml/kg/min, 32.7 ± 6.5 to 36.0 ± 6.2 ml/kg/min, and 34.4 ± 4.8 to 37.2 ± 5.2 ml/kg/min in TE, GE, and HE, respectively. Mean group difference for TE vs. HE was 1.6 ml/kg/min (95% confidence interval, CI, 0.7 to 3.1, p = 0.02), TE vs. GE 1.1 ml/kg/min (95% CI-0.5 to 2.5, p = 0.27), and GE vs. HE 0.6 ml/kg/min (95% CI -1.0 to 2.1, p = 1). However, on-treatment analysis showed no significant difference between groups. HIT was efficiently performed in three settings of cardiac rehabilitation, with respect to target exercise intensity, exercise attendance, and increase in peak VO2. Exercise mode was not essential for exercise capacity.	\N	\N
23613636	To investigate the significance of Twist2 for colorectal cancer (CRC). In this study, 93 CRC patients were included who received curative surgery in Eastern Hepatobiliary Surgery Hospital from January 1999 to December 2010. Records of patients' clinicopathological characteristics and follow up data were reviewed. Formalin-fixed, paraffin-embedded tissue blocks were used to observe the protein expression of Twist2 and E-cadherin by immunohistochemistry. Two independent pathologists who were blinded to the clinical information performed semiquantitative scoring of immunostaining. A total score of 3-6 (sum of extent + intensity) was considered as Twist2-positive expression. The expression of E-cadherin was divided into two levels (preserved and reduced). An exploratory statistical analysis was conducted to determine the association between Twist2 expression and clinicopathological parameters, as well as E-cadherin expression. Furthermore, the variables associated with prognosis were analyzed by Cox's proportional hazards model. Kaplan-Meier analysis was used to plot survival curves according to different expression levels of Twist2. Twist2-positive expression was observed in 66 (71.0%) samples and mainly located in the cytoplasm. Forty-three (46.2%) samples showed reduced expression of E-cadherin. There were no significant correlations between Twist2 expression and any of the clinicopathological parameters. However, Twist2-positive expression was significantly associated with reduced expression of E-cadherin (P = 0.040). Multivariate analysis revealed that bad M-stage [hazard ratio (HR) = 7.694, 95%CI: 2.927-20.224, P < 0.001] and Twist2-positive (HR = 5.744, 95%CI: 1.347-24.298, P = 0.018) were the independent risk factors for poor overall survival (OS), while Twist2-positive (HR = 3.264, 95%CI: 1.455-7.375, P = 0.004), bad N-stage (HR = 2.149, 95%CI: 1.226-3.767, P = 0.008) and bad M-stage (HR = 10.907, 95%CI: 4.937-24.096, P < 0.001) were independently associated with poor disease-free survival (DFS). Survival curves showed a definite trend for Twist2-negative patients to have longer OS and DFS than Twist2-negative patients, not only overall, but also for patients in different stages, especially for DFS of patients in stage III (P = 0.033) and IV (P = 0.026). Our data suggests, for the first time, that Twist2 is a valuable prognostic biomarker for CRC, particularly for patients in stage III and IV.	\N	\N
23617953	By definition, a generic product is considered interchangeable with the innovator brand product. Controversy exists about interchangeability, and attention is predominantly directed to contaminants. In particular for chronic, degenerative conditions such as in Parkinson's disease (PD) generic substitution remains debated among physicians, patients and pharmacists. The objective of this study was to compare the pharmaceutical quality of seven generic levodopa/benserazide hydrochloride combination products marketed in Germany with the original product (Madopar® / Prolopa® 125, Roche, Switzerland) in order to evaluate the potential impact of Madopar® generics versus branded products for PD patients and clinicians. Madopar® / Prolopa® 125 tablets and capsules were used as reference material. The generic products tested (all 100 mg/25 mg formulations) included four tablet and three capsule formulations. Colour, appearance of powder (capsules), disintegration and dissolution, mass of tablets and fill mass of capsules, content, identity and amounts of impurities were assessed along with standard physical and chemical laboratory tests developed and routinely practiced at Roche facilities. Results were compared to the original "shelf-life" specifications in use by Roche. Each of the seven generic products had one or two parameters outside the specifications. Deviations for the active ingredients ranged from +8.4% (benserazide) to -7.6% (levodopa) in two tablet formulations. Degradation products were measured in marked excess (+26.5%) in one capsule formulation. Disintegration time and dissolution for levodopa and benserazide hydrochloride at 30 min were within specifications for all seven generic samples analysed, however with some outliers. Deviations for the active ingredients may go unnoticed by a new user of the generic product, but may entail clinical consequences when switching from original to generic during a long-term therapy. Degradation products may pose a safety concern. Our results should prompt caution when prescribing a generic of Madopar®/Prolopa®, and also invite to further investigations in view of a more comprehensive approach, both pharmaceutical and clinical.	\N	\N
23620363	The number of missense mutations being identified in cancer genomes has greatly increased as a consequence of technological advances and the reduced cost of whole-genome/whole-exome sequencing methods. However, a high proportion of the amino acid substitutions detected in cancer genomes have little or no effect on tumour progression (passenger mutations). Therefore, accurate automated methods capable of discriminating between driver (cancer-promoting) and passenger mutations are becoming increasingly important. In our previous work, we developed the Functional Analysis through Hidden Markov Models (FATHMM) software and, using a model weighted for inherited disease mutations, observed improved performances over alternative computational prediction algorithms. Here, we describe an adaptation of our original algorithm that incorporates a cancer-specific model to potentiate the functional analysis of driver mutations. The performance of our algorithm was evaluated using two separate benchmarks. In our analysis, we observed improved performances when distinguishing between driver mutations and other germ line variants (both disease-causing and putatively neutral mutations). In addition, when discriminating between somatic driver and passenger mutations, we observed performances comparable with the leading computational prediction algorithms: SPF-Cancer and TransFIC. A web-based implementation of our cancer-specific model, including a downloadable stand-alone package, is available at http://fathmm.biocompute.org.uk.	\N	\N
23620431	To report the findings of en face adaptive optics (AO) near infrared (NIR) reflectance fundus flood imaging in eyes with geographic atrophy (GA). Observational clinical study of AO NIR fundus imaging was performed in 12 eyes of nine patients with GA, and in seven controls using a flood illumination camera operating at 840 nm, in addition to routine clinical examination. To document short term and midterm changes, AO imaging sessions were repeated in four patients (mean interval between sessions 21 days; median follow up 6 months). As compared with scanning laser ophthalmoscope imaging, AO NIR imaging improved the resolution of the changes affecting the RPE. Multiple hyporeflective clumps were seen within and around GA areas. Time-lapse imaging revealed micrometric-scale details of the emergence and progression of areas of atrophy as well as the complex kinetics of some hyporeflective clumps. Such dynamic changes were observed within as well as outside atrophic areas. in eyes affected by GA, AO nir imaging allows high resolution documentation of the extent of RPE damage. this also revealed that a complex, dynamic process of redistribution of hyporeflective clumps throughout the posterior pole precedes and accompanies the emergence and progression of atrophy. therefore, these clumps are probably also a biomarker of rpe damage. AO NIR imaging may, therefore, be of interest to detect the earliest stages, to document the retinal pathology and to monitor the progression oF GA. (ClinicalTrials.gov number, NCT01546181.).	\N	\N
23625177	Expression and function of the immunoregulatory molecule HLA-E was investigated in patients with relapsing-remitting (RR) multiple sclerosis (MS). Serum and cerebrospinal fluid (CSF) soluble (s)HLA-E and -G levels were measured by ELISA in 80 RRMS patients. Controls were patients with other inflammatory neurological disorders (OIND, n = 81) and noninflammatory neurological disorders (NIND, n = 86). Serum sHLA-E concentrations were higher in RRMS than in NIND patients only. CSF sHLA-E concentrations were higher in RRMS than controls. Increased CSF sHLA-E levels were detected in MRI inactive and clinically stable RRMS patients. sHLA-E intrathecal synthesis (ITS) was higher in RRMS than controls, and the number of patients with sHLA-E ITS above cut-off was higher i) in MS than controls, and ii) in clinically stable than clinically active MS patients. sHLA-E CSF levels and ITS correlated with i) the same sHLA-G parameters, and ii) disease duration. HLA-E expression and co-expression with CD markers were investigated in MS plaques from three different cases by immunohistochemistry and confocal microscopy, respectively. Infiltrating T lymphocytes and macrophages, as well as resident microglial cells and astrocytes expressed HLA-E. CSF samples from MS patients were finally tested for inhibitory activity of in vitro CTL and NK cell mediated cytotoxicity. sHLA-E⁺ were more effective than sHLA-E⁻ CSF samples in such inhibition. Maximum inhibition was achieved with sHLA-E⁺/sHLA-G⁺ CSF samples In conclusion, increased sHLA-E CSF levels may play an immunomodulatory role in MS, contributing to the inhibition of intrathecal inflammatory response. The potential of sHLA-E as biomarker of MS activity warrants further investigation.	\N	\N
23628099	The apex is a particular region of the prostate in its surgical dissection and pathological analysis. We sought to evaluate the prognostic value of the apical localization of prostate tumors. From 1988 to 2010, data pre- (age, clinical stage, preoperative PSA, biopsy Gleason score) and postoperative (prostate weight, pathologic stage TNM 2010, Gleason score, margin status) of 2765 total prostatectomies were collected prospectively. These data were compared according to existence or absence of tumor at the apex. The prognostic impact of tumor at the apex on biochemical recurrence-free survival (PSA>0.2 ng/mL) has been studied in univariate and multivariate models. One thousand eight hundred seventeen tumors had a location at the apex (65.7%). In univariate analysis, there was a significant difference in the clinical stage, the biopsy and pathological Gleason score, the result of curage, the pathological stage and the margin status between apical tumors and others. With a mean decline of 34.6 months, 502 patients had a biochemical recurrence (18.1%). Disease-free survival at 10 years was 60.7% for tumor at the apex versus 65.9% in other cases. The location at the apex was significantly associated with biochemical recurrence on univariate analysis (P=0.01). After adjustment for clinical and pathological stage, PSA level, Gleason score and surgical margins, the apex was not anymore a pejorative independent predictor (P=0.0087). The existence of tumor in the prostatic apex was associated with more aggressive tumoral criteria and was an independent and pejorative predictor of biochemical recurrence-free survival at 10 years in univariate analysis. The apical localization could be an additional argument in the decision of adjuvant therapy after prostatectomy.	\N	\N
23638302	Immune cells called mast cells can hinder rather than help the body's response to dengue virus, which suggests that mast cell products could be used as biomarkers to identify severe forms of the disease.	\N	\N
23644526	Vertebral metastases affect 20 to 50% of cancer patients and represent a major turning point in the disease from the functional impact they generate. Early treatment is mandatory to prevent or treat any neurological compression. Due to the high variability of clinical and radiological presentations, best care requires a multidisciplinary team, involving oncologists, radiation oncologists, interventional radiologists and spine surgeons. Recent advances in radiotherapy and interventional radiology have offered various efficient therapeutic solutions with relatively low morbidity rate in the management of symptomatic spine metastases. However, surgery remains the standard treatment for patients with rapidly progressive spinal cord compression or significant osteolytic lesion leading to a high risk of fracture. However, conventional surgical strategies are associated with significant morbidity and contraindicated in patients in poor general condition. In addition, postoperative complications are likely to affect patient's quality of life and delay the initiation of anticancer therapies. In order to reduce iatrogenic lesions, new "minimally invasive" techniques were developed to achieve immediate stabilisation and decompression while reducing the morbidity of the approach. We aim to inform the reader of the existence of these techniques so that each patient can benefit from treatment best suited to their situation.	\N	\N
23645623	Weight gain increases the prevalence of obesity, a risk factor for cardiovascular disease. Nevertheless, unintentional weight loss can be a harbinger of health problems. The Atherosclerosis Risk in Communities Study (1987-2009) included 15,792 US adults aged 45-64 years at baseline and was used to compare associations of long-term (30 years) and short-term (3 years) weight change with the risks of coronary heart disease (CHD) and ischemic stroke. Age-, gender-, and race-standardized incidence rates were 4.9 (95% confidence interval (CI): 4.6, 5.2) per 1,000 person-years for CHD and 2.5 (95% CI: 2.3, 2.8) per 1,000 person-years for stroke. After controlling for baseline body mass index and other covariates, long-term weight gain (since age 25 years) of more than 2.7% was associated with elevated CHD risk, and any long-term weight gain was associated with increased stroke risk. Among middle-aged adults, short-term (3-year) weight loss of more than 3% was associated with elevated immediate CHD risk (hazard ratio = 1.46, 95% CI: 1.18, 1.81) and stroke risk (hazard ratio = 1.45, 95% CI: 1.10, 1.92). Risk tended to be larger in adults whose weight loss did not occur through dieting. Avoidance of weight gain between early and middle adulthood can reduce risks of CHD and stroke, but short-term, unintentional weight loss in middle adulthood may be an indicator of immediate elevated risk that has not previously been well recognized.	\N	\N
23649916	CD146 is an adhesion molecule localized at endothelial cell junctions and facilitates cell-cell interactions. The circulating soluble form (sCD146) lacks both the intracellular and the transmembrane domains. In this study we show that CD146 expression was significantly decreased in the lung tissue of smokers with chronic obstructive pulmonary disease (COPD) and also in rats exposed to second-hand smoke (SHS). Concurrently, levels of sCD146 were increased in both the plasma and bronchoalveolar lavage fluid (BALF) of COPD patients as well as in BALF from rats exposed to SHS. Decreased or abolished CD146 protein expression in rat pulmonary micro- and macrovascular endothelial cells was found after treatment with cigarette smoke extract (CSE), proinflammatory cytokine interleukin 18 (IL-18) or after silencing CD146 expression with siRNA. The decrease in CD146 protein was accompanied by increased endothelial monolayer permeability and enhanced macrophage infiltration in vitro. In CD146 knockout (KO) mice, distinct perivascular oedema was seen and increased numbers of inflammatory cells, along with increased protein levels in BALF. Increased sCD146 was found in BALF and plasma from patients with COPD. The circulating plasma levels of sCD146 correlated positively with the presence of anti-endothelial cell antibodies (AECAs). sCD146 in combination with AECAs may be useful markers for early detection of COPD. Our study indicates that loss of CD146 function damages pulmonary endothelial integrity. This damage may represent part of the pathophysiological processes that are involved in the basic aetiology of COPD/emphysema.	\N	\N
23653428	Colistin is increasingly used as the last-resort treatment option against infections caused by multidrug-resistant (MDR) Gram-negative pathogens, but its nephrotoxicity is of concern, especially in severely ill patients. The aim of this study was to analyze the toxicity of colistin therapy in adults and children with hematological malignancies (HM) and hematopoietic stem cell transplantation (HSCT) recipients. Data on HSCT recipients and HM patients, treated with intravenous colistin (2.5-5 mg/kg/day in children and 3-6 million international units (IU) in adults, adjusted to renal function) during the period 2008-2011 in our center, were retrospectively collected and analyzed. Nephrotoxicity was defined according to the RIFLE criteria (Risk, Injury, Failure, Loss, and End-stage kidney disease). Twenty-nine children and adults received 38 courses of intravenous colistin (2.5-5 mg/kg/day in children and 3-6 × 10(6) IU in adults, adjusted to renal function) [allogeneic HSCT (22 courses) and HM (16 courses)] for 3-28 days (median 10 days) for empirical therapy for nosocomial clinical sepsis (28) or local infection (6), and bacteremia with MDR Gram-negative rods (4). Nephrotoxicity was observed at the end of 4 (10.5%) courses. In 32 (84%) courses, nephrotoxic medications were concomitantly administered. Two patients had convulsions, probably unrelated to colistin. Seven patients (18%) died while on colistin therapy. No death was attributed to an adverse effect of colistin. Treatment with intravenous colistin, with dosage adjusted to renal function, was relatively safe for HM/HSCT patients, even with concomitantly administered nephrotoxic medications. Concern about nephrotoxicity should not justify a delay in initiating empirical colistin treatment in situations where infection with MDR Gram-negative rods is likely.	\N	\N
23658247	The implementation of national estimated glomerular filatration rate reporting and the inclusion of renal-specific indicators in a primary care pay for performance (P4P) system since April 2006 has promoted identification and better management of risk factors related to chronic kidney disease (CKD). In the UK, the P4P framework is known as the Quality and Outcomes Framework (QOF). One of the key targets for intervention in primary care was hypertension. It is clear that hypertension is a major predictor of development and progression of CKD; thus, targeting better blood pressure control is likely to have a positive impact on outcomes in CKD. The aim of this study was to evaluate the effectiveness of renal indicators outlined in P4P on the management of hypertension in primary care. To estimate the cost implications of the resulting changes in prescribing patterns of antihypertensive medication following introduction of such indicators. We performed a prospective cohort study using a large primary care database. This cohort was taken from a database collated as part of a clinical decision support system used to assist the management of CKD in primary care. We investigated a total population of 90 250 individuals on general practitioner (GP) registers with a valid serum creatinine estimation in the 6-year study period. A total of 10 040 patients had confirmed stage 3-5 CKD in the 2 years pre-QOF and formed the study cohort. Patients were studied over three time periods, pre-QOF (1 April 2004 to 31 March 2006), 2 years post-QOF (1 April 2006 to 31 March 2008) and finally the two subsequent years (1 April 2008 to 31 March 2010). The mean systolic and diastolic blood pressures (BP) together with antihypertensive medication were analysed over the three time periods. Cost calculation was based on 2009 British National Formulary list prices for antihypertensives. The mean age of the cohort at the start of the study period was 64.8 years, 55% were female. In those patients with stage 3-5 CKD 83.9% were hypertensive, defined by a pre-P4P BP of >140/85 or currently taking antihypertensive medication. The proportion of patients with CKD 3-5 attaining the BP target of 145/80 increased from 41.5% in the pre-QOF period to 50.0% in the post-QOF period. This increase was even more marked for those with hypertension in the pre-QOF period (28.8-45.1%). In the hypertensive patients, mean BP fell from 146/79 mmHg to 140/76 in the first 2 years post-P4P [P < 0.01, analysis of variance (ANOVA)]. This BP reduction was sustained in the last 2 years of the study, 139/75 (P < 0.01, ANOVA). The proportion of hypertensive patients taking angiotensin-converting enzyme inhibitors or angiotensin blockers increased, this was also sustained in the third time period. An increase in the prescribing of diuretics, calcium channel blockers and β-blockers was also observed. The additional cost of increased prescribing was calculated to be €25.00 per hypertensive patient based on GP prescription data. Population BP control has improved since the introduction of P4P renal indicators, and this improvement has been sustained. This was associated with a significant increase in the use of antihypertensive medication, resulting in increased prescription cost. Longer-term follow-up will establish whether or not this translates to improved outcomes in terms of progression of CKD, cardiovascular disease and patient mortality.	\N	\N
23662931	An intradural somatic-to-autonomic anastomosis, or Xiao procedure, has been described to create a "skin-CNS-bladder" reflex that improves bladder and bowel function in patients with neurogenic bladder and bowel dysfunction. The authors present their experience with a 10-year-old boy with chronic neurogenic bladder and bowel dysfunction related to spinal cord injury who underwent the Xiao procedure. After undergoing a left L-5 ventral root to left S2-3 intradural anastomosis, the patient reported that his bladder and bowel dysfunction improved between 6 and 12 months. Two years after the procedure, however, he reported that there was no change in his bladder or bowel dysfunction as compared with his condition prior to the procedure. Frequent, systematic multidisciplinary evaluations produced conflicting data. Electrophysiological and histological evaluation of the previously performed anastomosis during surgical reexploration 3 years after the Xiao procedure revealed that the anastomosis was in anatomical continuity but neuroma formation had prevented reinnervation. Nerve action potentials were not demonstrable across the anastomosis, and stimulation of the nerve above and below the anastomosis created no bladder or perineal contractions. This is the first clinical report on the outcome of the Xiao procedure in a child with spinal cord injury outside of China. It is impossible to draw broad conclusions about the efficacy of the procedure based on a single patient with no demonstrable benefit. However, future studies should carefully interpret transient improvements in bladder function, urodynamic findings, and the patient's ability to void in response to scratching after the Xiao procedure. The authors' experience with the featured patient, in whom reinnervation could not be demonstrated, suggests that such changes could be related to factors other than the establishment of a skin-CNS-bladder reflex as a result of a somatic-to-autonomic anastomosis.	\N	\N
23664519	In the field of emerging innovative therapies, such as thrombopoietin mimetics, the question of who needs splenectomy remains highly relevant. Removal of the spleen is an accepted and potentially curative treatment of immune thrombocytopenia (ITP) after decades with a favorable economical-effect ratio but with relevant morbidity particularly in the young patients. ITP is rare and splenectomy is performed in a minority of children, which makes its research almost impossible, resulting in a poor standardization of the procedure. Hence, in children, recommendation and decision for splenectomy is individually based and rests on expert opinions. Furthermore, local practice and availability of health products affect the frequency of splenectomy. Current guidelines agree on one point: splenectomy should be postponed for at least 12 months after the initial diagnosis of ITP, due to the high probability of improvement or even spontaneous remission. However, evidence-based data are lacking and splenectomy remains controversial. This article reviews the current literature and delineates controversies and complexities of splenectomy in children with ITP. There is an urgent need for consensus of this procedure in pediatric patients.	\N	\N
23668671	Recent genome-wide association studies have identified multiple loci associated with BMI or the waist:hip ratio (WHR). However, evidence on gene-lifestyle interactions is still scarce, and investigation of the effects of well-documented dietary and other lifestyle data is warranted to assess whether genetic risk can be modified by lifestyle. We assessed whether previously established BMI and WHR genetic variants associate with obesity and weight change in the Finnish Diabetes Prevention Study, and whether the associations are modified by dietary factors or physical activity. Individuals (n 459) completed a 3 d food record and were genotyped for twenty-six BMI- and fourteen WHR-related variants. The effects of the variants individually and in combination were investigated in relation to obesity and to 1- and 3-year weight change by calculating genetic risk scores (GRS). The GRS were separately calculated for BMI and the WHR by summing the increasing alleles weighted by their published effect sizes. At baseline, the GRS were not associated with total intakes of energy, macronutrients or fibre. The mean 1- and 3-year weight changes were not affected by the BMI or WHR GRS. During the 3-year follow-up, a trend for higher BMI by the GRS was detected especially in those who reported a diet low in fibre (P for interaction=0·065). Based on the present findings, it appears unlikely that obesity-predisposing variants substantially modify the effect of lifestyle modification on the success of weight reduction in the long term. In addition, these findings suggest that the association between the BMI-related genetic variants and obesity could be modulated by the diet.	\N	\N
23669496	We evaluated the prevalence of chronotropic incompetence (CI), a marker of autonomic dysfunction, and its prognostic value in patients with chronic obstructive pulmonary disease (COPD). We performed a retrospective analysis of 449 patients with severe COPD who underwent a cardiopulmonary exercise test, after excluding patients with lung volume reduction surgery, left ventricular dysfunction and those not in sinus rhythm. CI was defined as percent predicted heart rate reserve (%HRR). Events were defined as death or lung transplant during a median follow-up of 68 months. Median age was 61 years; median percent predicted forced expiratory volume in one second (%FEV1) of 25% and median %HRR of 33%. The hazard ratio for an event in the lowest quartile of %HRR, taking the highest quartile as reference, was of 3.2 (95% confidence interval: 2.1-4.8; p<0.001). In a multivariate regression model, %HRR was an independent predictor of events. In conclusion, CI was an independent and powerful outcome predictor in patients with severe COPD.	\N	\N
23669598	Although human papillomavirus (HPV) infections have been causally linked to oral cavity squamous cell carcinoma (OSCC), the potential role of low-risk HPV (LR-HPV) types in the pathogenesis of this malignancy remains unclear. We sought to investigate the distribution of HPV genotypes and their prognostic significance in OSCC patients treated by radical surgery, either with or without adjuvant therapy. We studied two non-overlapping OSCC cohorts for the periods 2005-2006 (2005 cohort, n = 204) and 2010-2011 (2010 cohort, n = 206). Paraffin-embedded tissue blocks were collected, and the HPV genotype was determined using PCR plus HPV blot tests. The primary study endpoint was the prevalence of HPV genotypes. The secondary endpoints were the 2-year therapeutic outcomes. The overall prevalence of HPV infections did not differ significantly in the two study cohorts. However, the prevalence of LR-HPV was significantly higher in the 2010 cohort than in the 2005 cohort (p = 0.002). The overall prevalence of HPV infections was not significantly associated with the 2-year outcomes. However, multivariate analysis demonstrated that LR-HPV infection was a predictor of poor 2-year disease-free survival (p = 0.036, hazard ratio [HR] = 3.1), disease-specific survival (p = 0.014, HR = 3.8), and overall survival (p = 0.016, HR = 3.2) in the subgroups of OSCC patients with poor differentiation, pN2 lymph node metastases, or extracapsular spread (n = 150). LR-HPV infections may have an important role in determining the clinical outcomes of certain OSCC patients bearing specific risk factors.	\N	\N
23670309	It is a matter of debate whether increased brain iron levels are the cause or only the consequence of neurodegenerative process in degenerative parkinsonism. The aim of this study is to characterize disease-related changes in volumes and iron-related R2 values of basal ganglia and thalamus. 13 patients with progressive supranuclear palsy (PSP), 15 with a parkinsonian variant of multiple system atrophy (MSA-p), 29 with Parkinson's disease (PD), and 21 age-matched controls underwent 3-Tesla MRI. The R2 values and volumes were calculated for the selected subcortical structures (caudate nucleus, putamen, globus pallidus, and thalamus) using an automated region-based analysis. Voxel-based analysis was also performed to visualize a topographical correlation of R2 value and volume. The PSP group had significantly higher R2 values in globus pallidus and caudate nucleus (p < 0.05), whereas the MSA-p group had higher R2 values in putamen (p < 0.001) than PD and controls. The globus pallidus in PSP and the putamen in MSA-p were the most significant areas of atrophy to differentiate PSP, MSA-p and PD (AUC = 0.856, 0.832, respectively, p < 0.001). The R2 values in both structures increased in parallel with the extent of atrophy. They were negatively correlated with volumes in putamen (r = -0.777, p < 0.001) and globus pallidus (r = -0.409, p = 0.025) of MSA-p, and globus pallidus (r = -0.4, p = 0.043) of PSP. Voxel-based analysis identified higher R2 values in more severely atrophic sub-regions in these structures. We observed topographical differences of iron deposition as well as atrophy between MSA-p and PSP. Increased iron levels were related to the structural atrophy in basal ganglia. Our results imply that iron accumulation is likely an epiphenomenon of the degenerative process.	\N	\N
23682773	Some studies have shown differences in specific cognitive ability domains between the sexes at 60 years-of-age. However is important to analyze whether the rate of cognitive decline is also similar between the sexes after this age. The present study examined previously published literature to investigate whether cognitive decline is distinct between men and women after the age of 60 years. A systematic review was carried out with the PubMed, LILACS and PsycINFO databases (2001-2011) using the following search terms: aging, aged, cognitive function, mild cognitive impairment, mental health and cognition. We analyzed longitudinal research that used neuropsychological tests for evaluating cognitive function, showed results separated by sex and that excluded participants with dementia. Elderly women showed better performance in tests of episodic memory, whereas elderly men had a better visuospatial ability. Only one study detected distinct rates of cognitive decline in specific tests between the sexes. Despite differences observed in some domains, most of the studies showed that this rate is similar between the sexes until the age of 80 years. It is unclear whether sex influences the rate of cognitive decline after the age of 80 years. The present review observed that sex does not determine the rate of cognitive decline between 60 and 80 years-of-age. The contextual and cultural factors that involve men and women might determine a distinct decline between them, rather than sex alone.	\N	\N
23683938	The serum level of LOX-1 ligand containing ApoB (LAB) may reflect atherogenicity better than LDL cholesterol (LDLC), total LDL particles and usual measurement of oxidized LDL. The association between LAB and intima-media thickness (IMT) of carotid artery was investigated by ultrasound in US and Japan men. Participants were 297 US Caucasian and 310 Japanese men, aged 40-49 years without past history of cardiovascular disease. Serum LAB levels were measured by ELISAs with recombinant LOX-1 and monoclonal anti-apolipoprotein B antibody. Serum LAB levels [median (interquartile range), μg/L] were 1321 (936, 1730) in US Caucasians and 940 (688, 1259) in Japanese. For Caucasian men, average IMT was higher in higher LAB quartile, which was 0.653, 0.667, 0.688, and 0.702 mm, respectively (p for trend = 0.02). Linear regression analysis showed serum LAB was significantly associated with IMT after adjustment for LDLC or total LDL particles in addition to other traditional or novel risk factors for atherosclerosis such as C-reactive protein. However, there was no significant relationship between LAB and IMT in Japanese men. Serum LAB, a new candidate biomarker for residual risk, was associated with an increased carotid IMT in US Caucasian men independently of various risk factors; however, ethnic difference should be clarified in the future.	\N	\N
23685553	Current guidelines do not support the use of genetic profiles in risk assessment of coronary heart disease (CHD). However, new single nucleotide polymorphisms associated with CHD and intermediate cardiovascular traits have recently been discovered. We aimed to compare several multilocus genetic risk score (MGRS) in terms of association with CHD and to evaluate clinical use. We investigated 6 Swedish prospective cohort studies with 10 612 participants free of CHD at baseline. We developed 1 overall MGRS based on 395 single nucleotide polymorphisms reported as being associated with cardiovascular traits, 1 CHD-specific MGRS, including 46 single nucleotide polymorphisms, and 6 trait-specific MGRS for each established CHD risk factors. Both the overall and the CHD-specific MGRS were significantly associated with CHD risk (781 incident events; hazard ratios for fourth versus first quartile, 1.54 and 1.52; P<0.001) and improved risk classification beyond established risk factors (net reclassification improvement, 4.2% and 4.9%; P=0.006 and 0.017). Discrimination improvement was modest (C-index improvement, 0.004). A polygene MGRS performed worse than the CHD-specific MGRS. We estimate that 1 additional CHD event for every 318 people screened at intermediate risk could be saved by measuring the CHD-specific genetic score in addition to the established risk factors. Our results indicate that genetic information could be of some clinical value for prediction of CHD, although further studies are needed to address aspects, such as feasibility, ethics, and cost efficiency of genetic profiling in the primary prevention setting.	\N	\N
23685743	We evaluate sex-based differences in the effectiveness of early cardiac computed tomographic angiography (CCTA) and standard emergency department (ED) evaluation in patients with acute chest pain. In the Rule-Out Myocardial Infarction With Computer-Assisted Tomography (ROMICAT)-II multicenter, controlled trial, we randomized 1000 patients (47% women) 40 to 74 years of age with symptoms suggestive of acute coronary syndrome to an early CCTA or standard ED evaluation. In this prespecified analysis, women in the CCTA arm had a greater reduction in length of stay, lower hospital admission rates, and lesser increased cumulative radiation dose than men in a comparison of ED strategies (P for interaction ≤0.02). Although women had lower acute coronary syndrome rates than men (3% versus 12%; P<0.0001), sex differences in length of stay persisted after adjustment for baseline differences, including acute coronary syndrome rate (P for interaction <0.03). Length of stay was similar between sexes with normal CCTA findings (P=0.11). There was no missed acute coronary syndrome for either sex. No difference was observed in major adverse cardiac events between sexes and ED strategies (P for interaction =0.39). Women had more normal CCTA examinations than men (58% versus 37%; P<0.0001), less obstructive coronary disease by CCTA (5% versus 17%; P=0.0001), but similar normalcy rates for functional testing (P=0.65). Men in the CCTA arm had the highest rate of invasive coronary angiography (18%), whereas women had comparable low 5% rates regardless of ED strategy. This trial provides data supporting an early CCTA strategy as an attractive option in women presenting to the ED with symptoms suggestive of acute coronary syndrome. The findings may be explained by lower CAD prevalence and severity in women than men. http://www.clinicaltrials.gov. Unique identifier: NCT01084239.	\N	\N
23689410	Coronary heart disease and ischemic stroke are frequent coexistent conditions that share risk factors and pose major burdens to global health. Even though a clear relation has been established between extracranial internal carotid artery atherosclerosis and symptomatic or asymptomatic coronary heart disease, there is a gap in knowledge about the association between intracranial atherosclerosis and coronary heart disease. Intracranial atherosclerosis is associated with high risks of stroke recurrence and vascular death. More research and clinical trials are needed to answer whether early diagnosis of asymptomatic coronary heart disease and aggressive treatment can decrease the risk of vascular death in patients with ischemic stroke caused by intracranial atherosclerosis.	\N	\N
23698559	Animal models will be critical for preclinical evaluations of novel HIV eradication and/or functional cure strategies in the setting of suppressive combination antiretroviral therapy (cART). Here, the strengths, limitations, and challenges of recent efforts to develop nonhuman primate (NHP) models of cART-mediated suppression for use in studies of persistent virus and curative approaches are discussed. Several combinations of NHP species and viruses that recapitulate key aspects of human HIV infection have been adapted for cART-mediated suppression studies. Different cART regimens incorporating drugs targeting multiple different steps of the viral replication cycle have provided varying levels of virologic suppression, dependent in part upon the host species, virus, drug regimen and timing, and virologic monitoring assay sensitivity. New, increasingly sensitive virologic monitoring approaches for measurements of plasma viral RNA, cell-associated and tissue-associated viral RNA and DNA, and the replication-competent residual viral pool in the setting of cART in NHP models are being developed to allow for the assessment of persistent virus on cART and to evaluate the impact of viral induction/eradication strategies in vivo. Given the vagaries of each specific virus and host species, and cART regimen, each model will require further development and analysis to determine their appropriate application for addressing specific experimental questions.	\N	\N
23700280	Lymphoma-associated hemophagocytic lymphohistiocytosis (HLH) is a rare but fatal disease. Differences between B cell and T cell lymphoma-associated HLH remain unclear, specifically clinical characteristics and survival. We retrospectively analyzed 30 lymphoma-associated HLH patients from July 2004 to October 2012. Patients were divided into B cell (n = 13) and T cell (n = 17) lymphoma groups. Patients' age, performance status, presence of Epstein-Barr virus infection, international prognostic index, presence of disseminated intravascular coagulopathy, serum triglyceride, fibrinogen, and lactate dehydrogenase levels were not significantly different between B cell and T cell lymphoma groups. HLH was an indicator for treatment resistance in patients with B cell (p = 0.048), but not T cell (p = 0.217), lymphoma. Patients in the T cell lymphoma group, however, had higher serum ferritin levels than patients in the B cell lymphoma group (11,525.6 versus 3,790.6 ng/mL; p = 0.043). The median survival time for patients in the B cell and T cell lymphoma groups was 330 and 96 days, respectively. Although the difference was not statistically significant (p = 0.273), our results suggested a trend toward a better overall survival time in patients with B cell lymphoma. This survival advantage could be at least partially due to use of rituximab (p = 0.045) for the treatment of patients with B cell lymphoma. Our results also suggested that allogeneic hematopoietic stem cell transplantation could possibly provide survival benefits to T cell lymphoma-associated HLH by graft-versus-lymphoma effect.	\N	\N
23701659	Reduced endogenous pain inhibition, as part of the degenerative process, is presumed to be the mechanism underlying the common presence of pain in patients with Parkinson's disease (PD). The present study aimed to assess an endogenous pain inhibitory system in PD using the conditioned pain modulation paradigm. Twenty-six predominantly unilateral PD patients and 19 controls underwent psychophysical pain assessment before and after patients' morning dopaminergic medication. An unexpected increase in several parameters of pain perception for PD patients was found after dopaminergic medication (e.g. for 49°C noxious heat stimulation an increase from 70.6 ± 4.0 to 77.6 ± 4.0 on the numerical pain scale, P < 0.001). This increase was seen in patients with predominantly left-sided PD, regardless of the stimulated side (for 49°C noxious heat stimulation, predominantly left-sided PD patients, pain perception increased from 73.5 ± 6.8 to 85.0 ± 6.8, P < 0.001, whereas predominantly right-sided PD patients did not show a significant increase, 68.3 ± 6.8 to 70.4 ± 6.5, P = 0.777). Baseline efficiency of conditioned pain modulation inversely correlated with age at disease onset (r = -0.522; P = 0.009) and disease severity (Unified PD Rating Scale, r = 0.447; P = 0.032) but did not differ between patients and controls. Increased sensory response causing hyperalgesia occurs after dopaminergic medication in patients with predominantly left-sided PD.	\N	\N
23704428	Human monocytic ehrlichiosis (HME) is a tick-born disease that presents predominantly as a mild to moderate acute illness. Severe life-threatening disease has been reported with a case death rate of approximately 3%, often in immunosuppressed persons. A delay in therapy initiation has been proven to increase the morbidity of the disease. We report a case of an elderly immunocompetent man with severe HME disease and multiorgan failure to emphasise on the severity of this disease in the elderly, as well as the importance of early therapy for overall favourable prognosis.	\N	\N
23706729	The health of the tens of millions of street children globally is understudied. We undertook a systematic review of the existing quantitative literature regarding the health status of street children and youth in low- and middle-income countries to summarize available knowledge, identify underexplored areas of research, and inform the future research agenda regarding the health of this population. A total of 108 articles met our inclusion criteria. Demographic data and structural factors associated with street life are summarized. Although data in specific regions or diseases are sparse, the literature review illustrates that youth's survival behaviors and the exposures associated with poor shelter have resulted in disproportionate morbidity in the areas of infectious illness, psychiatric disease, reproductive health, and perhaps to a lesser extent, growth. Vast areas of health that may disproportionately affect street children in childhood or later on as adults have not been investigated, including chronic diseases and cognitive deficits. Studies of specific diseases or conditions vary considerably by region. Strengths and limitations of the literature are discussed and principles for future research in this area are proposed.	\N	\N
23709100	This multicenter analysis evaluated patient outcome and clinical pathologic features of thymic epithelial tumors after complete surgical resection and adjuvant treatment. Histologic classification and clinical staging were performed according to WHO classification and Masaoka staging system, respectively. We analyzed 62 patients, 20 (32%) of whom had myasthenia at diagnosis. Clinical and pathologic staging was as follows: 31 (50%) and 30 (48%) patients had stage I disease, 19 (30%) and 22 (35%) stage II, 5 (8%) and 3 (6%) stage III, 2 (4%) and 2 (3%) stage IVa, and 5 (8%) and 5 (8%) stage IVb, respectively. Histologic examination revealed 11 (19%) type A tumors, 19 (30%) type AB tumors, 7 (12%) type B1 tumors, 11 (17%) type B2 tumors, 11 (17%) type B3 tumors, and 3 (5%) type C tumors. Adjuvant therapies comprised chemotherapy in 3 (5%) patients and radiotherapy in 16 (26%) patients. Median follow-up was 71 months (range 1-145). DFS and OS at 48, 60, and 72 months were 89 and 89%, 86 and 97%, and 95% and 92%, respectively. Myasthenia at the onset of disease (P=0.18 for DFS; P=0.97) and tumor size>5 cm (P=0.94 for DFS; P=0.56) were not prognostic factors. TETs are rare and indolent tumors. Complete surgical resection followed by adjuvant therapies, such as chemotherapy and/or radiotherapy, in patients at risk of recurrence show very good DFS and OS results, even in cases with radically resected pleural-pulmonary metastases.	\N	\N
23712633	Ticagrelor, a recently approved platelet antagonist indicated for the reduction of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS), has been reported to cause dyspnea in more than 13% of patients. Dyspnea is not a clinically relevant adverse event with other medications indicated for ACS. One suggested mechanism of ticagrelor-induced dyspnea involves an increase in systemic adenosine concentrations through adenosine deaminase inhibition. Dyspnea, a subjective finding resulting from physiologic and sensory mechanisms, may be a consequence of increased systemic adenosine concentrations, leading to amplified and prolonged receptor activity. Current literature suggests, however, that pulmonary status is not compromised, with no reduction of efficacy seen in patients with ticagrelor-induced dyspnea, thus allowing clinicians to continue therapy without reservation. Still, patients with a history of asthma and chronic obstructive pulmonary disease may be more susceptible to ticagrelor-induced dyspnea, potentially leading to nonadherence and exacerbations of morbidity. Therefore, it is paramount that health care providers continually monitor these patients with the aims of maintaining medication therapy adherence and providing relevant options if dyspnea becomes intolerable.	\N	\N
23723040	We previously identified a four-generation family with medullary thyroid cancer (MTC) and a germline p.Y791F RET mutation whose cancer lacked a strong genotype-phenotype correlation. The entire gene coding region of the RET gene should be sequenced when genotype-phenotype discrepancies are observed in patients with multiple endocrine neoplasia type 2 (MEN 2), even if a RET hotspot mutation has been identified. A new genetic test was performed in the index case of this family with the p.Y791F RET germline mutation. The entire coding region of the RET gene was investigated by direct sequencing of PCR products. Once a mutation was identified, the target exon was sequenced in all at-risk relatives. An additional p.C634Y germline mutation in the RET gene was identified in the reported family. The double mutation occurred in cis and segregated with the phenotype. Through the Brazilian Genetic Screening Program developed at our institution, we additionally report the combination of these two mutations (p.C634Y/p.Y791F) in the RET gene in four other unrelated families. The overall penetrance of MTC and pheochromocytoma in patients with the p.C634Y/p.Y791F mutations was 79% and 13%, respectively. Our data emphasises that a comprehensive analysis of the RET gene may reveal multiple germline mutations in MEN 2 patients who exhibit an atypical clinical course of the disease.	\N	\N
23725082	To examine the effect of hypertensive disease of pregnancy (HDP) on the development of respiratory distress syndrome (RDS) in preterm neonates. A retrospective cohort study. All neonatal intensive care units in New South Wales and the Australian Capital Territory. A total of 18,845 preterm neonates aged between 24 and 36 weeks gestation admitted to the units from 1998 to 2006 were included for study purpose. Exclusion criteria were multiple pregnancies, chorioamnionitis, antepartum hemorrhage and neonates who developed respiratory diagnoses other than RDS. Effect of HDP on the development of RDS was measured. A total of 1093 neonates from hypertensive and 2274 from normotensive pregnancies with complete datasets were included. The association between HDP and the development of RDS was modified by gestational age (HDP-by-gestational age interaction p value <0.0001). Therefore the cohort was divided into extreme (24-28 weeks gestation, n = 752), severe (29-32 weeks gestation, n = 1448) and moderate (33-36 weeks gestation, n = 1167) preterm groups. HDP was associated with a decreased risk of RDS in the moderate preterm group (OR: 0.68; 95% CI: 0.48-0.98, p = 0.04) and a non-significant change in risk for the severe preterm group. Almost all neonates in the extreme preterm group experienced RDS. HDP is associated with a lower risk of developing RDS in moderate preterm neonates. This could have clinical implications in terms of risk stratification for this group of neonates.	\N	\N
23726393	The balance of risk and benefit from early neurosurgical intervention for conscious patients with superficial lobar intracerebral haemorrhage of 10-100 mL and no intraventricular haemorrhage admitted within 48 h of ictus is unclear. We therefore tested the hypothesis that early surgery compared with initial conservative treatment could improve outcome in these patients. In this international, parallel-group trial undertaken in 78 centres in 27 countries, we compared early surgical haematoma evacuation within 12 h of randomisation plus medical treatment with initial medical treatment alone (later evacuation was allowed if judged necessary). An automatic telephone and internet-based randomisation service was used to assign patients to surgery and initial conservative treatment in a 1:1 ratio. The trial was not masked. The primary outcome was a prognosis-based dichotomised (favourable or unfavourable) outcome of the 8 point Extended Glasgow Outcome Scale (GOSE) obtained by questionnaires posted to patients at 6 months. Analysis was by intention to treat. This trial is registered, number ISRCTN22153967. 307 of 601 patients were randomly assigned to early surgery and 294 to initial conservative treatment; 298 and 291 were followed up at 6 months, respectively; and 297 and 286 were included in the analysis, respectively. 174 (59%) of 297 patients in the early surgery group had an unfavourable outcome versus 178 (62%) of 286 patients in the initial conservative treatment group (absolute difference 3·7% [95% CI -4·3 to 11·6], odds ratio 0·86 [0·62 to 1·20]; p=0·367). The STICH II results confirm that early surgery does not increase the rate of death or disability at 6 months and might have a small but clinically relevant survival advantage for patients with spontaneous superficial intracerebral haemorrhage without intraventricular haemorrhage. UK Medical Research Council.	\N	\N
23731266	Existing nutritional guidelines suggest that protein requirements of adults with stage five chronic kidney disease undergoing haemodialysis (HD) or peritoneal dialysis (PD) are increased as a result of protein losses during dialysis. The present review aimed to update previous guidance and develop evidence-based practice guidelines on the protein requirements of adults undergoing maintenance dialysis. Following a PICO approach (Participants or Population, Intervention or Exposure, Comparison and Outcome), four research questions were formulated to investigate the total protein requirement and protein quality required by adults undergoing HD and PD. A comprehensive, systematic review was undertaken using the databases Medline, EMBASE and the Cochrane Library from 2005 to September 2009 for HD studies and from 1997 to September 2009 for PD studies. The literature search yielded 2931 studies, which were assessed for inclusion. Following appraisal, 19 studies in HD and 18 studies in PD met the inclusion criteria and were systematically reviewed. Limited good quality evidence supports the recommendations that: (i) adults undergoing maintenance HD require a minimum protein intake of 1.1 g kg(-1) ideal body weight (IBW) per day; and (ii) adults undergoing maintenance PD require a minimum protein intake of 1.0-1.2 kg(-1) IBW per day, in conjunction with an adequate energy intake. There were no studies that addressed the quality of protein for either HD or PD. Evidence suggests that nutritional status may be maintained with lower protein intakes than previously recommended. However, the evidence base is limited and further randomised controlled trials are required to establish the optimal protein intake for dialysis patients.	\N	\N
23742957	To determine the prevalence and persistence of new-onset clinical remission in rheumatoid arthritis (RA) patients. The Consortium of Rheumatology Researchers of North America (CORRONA) cohort was used to examine the prevalence of remission and associated comorbidities and RA therapies according to the 2011 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) remission criteria. Factors influencing the likelihood of remaining in remission were identified by logistic regression with generalized estimating equations. Analysis of variance and Tukey's test were used to determine differences in disability according to whether RA patients had been in remission or only low disease activity (LDA). A total of 2105 individuals met ACR/EULAR remission criteria at the most recent visit within CORRONA, yielding an 8% point prevalence of remission. Patients with certain comorbidities (e.g., heart failure) were significantly less likely to achieve or remain in remission compared to those without these conditions (p < 0.001 for each). Among prednisone users, the prevalence of remission was 1-6% (depending on dose) higher compared to those not on prednisone (10%). More than 50% of patients who had consistently been in remission for ≥1 year were able to remain in remission over the next year. Patients consistently in remission had less disability than patients who achieved LDA or who fluctuated between remission and LDA. Patients consistently in remission for at least 1 year had a high likelihood to remain in remission. These individuals might be considered the most likely candidates for de-escalation or withdrawal of RA treatments.	\N	\N
23745323	The GOLD 2011 recommendations for chronic obstructive pulmonary disease (COPD) introduce a new classification system to optimize treatment in individual patients. Except for FEV,, this classification incorporates breathlessness measurement using modified medical research council questionnaire (mMRC) or the COPD assessment Test (CAT) and the number of exacerbations. The aim of our study was to compare the GOLD 2010 and GOLD 2011 COPD. The study group consisted of 143 patients. Based on the post-bronchodilator FEV, only, as recommended in the GOLD 2010 report, there were 24 patients in stage I, 57patients in II, 43 in Ill and 19 in IV, respectively. In all patients, the number of exacerbations per year was noted and dyspnea was assessed with the modified MRC scale. The patients were subsequently graded to group A,B,C,D as proposed in the combined COPD assessment in GOLD 2011. Grading of 51 (35,7%) patients according to the GOLD 2011 criteria was difficult; there were 22 patients in GOLD stage I/II with > or =2 exacerbations per year and 29 patients in GOLD stage Ill/IV with < 2 exacerbations per year. They were grading to more risk group. The new classification according to GOLD 2011 lets on optimizations of the treatment, in most cases of COPD patients but in clinical practice, there may be problems with the classification of the patients with severe airway obstruction without frequent exacerbations and especially those with mild/moderate airflow limitation and frequent exacerbations.	\N	\N
23750230	All non-human great apes are endangered in the wild, and it is therefore important to gain an understanding of their demography and genetic diversity. Whole genome assembly projects have provided an invaluable foundation for understanding genetics in all four genera, but to date genetic studies of multiple individuals within great ape species have largely been confined to mitochondrial DNA and a small number of other loci. Here, we present a genome-wide survey of genetic variation in gorillas using a reduced representation sequencing approach, focusing on the two lowland subspecies. We identify 3,006,670 polymorphic sites in 14 individuals: 12 western lowland gorillas (Gorilla gorilla gorilla) and 2 eastern lowland gorillas (Gorilla beringei graueri). We find that the two species are genetically distinct, based on levels of heterozygosity and patterns of allele sharing. Focusing on the western lowland population, we observe evidence for population substructure, and a deficit of rare genetic variants suggesting a recent episode of population contraction. In western lowland gorillas, there is an elevation of variation towards telomeres and centromeres on the chromosomal scale. On a finer scale, we find substantial variation in genetic diversity, including a marked reduction close to the major histocompatibility locus, perhaps indicative of recent strong selection there. These findings suggest that despite their maintaining an overall level of genetic diversity equal to or greater than that of humans, population decline, perhaps associated with disease, has been a significant factor in recent and long-term pressures on wild gorilla populations.	\N	\N
23752073	Several studies have indicated that plasma citrulline levels reflect the extent of mucosal injury of the small intestine. This study was performed to determine whether plasma citrulline levels correlate with the disease activity in pediatric patients with Crohn disease (CD). A total of 63 CD and 23 ulcerative colitis (UC) patients were included in this study. Disease severity was assessed by pediatric CD activity index (PCDAI), pediatric UC activity index, simplified endoscopic activity score for CD, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR). The correlations among these variables and plasma citrulline levels were evaluated. We performed subgroup analysis whether correlations between plasma citrulline levels and disease activity depend on small bowel involvement in patients with CD. The plasma citrulline levels correlated negatively with CRP (r = -0.332, P = 0.008), ESR (r = -0.290, P = 0.022), and PCDAI (r = -0.424, P = 0.001) in patients with CD. The plasma citrulline levels were significantly lower in patients with jejunal involvement than in those without (P = 0.027). In subgroup analysis, patients with CD with jejunal involvement showed significantly negative correlations of plasma citrulline levels with CRP (r = -0.628, P = 0.016) and PCDAI (r = -0.632, P = 0.015); however, patients with CD without jejunal involvement revealed no correlations of plasma citrulline levels with CRP and PCDAI. There were no significant correlations between plasma citrulline levels and simplified endoscopic activity score for CD. There were no significant correlations of plasma citrulline levels with CRP, ESR, and pediatric UC activity index in patients with UC. Plasma citrulline levels correlated with disease severity as measured by PCDAI, CRP, and ESR in pediatric patients with CD with jejunal involvement.	\N	\N
23756272	To assess the effectiveness of a multidisciplinary team approach to reduce severe maternal morbidity in women with invasive placenta previa. We conducted a prospective study of 33 women with placenta previa and increta-percreta (diagnosed by ultrasound and/or magnetic resonance imaging) delivering at Mount Sinai Hospital, Toronto, following the introduction in January 2008 of a team-based approach to women with this condition. We included women who delivered by June 2012. We reviewed antenatal outpatient and inpatient records for use of six pre-defined team components by the attending staff obstetrician: (1) antenatal maternal-fetal medicine consultation, (2) surgical gynaecology consultation, (3) antenatal MRI, (4) interventional radiology consultation and preoperative placement of balloon catheters in the anterior divisions of the internal iliac arteries, (5) pre-planned surgical date, and (6) surgery performed by members of the invasive placenta surgical team. Antenatal course, delivery, and postpartum details were recorded to derive a five-point composite severe maternal morbidity score based on the presence or absence of: (1) ICU admission following delivery, (2) transfusion > 2 units of blood, (3) general anaesthesia start or conversion, (4) operating time in highest quartile (> 125 minutes), and (5) significant postoperative complications (readmission, prolonged postpartum stay, and/or pulmonary embolism). All 33 women survived during this time period. Two thirds (22/33) had either five or six of the six components of multidisciplinary care. Increasing use of multidisciplinary team components was associated with a significant reduction in composite morbidity (R2 = 0.228, P = 0.005). Team-based assessment and management of women with invasive placenta previa is likely to improve maternal outcomes and should be encouraged on a regional basis.	\N	\N
23774792	Both genetic inactivation and pharmacological inhibition of the cholesteryl ester synthetic enzyme acyl-CoA:cholesterol acyltransferase 1 (ACAT1) have shown benefit in mouse models of Alzheimer's disease (AD). In this study, we aimed to test the potential therapeutic applications of adeno-associated virus (AAV)-mediated Acat1 gene knockdown in AD mice. We constructed recombinant AAVs expressing artificial microRNA (miRNA) sequences, which targeted Acat1 for knockdown. We demonstrated that our AAVs could infect cultured mouse neurons and glia and effectively knockdown ACAT activity in vitro. We next delivered the AAVs to mouse brains neurosurgically, and demonstrated that Acat1-targeting AAVs could express viral proteins and effectively diminish ACAT activity in vivo, without inducing appreciable inflammation. We delivered the AAVs to the brains of 10-month-old AD mice and analyzed the effects on the AD phenotype at 12 months of age. Acat1-targeting AAV delivered to the brains of AD mice decreased the levels of brain amyloid-β and full-length human amyloid precursor protein (hAPP), to levels similar to complete genetic ablation of Acat1. This study provides support for the potential therapeutic use of Acat1 knockdown gene therapy in AD.	\N	\N
23782739	Shewanella spp. is infrequently recovered from clinical specimens. Following two outbreaks of food poisoning, eight Shewanella spp. strains were obtained from the fecal specimens of patients, food and food processing-related materials. Tetrodotoxin (TTX) was identified in the culture supernatants of these strains, and the toxin's biological activity was detected using a mouse bioassay. This study suggested that Shewanella strains can colonize and survive in human intestines. The study also raises the issues of the accumulation of TTX produced by Shewanella in food and the possible role of TTX-producing Shewanella in food poisoning.	\N	\N
23793899	Middle East Respiratory Syndrome coronavirus (MERS CoV) came to attention as an emerging pathogen causing severe respiratory illness in patients from the Middle East in September 2012. As of 14 June 2013, 58 human cases of MERS CoV infection have been confirmed, including 33 deaths (case fatality rate of 57%). MERS CoV is a beta-coronavirus, in the same family as SARS-CoV, and shares a probable origin from bats. No animal reservoir or intermediates have been definitely implicated in transmission. Limited human-to-human transmission has occurred within several clusters, as individuals without a recent travel history have become infected after exposure to an ill returned traveler.	\N	\N
23811578	Acute thallium poisoning rarely occurs but is a serious and even fatal medical condition. Currently, patients with acute thallium poisoning are usually treated with Prussian blue and blood purification therapy. However, there are few studies about these treatments for acute thallium poisoning. Nine patients with acute thallium poisoning from 1 family were treated successfully with Prussian blue and different types of blood purification therapies and analyzed. Prussian blue combined with sequential hemodialysis, hemoperfusion and/or continuous veno-venous hemofiltration were effective for the treatment of patients with acute thallium poisoning, even after delayed diagnosis. Blood purification therapies help in the clearance of thallium in those with acute thallium poisoning. Prussian blue treatment may do the benefit during this process.	\N	\N
23815257	A hallmark of acute inflammation involves the recruitment of polymorphonuclear leukocytes (neutrophils) to infected or injured tissues. The processes underlying this recruitment are complex, and include multiple mechanisms of intercellular communication between neutrophils and the inflamed tissue. In recent studies of the systemic and pulmonary vasculature, interest has increased in novel forms of intercellular communication, such as microparticle exchange and gap junctional intercellular communication. To understand the roles of these novel forms of communication in the onset, progression, and resolution of inflammatory lung injury (such as acute respiratory distress syndrome), we review the literature concerning the contributions of microparticle exchange and gap junctional intercellular communication to neutrophil-alveolar crosstalk during pulmonary inflammation. By focusing on these cell-cell communications, we aim to demonstrate significant gaps of knowledge and identify areas of considerable need for further investigations of the processes of acute lung inflammation.	\N	\N
23817139	Animal models of chronic kidney disease (CKD) approximate the human condition and are keys to understanding its pathogenesis and to developing rational treatment strategies. The ethical use of animals requires a detailed understanding of the strengths and limitations of each species and the disease model, and the way in which findings can be translated from animals to humans. While not perfect, the careful use of animal experiments offers the opportunity to examine individual mechanisms in an accelerated time frame.	\N	\N
23830210	Postoperative chylothorax is a frequently encountered pathology occurring in up to 4% of patients undergoing surgery for repair of congenital heart disease. Symptomatic thrombosis is associated with chylothorax and may contribute to its severity and duration. Furthermore, vessel thrombosis resulting in persistent vessel occlusion may impede future treatments, diagnostic studies and cardio-surgical interventions. The objective of this study was to determine the incidence of upper system thrombosis in pediatric congenital heart patients with confirmed chylothorax with ultrasound screening of all patients diagnosed with chylothorax. All pediatric patients with confirmed with chylothorax underwent doppler ultrasound of the upper venous system as per hospital standard. This retrospective cohort study enrolled all children between February 1, 2010-August 2012, post cardiac surgery with confirmed chylothorax to determine the incidence of all thrombosis. There were 1396 children who underwent 1396 cardiac surgical procedures during the study time with 760 undergoing cardiopulmonary bypass. Development of chylothorax occurred in 54 of 1396, 3.9% (95%CI 3.0;5.0) procedures in all children. In those children with chylothorax, 28 of 54 episodes, 51.8% (95%CI 38.9;64.6) had confirmed VTE. The 51.8% incidence in this study demonstrates a 2.6 fold increase in risk of thrombosis compared to 20% in children with heart disease and central venous lines and may result in serious clinical consequences. The contribution of upper venous system thrombosis to chylothorax is unknown. Often, clinical suspicion of chylothorax exists, however the lack of a standardized approach to objective diagnosis results in delayed confirmation. Approaches to therapy either treatment of confirmed thrombosis or prevention of thrombosis in patients with chylothorax require formal evaluation. Future studies are urgently needed.	\N	\N
23832758	Kallikrein 6 (KLK6) is a secreted serine protease preferentially expressed by oligodendroglia in CNS white matter. Elevated levels of KLK6 occur in actively demyelinating multiple sclerosis (MS) lesions and in cases of spinal cord injury (SCI), stroke, and glioblastoma. Taken with recent evidence establishing KLK6 as a CNS-endogenous activator of protease-activated receptors (PARs), we hypothesized that KLK6 activates a subset of PARs to regulate oligodendrocyte physiology and potentially pathophysiology. Here, primary oligodendrocyte cultures derived from wild type or PAR1-deficient mice and the murine oligodendrocyte cell line, Oli-neu, were used to demonstrate that Klk6 (rodent form) mediates loss of oligodendrocyte processes and impedes morphological differentiation of oligodendrocyte progenitor cells (OPCs) in a PAR1-dependent fashion. Comparable gliopathy was also elicited by the canonical PAR1 agonist, thrombin, as well as PAR1-activating peptides (PAR1-APs). Klk6 also exacerbated ATP-mediated oligodendrogliopathy in vitro, pointing to a potential role in augmenting excitotoxicity. In addition, Klk6 suppressed the expression of proteolipid protein (PLP) RNA in cultured oligodendrocytes by a mechanism involving PAR1-mediated Erk1/2 signaling. Microinjection of PAR1 agonists, including Klk6 or PAR1-APs, into the dorsal column white matter of PAR1(+/+) but not PAR1(-/-) mice promoted vacuolating myelopathy and a loss of immunoreactivity for myelin basic protein (MBP) and CC-1(+) oligodendrocytes. These results demonstrate a functional role for Klk6-PAR1 signaling in oligodendroglial pathophysiology and suggest that antagonists of PAR1 or its protease agonists may represent new modalities to moderate demyelination and to promote myelin regeneration in cases of CNS white matter injury or disease.	\N	\N
23838529	Classical multiple sclerosis (CMS) and neuromyelitis optica spectrum disorders (NMOSD) are distinct central nervous system inflammatory demyelinating disorders (CNS IDD). Early diagnosis of CNS IDD is important as appropriate immunotherapies to optimize prognosis. We studied the diagnoses of CNS IDD among Hong Kong Chinese in a hospital-based setting. Consecutive Chinese patients who presented to our hospital with clinically isolated syndrome and subsequently diagnosed to have CNS IDD from 1980 to 2010 were reviewed. Patients with known diagnosis of CNS IDD referred for further care were excluded. Serial sera were assayed for aquaporin-4 autoantibodies (AQP4 Ab), at least 3 assays within 2-5years. A total of 210 patients diagnosed to have CNS IDD with disease duration of at least 2years were studied. Among 198 patients with serial sera available, 40 (20.2%, 20 had NMO and 20 other NMOSD) were AQP4 Ab-positive. Four patients who were AQP4 Ab-negative on the initial assay converted to AQP4 Ab-positive on repeated assays. The diagnoses of 210 patients were CMS in 88 (41.9%), NMOSD 47 (22.4%, 27 NMO, 20 other NMOSD), single attack of myelitis 23 (11.0%), single attack of optic neuritis 21 (10.0%), relapsing myelitis 10 (4.8%), acute disseminated encephalomyelitis (ADEM) 9 (4.3%), relapsing optic neuritis in 6 (2.9%), opticospinal multiple sclerosis 3 (1.4%) and single attack of brainstem encephalitis 3 (1.4%). Compared to CMS, NMOSD patients had older onset age, lower frequencies of brain MRI abnormalities and CSF OCB, higher frequency of LETM, higher CNS inflammation attack frequency in the first 2years, worse clinical outcome with higher EDSS score and mortality rate. This hospital-based study suggests that CMS (41.9%) and NMOSD (22.4%) are the most common CNS IDD among Hong Kong Chinese. NMOSD has worse clinical outcome than CMS. Detection of AQP4 Ab facilitates early diagnosis and prompts immunotherapies of NMOSD.	\N	\N
23846297	Decoy receptor 3 (DcR3) is abundantly expressed in human tumors and protects cells from a wide range of apoptotic stimuli. In this study, we demonstrate that DcR3 is overexpressed in pancreatic carcinoma cells, and that the pancreatic carcinoma cell lines, Panc-1 and SW1990, are resistant to Fas ligand (FasL)-mediated apoptosis. To further define the function of DcR3 in cell growth and apoptosis, we used small interfering RNA (siRNA) to knockdown the expression of the DcR3 gene in Panc-1 and SW1990 cells. Our results revealed that the silencing of DcR3 expression enhanced the inhibitory effects of FasL and reduced the capabiltiy of the cells for proliferation and colony formation in vitro. In addition, the downregulation of DcR3 modulated the cell apoptotic regulators, Fas-associated death domain (FADD), caspase‑3 and caspase‑8, thus triggering cell apoptosis. Furthermore, the knockdown of DcR3 inhibited the growth of Panc-1 tumor xenografts. Taken together, our findings indicate that DcR3 is important in cancer progression and may be a used as a potential therapeutic target for the gene therapy of pancreatic carcinoma.	\N	\N
23849416	Abiraterone, an androgen synthesis inhibitor, has been successfully used in the treatment of castration-resistant prostate cancer (CRPC) for 2 yr. Enzalutamide is a second-generation nonsteroidal antiandrogen that has recently been approved for the same indication. This is the first study to evaluate the effectiveness of enzalutamide after failure of abiraterone. Thirty-five patients were identified as having received sequential therapy with abiraterone followed by enzalutamide. All patients had undergone prior docetaxel chemotherapy, and no patient had received ketoconazole. Posttreatment changes in prostate-specific antigen (PSA) were used to determine the activity of enzalutamide in patients who had received prior abiraterone. The median duration of abiraterone treatment was 9.0 mo (range: 2.0-19.0 mo). Of the 35 patients, 16 (45.7%) achieved a >50% decline in PSA, and 14 (40%) had a rising PSA as the best response. The median duration of subsequent enzalutamide treatment was 4.9 mo (Kaplan-Meier estimate; 95% confidence interval [CI], 2.4-7.4). Seven of 16 CRPC patients who were initially abiraterone-sensitive (43.8%) and 3 of 19 CRPC patients who were initially abiraterone-insensitive (15.8%) showed a >50% PSA decline while taking enzalutamide. Of the 35 patients, 17 (48.6%) were primarily enzalutamide-resistant and showed a rising PSA as the best response. Median time to progression was 4.0 mo (95% CI, 2.0-6.0) for 18 of 35 patients with at least one declining PSA value while taking enzalutamide (51.4%). Of the 17 patients who were assessable radiologically, only 1 (2.9%) attained a confirmed partial response. Small sample size was the major limitation. Enzalutamide treatment achieved only a modest response rate in patients progressing after abiraterone. Although cross-resistance between abiraterone and enzalutamide was a common phenomenon, it was not inevitable, and a small but significant number of patients showed significant benefit from sequential treatment.	\N	\N
23850538	A few years ago, Anisakis infection was almost unknown. Since the first observation in the Netherlands in 1960, several cases of gastrointestinal infections due to a zoonosis sustained by this nematode have been described in countries in which the consumption of raw or uncooked fish (e.g., marinated or salted) is common. Japan alone accounts for 90% of all cases of anisakiasis described in the literature because of the widespread use of raw fish in traditional Japanese cuisine, with sushi and sashimi. Nonetheless, other cases have been reported in Europe, North and South America, and Asia. In Italy, this zoonosis is rare and mostly transmitted by the ingestion of marinated anchovies in coastal areas, or fashion foods (sushi, sashimi, etc.) in inland areas. Once eaten, this parasite can cause an acute form of disease characterized by severe abdominal pain, and for this reason many patients receive the final diagnosis only on obtaining the surgical specimen. Since conservative medical treatment for acute anisakiasis relies on endoscopic removal of the nematode from the gastrointestinal wall if performed within 12h from the ingestion of contaminated fish, it should be compulsory to consider this parasitosis in the accident and emergency department. Here we describe two cases of infection by Anisakis simplex due to ingestion of marinated anchovies in a coastal area of the Tyrrhenian Sea and discuss the types and varieties of Anisakis infection in humans.	\N	\N
23861956	Severe stress experienced in early life may have long-term effects on adult physiological and psychological health and well-being. We studied physical and psychosocial functioning in late adulthood in subjects separated temporarily from their parents in childhood during World War II. The 1803 participants belong to the Helsinki Birth Cohort Study, born 1934-44. Of them, 267 (14.8%) had been evacuated abroad in childhood during WWII and the remaining subjects served as controls. Physical and psychosocial functioning was assessed with the Short Form 36 scale (SF-36) between 2001 and 2004. A test for trends was based on linear regression. All analyses were adjusted for age at clinical examination, social class in childhood and adulthood, smoking, alcohol intake, physical activity, body mass index, cardiovascular disease and diabetes. Physical functioning in late adulthood was lower among the separated men compared to non-separated men (b = -0.40, 95% confidence interval [95% CI]: -0.71 to -0.08). Those men separated in school age (>7 years) and who were separated for a duration over 2 years had the highest risk for lower physical functioning (b = -0.89, 95% CI: -1.58 to -0.20) and (b = -0.65, 95% CI: -1.25 to -0.05), respectively). Men separated for a duration over 2 years also had lower psychosocial functioning (b = -0.70, 95% CI: -1.35 to -0.06). These differences in physical and psychosocial functioning were not observed among women. Early life stress may increase the risk for impaired physical functioning in late adulthood among men. Timing and duration of the separation influenced the physical and psychosocial functioning in late adulthood.	\N	\N
23866601	The lecture considers a number of molecular and cellular mechanisms underlying the structural and functional rearrangement and development of renal and cardiac fibrosis in chronic kidney disease (CKD). It details the key component of disadaptative organ remodeling (the formation of myofibroblasts via epithelial-mesenchymal and endothelial-mesenchymal transdifferentiation) and the role of leading angiofibrogenic mediators (angiotensin II, transforming growth factor-beta type 1, a plasminogen activator inhibitor type 1, etc.) in the regulation of these processes. Investigation of the molecular and cellular bases of organ fibrosis, including the factors of dysregulated activation, differentiation and survival of microfibroblasts, makes it possible to specify the mechanisms of action of traditional nephro- and cardioprotective agents, to offer a possibility for a goal-oriented (target) effect on individual fibrogenic components, and to expand the arsenal of medications suppressing renal and cardiac remodeling.	\N	\N
23868901	Dabigatran is an oral direct thrombin inhibitor widely used to prevent and treat various thromboembolic complications. An advantage of this agent over other anticoagulants is that routine laboratory monitoring and related dose adjustments are considered unnecessary. A major disadvantage is the absence of a reliable means of reversing its anticoagulant effect. After U.S. Food and Drug Administration approval, recently emerged data suggest a higher bleeding risk with dabigatran, especially in the elderly. Clinicians are thus faced with caring for patients with serious bleeding events without readily available tests to measure drug levels or the anticoagulant effects of dabigatran and without effective antidotes to rapidly reverse the anticoagulant effect. On the basis of dabigatran's pharmacokinetic profile, hemodialysis and continuous renal replacement therapy have been used to remove dabigatran with the hope, still unproven, that this would rapidly reverse the anticoagulant effect and reduce bleeding in patients with normal and those with reduced kidney function. However, the best clinical approach to the patient with serious bleeding is not known, and the risks of placing a hemodialysis catheter in an anticoagulated patient can be substantial. This article reviews this issue, addressing clinical indications, drug pharmacokinetics, clinical and laboratory monitoring tests, and dialytic and nondialytic approaches to reduce bleeding in dabigatran-treated patients.	\N	\N
23871729	Acute ischemic stroke is a major cerebrovascular disease with potential morbidity and mortality. Despite the availability of thrombolytic therapy in some centers, risk factor modification and rehabilitation therapy are the mainstays of stroke management. There is supporting evidence that Ginkgo biloba may afford neuroprotection and improve the outcomes of patients with acute ischemic stroke. In a double-blind, placebo-controlled, randomized controlled trial, we assessed the efficacy of G biloba on functional outcome in patients with acute stroke. The National Institutes of Heath Stroke Scale (NIHSS) was used to measure functional outcome. A total of 102 patients with acute ischemic stroke were studied. All patients received either G biloba or placebo tablets for 4 months. This trial was registered to the Iranian Registry of Clinical Trials (www.irct.ir; trial IRCT138804212150N1). There were 52 patients who received G biloba and 50 patients who were in the placebo group. Age, sex distribution, previous medical condition, and laboratory data did not have any significant difference between the 2 groups (P>.05). The mean difference of 4-month follow-up NIHSS scores and NIHSS scores at admission was 4.7±2.7 and 4.1±3.0 in the G biloba and placebo groups, respectively (P>.05). The primary outcome-a 50% reduction in the 4-month follow-up NIHSS score compared to the baseline NIHSS score-was reached in 17 patients (58.6%) and 5 patients (18.5%) in the G biloba and placebo groups, respectively (P<.05). The risk ratio and number needed to treat were 3.16 (confidence interval 1.35-7.39) and 2.50 (confidence interval 1.58-5.90), respectively. In addition, multivariate regression adjusted for age and sex revealed a significant NIHSS decline in the G biloba group compared to the placebo group (P<.05). Our data suggest that G biloba may have protective effects in ischemic stroke. Therefore, the administration of G biloba is recommended after acute ischemic stroke.	\N	\N
23872666	Sequences of human endogenous retroviruses (HERVs) are members of the long terminal repeat (LTR) retrotransposon family. Although the expression of HERV has long been a topic of investigation, HERV-insertion polymorphisms are not well known, and a genetic association between HERV-insertion polymorphisms and cancer has never been reported. To identify novel HERV loci in the genome from cancer tissues, we carried out the inverse PCR method targeting a conserved LTR region of HML-2, which is the most recently acquired HERV group. Novel two insertions, HML-2_sLTR(1p13.2) and HML-2_sLTR(19q12), were identified as insertionally polymorphic solo LTRs. Furthermore, a significant prevalence of HML-2_sLTR(1p13.2) homozygosity was detected in female never-smoking patients aged 60 years and over who had lung adenocarcinoma [versus the other genotyping; odds ratio (OR): 1.97; 95% confidence interval (CI): 1.01-3.81]. In another cohort consisting of female never-smoking patients with lung adenocarcinoma, a prevalence of HML-2_sLTR(1p13.2) homozygosity tended to be high in patients aged 60 years and over (versus the other genotyping; OR: 2.03; 95% CI: 0.96-4.29), whereas a low prevalence of HML-2_sLTR(1p13.2) homozygosity was detected in patients <60 years old (versus the other genotyping; OR: 0.31; 95% CI: 0.11-0.94). Our results suggest that HML-2_sLTR(1p13.2) is involved with the susceptibility to lung adenocarcinoma in female never-smokers in an age-dependent manner and that other HERV polymorphisms related to human diseases might remain to be identified in the human genome.	\N	\N
23874931	The HIV-1 characteristics associated with mother to child transmission (MTCT) are still poorly understood and if known would indicate where intervention strategies should be targeted. In contrast to horizontally infected individuals, exposed infants possess inherited antibodies (Abs) from their mother with the potential to protect against infection. We investigated the HIV-1 gp160 envelope proteins from seven transmitting mothers (TM) whose children were infected either during gestation or soon after delivery and from four non-transmitting mothers (NTM) with similar viral loads and CD4 counts. Using pseudo-typed viruses we tested gp160 envelope glycoproteins for TZM-bl infectivity, CD4 and CCR5 interactions, DC-SIGN capture and transfer and neutralization with an array of common neutralizing Abs (NAbs) (2F5, 2G12, 4E10 and b12) as well as mother and infant plasma. We found no viral correlates associated with HIV-1 MTCT nor did we find differences in neutralization with the panel of NAbs. We did, however, find that TM possessed significantly higher plasma neutralization capacities than NTM (P = 0.002). Furthermore, we found that in utero (IU) TM had a higher neutralization capacity than mothers transmitting either peri - partum (PP) or via breastfeeding (BF) (P = 0.002). Plasma from children infected IU neutralized viruses carrying autologous gp160 viral envelopes as well as those from their corresponding mothers whilst plasma from children infected PP and/or BF demonstrated poor neutralizing capacity. Our results demonstrate heightened autologous NAb responses against gp120/gp41 can associate with a greater risk of HIV-1 MTCT and more specifically in those infants infected IU. Although the number of HIV-1 transmitting pairs is low our results indicate that autologous NAb responses in mothers and infants do not protect against MTCT and may in fact be detrimental when considering IU HIV-1 transmissions.	\N	\N
23876833	Tyrosine kinase inhibitors treatment in responding chronic myeloid leukaemia (CML) patients is generally continued indefinitely. In this randomised phase II trial, we investigated whether CML patients in molecular response(4.5) (MR(4.5), quantitative reverse-transcription polymerase chain reaction (RQ-PCR)) after previous combination therapy with imatinib and cytarabine may discontinue imatinib treatment safely. Thirty-three patients from the HOVON 51 study with an MR(4.5) for at least 2 years who were still on imatinib treatment were randomised between continuation of imatinib (arm A, n=18) or discontinuation of imatinib (arm B, n=15). After a median follow up of 36 months since randomisation, 3 patients (17%) in arm A and 10 patients (67%) in arm B had a molecular relapse. All 3 relapsing patients in arm A had also stopped imatinib after randomisation. All but one relapsing patient relapsed within 7 months after discontinuation of imatinib. The molecular relapse rate at 12 and 24 months after randomisation was 0% and 6% (arm A) and 53% and 67% (arm B) respectively. As-treated analysis revealed 56% and 61% relapses at 1 and 2 years since cessation in patients who discontinued imatinib, in contrast to 0% of patients who continued imatinib. All evaluable patients remained sensitive to imatinib after reinitiation and regained a molecular response. Our data suggest that discontinuation of imatinib is safe in patients with durable MR(4.5).	\N	\N
23877014	This study aimed to evaluate the efficacy of radiation therapy for pelvic lymph node metastasis from uterine cervical cancer and identify an optimal radiation regimen. A total of 111 metastatic pelvic lymph nodes, ranging from 11 to 56 mm (median, 25 mm) on CT/MRI, in 62 patients with uterine cervical cancer were treated initially with curative radiation therapy, with 46 patients receiving concurrent chemotherapy. Total radiation doses ranged from 45 to 61.2 Gy (median, 50.4 Gy) in 1.8-2 Gy (median, 1.8 Gy) fractions. At a median follow-up of 33 months, 46 of the 62 patients survived. Only 2 irradiated lymph nodes, 24 and 28 mm in diameter, in 1 patient progressed after irradiation alone with 50.4 Gy in 1.8 Gy fractions. All 33 metastatic lymph nodes ≥ 30 mm in diameter were controlled by irradiation at a median dose of 55.8 Gy. The 3-year lymph node-progression free rates were 98.2% in all 62 patients and 98.0% in all 111 metastatic lymph nodes. Except for transient hematologic reactions, 2 patients developed grade ≥ 3 therapy-related toxicities, 1 with an ulcer and the other with perforation of the sigmoid colon. In addition, 2 patients experienced ileus after irradiation. Radiation therapy effectively controlled pelvic lymph node metastases in patients with uterine cervical cancer, with most nodes <24 mm in diameter controlled by total doses of 50.4 Gy in 1.8 Gy fractions and larger nodes controlled by 55.8 Gy, particularly with concurrent chemotherapy. Higher doses to metastatic lymph nodes may increase intestinal toxicities.	\N	\N
23880785	The most abundant urinary protein, Tamm-Horsfall protein, later renamed uromodulin, is expressed exclusively by the thick ascending limb cells of the kidney and released into urine from the apical cell membrane. Uromodulin is believed to protect against urinary tract infections and stones, but its other physiologic functions have remained obscure until recently. Renewed interest in uromodulin has been brought about by the identification of uromodulin mutations as causes of a discrete group of diseases that are distinct from nephronophthisis. The three overlapping clinical uromodulin-associated kidney diseases (UAKD) are medullary cystic disease type 2, familial juvenile hyperuricemic nephropathy and glomerulocystic kidney disease. Previously thought of as "adult diseases", it is now recognized that they may also present in childhood and even in infancy. Common characteristics of all three diseases are autosomal dominant inheritance, unremarkable urine sediment and slow progression to end-stage renal disease (ESRD). They are frequently associated with hyperuricemia and gout. These diseases appear to result from failure of the mutant uromodulin to be incorporated into the apical cilium, thereby placing UAKD in the category of "ciliopathies". In addition to causing specific UAKD, certain uromodulin gene polymorphisms have been linked to ESRD in general, suggesting that uromodulin plays a modulatory role in kidney disease progression.	\N	\N
23886073	Influenza A and B viruses form different genera, which were originally distinguished by antigenic differences in their nucleoproteins and matrix 1 proteins. Cross-protection between these two genera has not been observed in animal experiments, which is consistent with the low homology in viral proteins common to both viruses except for one of three polymerase proteins, polymerase basic 1 (PB1). Recently, however, antibody and CD4+ T cell epitopes conserved between the two genera were identified in humans. A protective antibody epitope was located in the stalk region of the surface glycoprotein, hemagglutinin, and a CD4+ T cell epitope was located in the fusion peptide of the hemagglutinin. The fusion peptide was also found to contain antibody epitopes in humans and animals. A short stretch of well-conserved peptide was also identified in the other surface glycoprotein, neuraminidase, and antibodies binding to this peptide were generated by peptide immunization in rabbits. Although PB1, the only protein which has relatively high overall sequence homology between influenza A and B viruses, is not considered an immunodominant protein in the T cell responses to influenza A virus infection, amino acid sequence comparisons show that a considerable number of previously identified T cell epitopes in the PB1 of influenza A viruses are conserved in the PB1 of influenza B viruses. These data indicate that B and T cell cross-reactivity exists between influenza A and B viruses, which may have modulatory effects on the disease process and recovery. Although the antibody titers and the specific T cell frequencies induced by natural infection or standard vaccination may not be high enough to provide cross protection in humans, it might be possible to develop immunization strategies to induce these cross-reactive responses more efficiently.	\N	\N
23894446	A prostacyclin analogue, ONO-1301, is reported to upregulate beneficial proteins, including stromal cell derived factor-1 (SDF-1). We hypothesized that the sustained-release delivery of ONO-1301 would enhance SDF-1 expression in the acute myocardial infarction (MI) heart and induce bone marrow cells (BMCs) to home to the myocardium, leading to improved cardiac function in mice. ONO-1301 significantly upregulated SDF-1 secretion by fibroblasts. BMC migration was greater to ONO-1301-stimulated than unstimulated conditioned medium. This increase was diminished by treating the BMCs with a CXCR4-neutralizing antibody or CXCR4 antagonist (AMD3100). Atelocollagen sheets containing a sustained-release form of ONO-1301 (n = 33) or ONO-1301-free vehicle (n = 48) were implanted on the left ventricular (LV) anterior wall immediately after permanent left-anterior descending artery occlusion in C57BL6/N mice (male, 8-weeks-old). The SDF-1 expression in the infarct border zone was significantly elevated for 1 month in the ONO-1301-treated group. BMC accumulation in the infarcted hearts, detected by in vivo imaging after intravenous injection of labeled BMCs, was enhanced in the ONO-1301-treated hearts. This increase was inhibited by AMD3100. The accumulated BMCs differentiated into capillary structures. The survival rates and cardiac function were significantly improved in the ONO-1301-treated group (fractional area change 23±1%; n = 22) compared to the vehicle group (19±1%; n = 20; P = 0.004). LV anterior wall thinning, expansion of infarction, and fibrosis were lower in the ONO-1301-treated group. Sustained-release delivery of ONO-1301 promoted BMC recruitment to the acute MI heart via SDF-1/CXCR4 signaling and restored cardiac performance, suggesting a novel mechanism for ONO-1301-mediated acute-MI heart repair.	\N	\N
23899604	In the mammalian nervous system, axons are commonly surrounded by myelin, a lipid-rich sheath that is essential for precise and rapid conduction of nerve impulses. In the peripheral nervous system (PNS), myelin sheaths are formed by Schwann cells which wrap around individual axons. While the tyrosine kinase receptors ERBB2 and ERBB3 are established mediators of peripheral myelination, less is known about the functions of the related epidermal growth factor receptor (EGFR) in the regulation of PNS myelination. Here, we report a peripheral neurodegenerative disease caused by increased EGFR activation. Specifically, we characterize a symmetric and distally pronounced, late-onset muscular atrophy in transgenic mice overexpressing the EGFR ligand epigen. Histological examination revealed a demyelinating neuropathy and axon degeneration, and molecular analysis of signaling pathways showed reduced protein kinase B (PKB, AKT) activation in the nerves of Epigen-tg mice, indicating that the muscular phenotype is secondary to PNS demyelination and axon degeneration. Crossing of Epigen-tg mice into an EGFR-deficient background revealed the pathology to be completely EGFR-dependent. This mouse line provides a new model for studying molecular events associated with early stages of peripheral neuropathies, an essential prerequisite for the development of successful therapeutic interventions.	\N	\N
23902839	To explore the value of sentinel lymph nodes (SLN) metastasis status in predicting the presence of residual disease in non-sentinel lymph nodes (nSLN) and the feasibility of avoiding or reducing the scope of axillary lymph node dissection (ALND) for patients with single positive SLN. A retrospective study was conducted for 2265 patients with invasive breast carcinomas undergoing sentinel lymph nodes biopsy (SLNB) at Shandong Cancer Hospital between November 1999 and December 2011. And 1228 patients with axillary dissection were screened and divided into 5 groups of (-), (1/n), (1/1), (n/N), (n/n) (n ≥ 2, N ≥ 3, N > n) according to the status of SLN metastasis. The nSLN metastasis rate of SLN(-), (1/n), (1/1), (n/N) and (n/n) groups was 11.8%(73/618), 25.2%(65/258), 49.6%(67/135), 48.4%(60/124)and 65.6%(61/93)respectively. A comparison of SLN(-), (1/n), (1/1), (n/N), and (n/n) groups of nSLN metastasis showed a significant difference (P = 0.000). The differences of nSLN metastasis between SLN(-) and other groups (including 1/n, 1/1, n/N, n/n group) were significant (P = 0.000). This difference was also significant between SLN (1/n) and other positive groups (include 1/1, n/N, n/n group) (P = 0.000), but not significant between SLN(1/1), (n/N) and (n/n) groups (P = 0.842, 0.017, 0.042 respectively, Chi-square segmentation). No significant difference existed between axillary lymph node metastasis on Level II and III of SLN 1/n group and SLN(-) group (P = 0.012, 0.570,χ(2) segmentation). The status of SLN metastasis is one of influencing factors for the nSLN metastasis of patients with invasive breast cancer. The possibility of non-sentinel lymph node involvement for patients with single SLN metastasis was smaller than that of other SLN-positive patients. It is safe for some SLN 1/n patients to undergo low lymph node dissection. But ALND is not avoided for patients with single positive SLN (SLN 1/n n ≥ 2). Their clinicopathological variables should be also considered.	\N	\N
23905909	Peripheral arterial diseases associated with an increased risk of death in kidney transplant patients. Natriuretic peptide has anti-atherosclerotic effects. We sought to evaluate the relation between ankle-brachial index and fasting serum long-acting natriuretic peptide concentrations in kidney transplant patients. Fasting blood samples were obtained from 69 kidney transplant patients. Serum long-acting natriuretic peptide concentrations were measured using a commercially available enzyme immunoassay kit. Left or right ankle-brachial index values that were < 0.9 were included in the low ankle-brachial index group. Fifteen patients (21.7%) were enrolled in the low ankle-brachial index group. Increased waist circumference (P = .013), higher serum total cholesterol levels (P = .019), higher triglyceride levels (P = .002), and decreased serum long-acting natriuretic peptide concentrations (P = .006) were noted in the low ankle-brachial index group. Univariate linear regression analysis indicated that the left/right ankle-brachial index values of the subjects were negatively correlated with serum triglycerides (P = .008 or P < .001) and fasting glucose levels (P = .034 or P = .012), but were positively correlated with long-acting natriuretic peptide concentrations (P = .011 or P = .011). Multivariate forward stepwise linear regression analyses of the significant variables revealed that serum triglycerides and long-acting natriuretic peptide levels were independent predictors of the left/right ankle-brachial index values of kidney transplant patients. Serum long-acting natriuretic peptide concentrations correlate positively with ankle-brachial index values among the kidney transplant patients.	\N	\N
23908572	To evaluate the clinical usefulness of binocular multifocal electroretinography (mfERG) by comparing results with conventional monocular mfERG in patients with monocular macular disease. mfERG testing was conducted on 32 patients with monocular macular disease and 30 normal subjects. An initial mfERG was simultaneously recorded from both eyes with two recording electrodes under binocular stimulation. A second mfERG was subsequently recorded with conventional monocular stimulation. Amplitudes and implicit times of each ring response of the binocular and monocular recordings were compared. Ring ratios of the binocular and monocular recording were also compared. In the macular disease group, there were no statistical differences in amplitude or implicit time for each of the five concentric rings between the monocular and binocular recordings. However, with binocular simulation, the ring ratios (ring 1 / ring 4, ring 1 / ring 5) were significantly reduced in the affected eye. In the normal control group, there were no statistical differences in any parameters between the monocular and binocular recordings. Binocular mfERG could be a good alternative to the conventional monocular test. In addition, given that the test needs stable fixation of the affected eye during the binocular test, the reliability of the test results could be improved, especially for patients with monocular macular disease.	\N	\N
23934213	Human Nijmegen breakage syndrome, caused by the hypomorphic mutation of Nbn gene, is a hereditary instability disease, characterized by chromosomal instability, immunodeficiency, radiosensitivity, cancer predisposition and microcephaly. To study the roles of Nbn protein in microcephaly, Nbn gene was specifically deleted in the central nervous system of mice by nestin-Cre targeting gene system (Frappart et al. in Nat Med 11:538-544, 2005). Strikingly, newborn Nbn-deficient mice exhibit the evident microcephalic cerebellum, which contributes to severe ataxia and balance deficiency. In this study, we first report that PI3K/AKT/mTOR signaling pathway that performs neurotrophic-protecting role in neuronal growth is significantly inhibited in newborn Nbn-deficient cortex and cerebellum. In addition, JNK signaling and ATR signaling are likely to converge to regulate the cerebellar apoptosis of newborn Nbn-deficient mice.	\N	\N
23935207	This Phase II trial was designed to evaluate the safety and efficacy of neoadjuvant oxaliplatin and capecitabine and bevacizumab without radiotherapy in patients with poor-risk rectal cancer. Patients with magnetic resonance imaging-defined poor-risk rectal cancer received neoadjuvant oxaliplatin and capecitabine and bevacizumab followed by total mesorectal excision or more extensive surgery. Between February 2010 and December 2011, 32 patients were enrolled in this study. The completion rate of the scheduled chemotherapy was 91%. Reasons for withdrawal were refusal to continue therapy in two patients and disease progression in one, with two of these three patients not undergoing surgery. Among the 29 patients who completed the scheduled chemotherapy, one refused surgery within 8 weeks after the completion of chemotherapy, which was the period stipulated by the protocol, and another had rectal perforation, requiring urgent laparotomy. As a result, the completion rate of this experimental treatment was 84%. Of the 30 patients who underwent surgery, the R0 resection rate was 90% and a postoperative complication occurred in 43%. A pathological complete response was observed in 13% and good tumor regression was exhibited in 37%. Neoadjuvant oxaliplatin and capecitabine plus bevacizumab for poor-risk rectal cancer caused a high rate of anastomotic leakage and experienced a case with perforation during chemotherapy, both of which were bevacizumab-related toxicity. Although the short-term results with the completion rate of 84.4% and the pathological complete response rate of 13.3% were satisfactory, we have to reconsider the necessity of bevacizumab in neoadjuvant chemotherapy (UMIN number, 000003507).	\N	\N
23955530	Type 1 diabetes (T1D) is one of the most common chronic diseases with childhood onset, and the disease incidence has increased two to fivefold over the past half century by as yet unknown means. T1D occurs when the body's immune system turns against itself, destroying in a very specific and targeted way-the pancreatic β-cells. T1D results from poorly defined interactions between susceptibility genes and environmental determinants. In contrast to the rapid progress in finding T1D genes, identification and confirmation of environmental determinants remain a formidable challenge. This review article will give an overview of ongoing prospective cohort studies aiming to identify the environmental trigger(s) causing T1D.	\N	\N
23956301	Human papillomavirus 16 (HPV16) infection causes 50 % or more of cervical cancers in women. The HPV16 E7 oncogene is continuously expressed in infected epithelium with its oncogenicity linked to cervical cancer. The E7 protein is an ideal target in control of HPV infection through T-cell-mediated immunity. Using HPV16 E7-transgenic mouse keratinocytes (KCs-E7) to investigate T-cell-mediated immune responses, we have shown previously that HPV16-encoded E7 protein inhibits IFN-γ-mediated enhancement of MHC class I antigen processing and T-cell-induced target cell lysis. In this study, we found that HPV16 E7 suppresses IFN-γ-induced phosphorylation of STAT1((Tyr701)), leading to the blockade of interferon regulatory factor-1 (IRF-1) and transporter associated antigen processing subunit 1 (TAP-1) expression in KCs-E7. The results of a (51)Cr release assay demonstrated that IFN-γ-treated KCs-E7 escaped from CTL recognition because HPV16 E7 downregulated MHC class I antigen presentation on KCs. Restoration of IRF-1 expression in KCs-E7 overcame the inhibitory effect of E7 protein on IFN-γ-mediated CTL lysis and MHC class I antigen presentation on KCs. Our results suggest that HPV16 E7 interferes with the IFN-γ-mediated JAK1/JAK2/STAT1/IRF-1 signal transduction pathway and reduces the efficiency of peptide loading and MHC class I antigen presentation on KCs-E7. These results may reveal a new mechanism whereby HPV16 escapes from immune surveillance in vivo.	\N	\N
23962064	Understanding how alveoli and the underlying capillary network develop and how these mechanisms are disrupted in disease states is critical for developing effective therapies for lung regeneration. Recent evidence suggests that lung angiogenesis promotes lung development and repair. Vascular endothelial growth factor (VEGF) preserves lung angiogenesis and alveolarization in experimental O2-induced arrested alveolar growth in newborn rats, but combined VEGF+angiopoietin 1 treatment is necessary to correct VEGF-induced vessel leakiness. Hypoxia-inducible factors (HIFs) are transcription factors that activate multiple O2-sensitive genes, including those encoding for angiogenic growth factors, but their role during postnatal lung growth is incompletely understood. By inducing the expression of a range of angiogenic factors in a coordinated fashion, HIF may orchestrate efficient and safe angiogenesis superior to VEGF. We hypothesized that HIF inhibition impairs alveolarization and that HIF activation regenerates irreversible O2-induced arrested alveolar growth. HIF inhibition by intratracheal dominant-negative adenovirus (dnHIF-1α)-mediated gene transfer or chetomin decreased lung HIF-1α, HIF-2α, and VEGF expression and led to air space enlargement and arrested lung vascular growth. In experimental O2-induced arrested alveolar growth in newborn rats, the characteristic features of air space enlargement and loss of lung capillaries were associated with decreased lung HIF-1α and HIF-2α expression. Intratracheal administration of Ad.HIF-1α restored HIF-1α, endothelial nitric oxide synthase, VEGF, VEGFR2, and Tie2 expression and preserved and rescued alveolar growth and lung capillary formation in this model. HIFs promote normal alveolar development and may be useful targets for alveolar regeneration.	\N	\N
23962825	G protein-mediated signal transduction is essential for the regulation of cardiovascular function, including heart rate, growth, contraction, and vascular tone. Regulators of G protein Signaling (RGS proteins) fine-tune G protein-coupled receptor-induced signaling by regulating its magnitude and duration through direct interaction with the α subunits of heterotrimeric G proteins. Changes in the RGS protein expression and/or function in the heart often lead to pathophysiological changes and are associated with cardiac disease in animals and humans, including hypertrophy, fibrosis development, heart failure, and arrhythmias. This article focuses on Regulator of G protein Signaling 2 (RGS2), which is widely expressed in many tissues and is highly regulated in its expression and function. Most information to date has been obtained in biochemical, cellular, and animal studies, but data from humans is emerging. We review recent advances on the functional role of cardiovascular RGS2 and the mechanisms that determine its signaling selectivity, expression, and functionality. We highlight key unanswered questions and discuss the potential of RGS2 as a therapeutic target.	\N	\N
23968196	Actinic prurigo (AP) is an idiopathic photodermatosis that usually onsets during childhood and predominates in women. It is characterized by the symmetrical involvement of sun-exposed areas of the skin, lips, and conjunctiva. This study aimed to analyze the risk factors associated with AP using a case-control design. All patients diagnosed with AP during 1990-2006 at Dr. Manuel Gea González General Hospital in Mexico City were included. Respective controls were recruited. Race, demographic, geographic, socioeconomic, environmental, clinical, and nutritional risk factors were assessed. A total of 132 persons were enrolled. These included 44 cases and two control groups comprising, respectively, dermatology and non-dermatology outpatients without AP or any autoimmune disease. Distribution by gender, age, place of birth, place of residence, and economic status did not differ significantly among the three groups. A total of 256 variables were analyzed. Only 19 variables were found to be statistically significant (P < 0.05). These were: use of a boiler; use of firewood; car ownership; use of earthenware; mixed material housing; socioeconomic level 1; sun exposure; use of soap; lemon consumption; use of moisturizing hair cream; living with pets in the house; living with farm animals; age; having a family member with AP; having had surgery; having had trauma; having been hospitalized; use of oral medication; and use of herbal medication. Of 40 macro- and micronutrients analyzed, 11 were found to have statistically significant effects (P < 0.05). Multiple epidemiologic, geographic, clinical, and immunologic factors are involved in the etiology of AP. This study proposes a clear line for research directed at specific risk factors that refer to an individual's clinical, allergic, health, and socioeconomic status. Further study should also investigate the etiologic role of diet in AP and the molecular mechanisms behind the development of AP to establish whether AP is caused by exposure to polycyclic aromatic hydrocarbons.	\N	\N
23982030	To determine the rate of unplanned PICU readmissions, examine the characteristics of index admissions associated with readmission, and compare outcomes of readmissions versus index admissions. Retrospective cohort analysis. Ninety North American PICUs that participated in the Virtual Pediatric Intensive Care Unit Systems. One hundred five thousand four hundred thirty-seven admissions between July 2009 and March 2011. None. Unplanned PICU readmission within 48 hours of index discharge was the primary outcome. Summary statistics, bivariate analyses, and mixed-effects logistic regression model with random effects for each hospital were performed.There were 1,161 readmissions (1.2%). The readmission rate varied among PICUs (0-3.3%), and acute respiratory (56%), infectious (35%), neurological (28%), and cardiovascular (20%) diagnoses were often present on readmission. Readmission risk increased in patients with two or more complex chronic conditions (adjusted odds ratio, 1.72; p < 0.001), unscheduled index admission (adjusted odds ratio, 1.37; p < 0.001), and transfer to an intermediate unit (adjusted odds ratio, 1.29; p = 0.004, compared with ward). Trauma patients had a decreased risk of readmission (adjusted odds ratio, 0.67; p = 0.003). Gender, race, insurance, age more than 6 months, perioperative status, and nighttime transfer were not associated with readmission. Compared with index admissions, readmissions had longer median PICU length of stay (3.1 vs 1.7 d, p < 0.001) and higher mortality (4% vs 2.5%, p = 0.002). Unplanned PICU readmissions were relatively uncommon, but were associated with worse outcomes. Several patient and admission characteristics were associated with readmission. These data help identify high-risk patient groups and inform risk-adjustment for standardized readmission rates.	\N	\N
23983044	To determine the differences in carotid intima-media thickness (CIMT) between patients with psoriatic diseases with and without metabolic syndrome. Eligible patients from the Cardiometabolic Outcome Measures in Psoriatic Arthritis Study database, which is comprised of both psoriasis and psoriatic arthritis (PsA) patients enrolled at 2 academic medical centers, were included. Detailed cardiovascular (CV) risk factors, including metabolic syndrome profiles, medication use, disease activity, and CIMT, were examined. A total of 343 patients with psoriatic disease were evaluated (42.28% with psoriasis and 57.72% with PsA). PsA patients were significantly older, with longer disease duration and higher blood pressure, body mass index, and C-reactive protein (CRP) level. PsA patients took more disease-modifying antirheumatic drugs (DMARDs) and corticosteroids and underwent more CV procedures. There were no differences in prior CV events, family history of CV risk, and Framingham/Adult Treatment Panel III Risk Score. PsA patients had a higher risk of metabolic syndrome (univariate odds ratio [OR] 1.78 [95% confidence interval (95% CI) 1.08-2.95], P = 0.025). Even after adjusting for age, CRP level, and diastolic blood pressure, PsA patients not taking DMARDs were twice as likely to have metabolic syndrome compared to psoriasis patients (adjusted OR 2.09 [95% CI 0.78-5.59], P = 0.049). PsA patients with metabolic syndrome had the thickest CIMT compared to any other group (P < 0.001). PsA patients had an increased prevalence of metabolic syndrome with significantly greater CIMT measurements compared to patients with psoriasis. Furthermore, PsA patients with metabolic syndrome had the greatest CIMT measurements compared to PsA patients without metabolic syndrome and psoriasis patients with or without metabolic syndrome. Incremental increases in inflammatory pathways in PsA may contribute to a higher CV risk as compared to psoriasis patients.	\N	\N
23987905	This study evaluated effectiveness of three different surgical strategies for treating ascending aorta aneurysm, with or without involvement of the aortic root, associated with bicuspid aortic valve (BAV). Between 2005 and 2011, 150 consecutive patients underwent a Bentall operation in the presence of ascending aorta and aortic root dilation exceeding 45 mm in diameter and malfunctioning BAV (n = 46, group 1); separate aortic valve and ascending aorta replacement in presence of ascending aorta dilation exceeding 45 mm, aortic root of less than 45 mm, and malfunctioning BAV (n = 77, group 2); or ascending aorta replacement, with or without BAV repair, in the presence of ascending aorta dilation exceeding 45 mm, aortic root of less than 45 mm, and normally functioning or mildly insufficient BAV (n = 27, group 3). Compared with groups 2 and 3, group 1 patients were younger and affected by more severe BAV insufficiency and worse left ventricular function. In groups 1, 2, and 3, respectively, operative mortality was 2.1%, 1.3%, and 0%, and 5-year survival was 94% ± 4%, 92% ± 3.4%, and 100%. At 5 years, no patient in any group required reoperation on the ascending aorta or experienced aortic complications. In groups 2 and 3, root dimensions did not increase and were also significantly smaller compared with preoperative measurements (p < 0.05). Aortic regurgitation grade in group 3 (0.5 ± 0.8/4+) did not increase compared with the preoperative grade (0.8 ± 0.9/4+). At midterm follow-up, the Bentall operation remains associated with optimal results for the treatment of BAV, despite a worse preoperative presentation. In presence of a mildly diseased or normal aortic root and normal BAV function at the time of operation, less invasive surgical procedures, BAV-sparing, or repair procedures, appear to offer gratifying results.	\N	\N
23993863	Despite extensive study, few therapeutic targets have been identified for glioblastoma (GBM). Here we show that patient-derived glioma sphere cultures (GSCs) that resemble either the proneural (PN) or mesenchymal (MES) transcriptomal subtypes differ significantly in their biological characteristics. Moreover, we found that a subset of the PN GSCs undergoes differentiation to a MES state in a TNF-α/NF-κB-dependent manner with an associated enrichment of CD44 subpopulations and radioresistant phenotypes. We present data to suggest that the tumor microenvironment cell types such as macrophages/microglia may play an integral role in this process. We further show that the MES signature, CD44 expression, and NF-κB activation correlate with poor radiation response and shorter survival in patients with GBM.	\N	\N
24010694	Lenalidomide is an immunomodulatory drug approved by the AEMPS and the EMA, in combination with dexamethasone, for the treatment of multiple myeloma in adult patients who have received at least one prior therapy. Moreover, it has recently been approved for the treatment of patients with transfusion-dependent anaemia due to low- or intermediate-1-risk myelodysplastic syndromes associated with an isolated deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate. It has also shown to be active in other hematologic and no hematologic diseases. Growing evidence of its use entails a challenge when situating the drug in a cost-effective way to treat these diseases. On this article we review the available evidence on the use of lenalidomide in the second line treatment of patients with chronic lymphocytic leukemia, primary amyloidosis and primary myelofibrosis, and in the first line treatment of patients with myelodysplastic syndrome, and also the evidence of other immunomodulators. Different clinical practice guidelines and scientific evidence portals consider lenalidomide a valid alternative in the first-line treatment of patients with myelodysplastic syndromes, specially those with the deletion of 5q, and in second line for patients with chronic lymphocytic leukemia. However, the available evidence of lenalidomide in the treatment of patients with primary amyloidosis and primary myelofibrosis is limited, ant thus is not considered as the first choice treatment. In any case, the treatment of choice should consider the safety profile in each patient, the previous treatments that has received and the own therapeutic protocols of each center.	\N	\N
24016609	Retinopathy of prematurity (ROP) is a leading cause of childhood blindness. This retrospective study investigated ROP, including incidence, demographic information,risk factors, treatments, and refractive outcomes, in southern Taiwan over a 10-year period. The authors retrieved the National Cheng Kung University Hospital database between the years 2000 and 2009 for newborns with a gestational age less than 32 weeks and/or with a birth weight less than 1500 g who had been screened for ROP. We recorded sex, birth weight, gestational age, in-hospital versus out-of-hospital birth, paternal and maternal ages, whether there were multiple gestations, parity, Apgar scores, length of hospital stay, risk factors, presence and severity of ROP and whether it was treated, and refraction at the last visit. Regression analyses were performed to identify risk factors for ROP. A total of 503 live births were included. ROP was identified in 190 (37.8%) and met criteria for treatment in 59 (11.7%).ROP was diagnosed as stage 1, 2, 3, 4, and 5 in 61 (12.1%), 36 (7.2%), 81 (16.1%), 11 (2.2%), and 1 (0.2%) infant, respectively. Lower birth weight and younger gestational age were risk factors for greater severity of ROP (p < 0.001). Of the 167 with extremely low birth weight (<1000 g), 118 (70.7%) had ROP and 49 (29.3%) required treatment. On univariate analysis, low birth weight, younger gestational age, and risk factors such as respiratory distress syndrome, chronic lung disease, patent ductus arteriosus, surfactant usage, indomethacin usage, sepsis, upper gastrointestinal bleeding, blood transfusion, and necrotizing enterocolitis were associated with ROP. Multivariate logistic regression analysis showed that only lower birth weight was a significant and independent risk factor for ROP. Myopia (76%)and anisometropia (28%)were common in advanced ROP. Low birth weight is a major risk factor for ROP. Infants with extremely low birth weight had a higher risk of severe ROP. Common ocular sequelae of advanced ROP were myopia and anisometropia.	\N	\N
24021446	We present two young patients with morphea or localized scleroderma undergoing systemic treatment, who developed papular lesions on pre-existing sclerotic plaques. Histology was compatible with a papular presentation of morphea and other entities in the differential diagnosis were ruled out. We believe this is a very uncommon presentation of activity in lesions of morphea and should be made known to clinicians so that activity and progression of the disease can be recognized and treated to avoid complications.	\N	\N
24032423	Spinocerebellar ataxia type 1 (SCA1) is a hereditary, progressive and fatal movement disorder that primarily affects the cerebellum. Non-invasive imaging markers to detect early disease in SCA1 will facilitate testing and implementation of potential therapies. We have previously demonstrated the sensitivity of neurochemical levels measured by (1) H magnetic resonance spectroscopy (MRS) to progressive neurodegeneration using a transgenic mouse model of SCA1. In order to investigate very early neurochemical changes related to neurodegeneration, here we utilized a knock-in mouse model, the Sca1(154Q/2Q) line, which displays milder cerebellar pathology than the transgenic model. We measured cerebellar neurochemical profiles of Sca1(154Q/2Q) mice and wild-type littermates using 9.4T MRS at ages 6, 12, 24, and 39 weeks and assessed the cerebellar pathology of a subset of the mice at each time point. The Sca1(154Q/2Q) mice displayed very mild cerebellar pathology even at 39 weeks, however, were distinguished from wild types by MRS starting at 6 weeks. Taurine and total choline levels were significantly lower at all ages and glutamine and total creatine levels were higher starting at 12 weeks in Sca1(154Q/2Q) mice than controls, demonstrating the sensitivity of neurochemical levels to neurodegeneration related changes in the absence of overt pathology. We measured cerebellar neurochemical alterations in a knock-in mouse model of spinocerebellar ataxia type 1, a hereditary movement disorder, using ultra-high field magnetic resonance spectroscopy (MRS). Very early neurochemical alterations were detectable prior to overt pathology in the volume-of-interest for MRS. Alterations were indicative of osmolytic changes and of disturbances in membrane phospholipid and energy metabolism.	\N	\N
24039761	Pig is an important agricultural animal for meat production and provides a valuable model for many human diseases. Functional studies have demonstrated that microRNAs (miRNAs) play critical roles in almost all aspects of skeletal muscle development and disease pathogenesis. To investigate the miRNAs involved in regulating different periods of skeletal muscle development, we herein performed a comprehensive research for porcine microRNAome (miRNAome) during 10 skeletal muscle developmental stages including 35, 49, 63, 77, 91 dpc (days post coitum) and 2, 28, 90, 120, 180 dpn (days postnatal) using Solexa sequencing technology. Our results extend the repertoire of pig miRNAome to 247 known miRNAs processed from 210 pre-miRNAs and 297 candidate novel miRNAs through comparison with known miRNAs in the miRBase. Expression analysis of the 15 most abundant miRNAs in every library indicated that functional miRNAome may be smaller and tend to be highly expressed. A series of muscle-related miRNAs summarized in our study present different patterns between myofibers formation phase and muscle maturation phase, providing valuable reference for investigation of functional miRNAs during skeletal muscle development. Analysis of temporal profiles of miRNA expression identifies 18 novel candidate myogenic miRNAs in pig, which might provide new insight into regulation mechanism mediated by miRNAs underlying muscle development.	\N	\N
24050030	To evaluate serum and peritoneal concentrations of amyloid protein A in women with endometriosis and to compare them with those of women without endometriosis. A prospective study evaluated 76 women suspected of having pelvic endometriosis. Fifty-seven women (group A) were confirmed by videolaparoscopy and had their serum and peritoneal amyloid A concentrations measured by ELISA. The average levels from group A were compared to those obtained in group B. Group B was composed of 13 women without endometriosis, submitted to elective laparoscopy for tubal ligation. Peritoneal amyloid A concentrations in group A (310.3 +/- 97.8 ng/mL) were higher than those of group B (53.4 +/- 58.2 ng/mL); p = 0.0. However, serum concentrations in groups A (14.01 +/- 32.3 ng/mL) and B (9.5 +/- 15.9 ng/mL) did not differ significantly; p = 0.35. The peritoneal amyloid A protein concentration in pelvic endometriosis was higher when compared to normal controls, corroborating the inflammatory nature of the disease. This finding suggests that the procedure of evaluating the peritoneal amyloid A concentration in endometriosis merits further investigation.	\N	\N
24052521	Resistin, which is derived from the gene of RSTN, belongs to a family of cysteine-rich secretory proteins called resistin-like molecules (RELMs). Increased serum resistin levels are associated with coronary artery disease (CAD) and the risk of cardiovascular death. Patients (n = 214) with an initial diagnosis of stable angina pectoris, unstable angina pectoris, and myocardial infarction without ST-segment elevation and referred to catheter laboratory for coronary angiography were enrolled in the study. We aimed to investigate the relationship between increased serum resistin level and CAD. The severity of CAD was calculated by the Gensini scoring system. In conclusion, we established a significant correlation between serum resistin levels and CAD (P = .010). Also, serum resistin levels correlated with the Gensini score that represents the severity of CAD angiographically (P = .010).	\N	\N
24063011	Aspergillus fumigatus is a ubiquitously present respiratory pathogen. The outcome of a pulmonary disease may vary significantly with fungal viability and host immune status. Our objective in this study was (1) to assess the ability of inhaled irradiation-killed or live A. fumigatus spores to induce allergic pulmonary disease and (2) to assess the extent to which inhaled dead or live A. fumigatus spores influence pulmonary symptoms in a previously established allergic state. Our newly developed fungal delivery apparatus allowed us to recapitulate human exposure through repeated inhalation of dry fungal spores in an animal model. We found that live A. fumigatus spore inhalation led to a significantly increased humoral response, pulmonary inflammation, and airway remodeling in naïve mice and is more likely to induce allergic asthma symptoms than the dead spores. In contrast, in allergic mice, inhalation of dead and live conidia recruited neutrophils and induced goblet cell metaplasia. This data suggests that asthma symptoms might be exacerbated by the inhalation of live or dead spores in individuals with established allergy to fungal antigens, although the extent of symptoms was less with dead spores. These results are likely to be important while considering fungal exposure assessment methods and for making informed therapeutic decisions for mold-associated diseases.	\N	\N
24064013	Since the publication of the first reports on the efficiency of colchicine in familial Mediterranean fever (FMF), very few randomised studies have investigated issues related to its long-term use. Thus, different approaches taken by physicians involved in FMF care, are exclusively empiric, emulative, and based on case-reports or case-series. Problems such as colchicine intolerance and colchicine resistance have not been solved yet. This paper aims to evaluate trends in colchicine therapy among physicians taking care of FMF patients around the world. We conducted a survey by sending questionnaires to FMF research and treatment centres in Europe and Asia. Many issues (such as dosages, schedules, side effects, interactions, efficacy and toxicity monitoring, definition of colchicine intolerance, colchicine resistance and responsiveness, etc) have been investigated. When more than 70% of physicians responded giving similar answers to an item, the response was considered as a 'trend'. A comparison between answers of physicians from FMF-prevalent and non-prevalent countries was also made. Thirty-five physicians from 11 countries filled the questionnaires, taking care of a total of more than 15000 FMF patients (pts). Different approaches were evident among the various physicians. Statistically significant different approaches between physicians from FMF-prevalent countries with respect to those from non-prevalent countries were found in items like colchicine during pregnancy, severity score and blood tests for disease monitoring. No consensus was found regarding the definition of colchicine resistance. The current study demonstrated significant variations in the strategy of colchicine therapy for FMF around the world and re-emphasised the need for standardised definitions of colchicine resistance and colchicine intolerance.	\N	\N
24072601	Increasing evidence suggests low disease activity or remission is achievable in rheumatoid arthritis (RA). Using a treat to target strategy (T2T) has been shown to achieve these targets of remission or low disease activity in RA. In order to successfully treat to target, rheumatologists need reliable measures of disease activity to switch and/or escalate therapy to achieve or maintain therapeutic targets. Multiple disease-activity measures have been developed for both research and clinical practice. For clinical practice, the American College of Rheumatology (ACR) has recommended the PAS, PAS II, RAPID 3, CDAI, DAS 28, and SDAI for measuring disease activity in rheumatoid arthritis. Each of these measures has strengths and limitations, but they all accurately reflect disease activity, discriminate well between disease states, and are feasible to perform in the clinical setting. Implementation in the clinical setting can be optimized through leveraging technology and systems redesign. Tools such as web-based and smartphone applications have been developed to increase the ease with which these measures can be deployed. Disease-activity measurement in rheumatoid arthritis is included in the rheumatoid arthritis quality measures group in the Centers for Medicare and Medicaid Services' incentive-based Physician Quality Reporting System.	\N	\N
24098438	Seminoma is one of the most common Testicular Germ Cell Tumours that originates during embryonic development due to an alteration of the local niche that in turn results in a delayed or blocked differentiation of Primordial Germ Cells. The block of differentiation is actually a common way to develop cancer disease as postulated by the "embryonic rest theory of cancer". In agreement with this theory different studies have demonstrated that embryonic cues display the capacity of reprogramming aggressive cancer cells towards a less aggressive phenotype. Herein we investigate the ability of a culture medium added with 10% egg albumen (EW, Egg White) to modulate seminoma cell phenotype and behaviour, by ensuring a proper set of morphogenetic signals. We chose to use the TCam-2 seminoma cell line that has been established as the only available cell line, obtained from a primary testicular seminoma. EW is able to: 1) modify TCam-2 cell spreading rate and cell-substrate adhesion without affecting proliferation and survival indexes; 2) modulate TCam-2 actin distribution pattern increasing cortical localization of actin filaments; 3) increase TCam-2 cell-cell junction capability; 4) decrease both chemo-sensitive and collective TCam-2 migratory behaviour. According to these observations morphometric fractal analysis revealed the ability of EW to increase Circularity and Solidity parameters and, consequently, to decrease Fractal dimension. Prompted by these observations we hypothesize that EW treatment could rescue, at least in part, the neoplastic-metastatic behaviour of seminoma cells.	\N	\N
24102319	Transient receptor potential (TRP) channels are important mediators of sensory signals with marked effects on cellular functions and signalling pathways. Indeed, mutations in genes encoding TRP channels are the cause of several inherited diseases in humans (the so-called 'TRP channelopathies') that affect the cardiovascular, renal, skeletal and nervous systems. TRP channels are also promising targets for drug discovery. The initial focus of research was on TRP channels that are expressed on nociceptive neurons. Indeed, a number of potent, small-molecule TRPV1, TRPV3 and TRPA1 antagonists have already entered clinical trials as novel analgesic agents. There has been a recent upsurge in the amount of work that expands TRP channel drug discovery efforts into new disease areas such as asthma, cancer, anxiety, cardiac hypertrophy, as well as obesity and metabolic disorders. A better understanding of TRP channel functions in health and disease should lead to the discovery of first-in-class drugs for these intractable diseases. With this review, we hope to capture the current state of this rapidly expanding and changing field.	\N	\N
24107731	The metabolic dysfunction accompanying the polycystic ovary syndrome (PCOS) may increase the risk of hypertension and cardiovascular disease (CVD). Although menopause per se may be an additional risk factor of CVD, the association between PCOS in postmenopausal women and cardiovascular risk has not been adequately investigated. We aimed to evaluate the effect of PCOS on markers of subclinical atherosclerosis in nondiabetic postmenopausal women. This cross-sectional study included 286 postmenopausal women with intact ovaries. PCOS phenotype was defined if three of the following were present: insulin resistance, current hyperandrogenism or history of clinical androgen excess, history of infertility, central obesity and history of irregular menses. Traditional CVD risk factors, as well as indices of arterial structure (intima-media thickness, atheromatous plaques presence) and function [flow-mediated dilation, pulse wave velocity (PWV), augmentation index] were compared between women with a PCOS phenotype and the rest of the sample, who served as controls. Women with the PCOS phenotype (N=43) had higher SBP and triglycerides and lower high-density lipoprotein (HDL)-cholesterol than controls. Mean values of PWV differed significantly between PCOS cases and controls (9.46±1.74 vs. 8.60±1.51 m/s, P=0.001, univariate). Multivariate regression analysis showed that the PCOS phenotype, age and SBP were the only independent predictors of PWV. Arterial stiffness is increased in asymptomatic, nondiabetic women with a putative PCOS phenotype, independently of age, BMI or blood pressure. This might present one mechanism through which PCOS increases the risk of CVD and hypertension later in life.	\N	\N
24108471	Brain vasculature is uniquely programmed to protect central nervous system tissues and respond to their metabolic demands. These functions are subverted during the development of primary and metastatic brain tumors, resulting in vascular perturbations that are thought to contribute to progression and comorbidities of the underlying disease, including thrombosis and hemorrhage. Chronic activation of the coagulation system is particularly obvious in glioblastoma multiforme (GBM), where intratumoral vasoocclusive thrombosis may contribute to hypoxia, pseudopalisading necrosis, and angiogenesis. GBM is also associated with spontaneous or iatrogenic bleeding, and the emission of circulating procoagulants implicated in the unusually high risk of peripheral venous thromboembolism. Tissue factor (TF) expression is elevated in several types of brain tumors, including adult and pediatric GBM, as is the production of TF-containing microparticles (TF-MPs). Both TF expression and its vesicular emission are regulated by tumor microenvironment (e.g., hypoxia), in concert with activated oncogenic and growth factor pathways (RAS, EGFR, MET), as well as the loss of tumor suppressor gene activity (PTEN). Discovery of distinct oncogenic networks led to recognition of unique molecular subtypes within brain tumors, of which GBM (proneural, neural, classical, and mesenchymal), and medulloblastoma (SHH, WNT, group 3, and group 4) exhibit subtype-specific composition of the tumor coagulome. It remains to be established whether mechanisms of thrombosis and biological effects of coagulation in brain tumors are also subtype specific. In this regard, TF pathway represents a paradigm, and its impact on tumor dormancy, inflammation, angiogenesis, formation of cancer stem cell niches, and dissemination is a subject of considerable interest. However, establishing the extent to which TF and TF-MPs contribute to pathogenesis and thromboembolic disease in the context of primary and secondary brain tumors may require molecular stratification of patient populations. We suggest that a better understanding of these molecular linkages may pave the way to a more effective (targeted) therapy, prophylaxis, adjunctive use of anticoagulants, and other agents able to modulate interactions between brain tumors and the coagulation system.	\N	\N
24124671	To explore the exercise characteristics of patients with idiopathic pulmonary arterial hypertension (IPAH). From November 2010 to September 2012 , 76 consecutive IPAH patients and 24 healthy controls from Fuwai Cardiovascular Hospital were enrolled to undergo cardiopulmonary exercise testing. The exercise parameters were compared. Correlations among peak oxygen consumption, anaerobic threshold, peak oxygen pulse, New York Heart Association (NYHA) class, N-terminal pro-brain natriuretic peptide (NT-proBNP), 6-minute walking distance (6 MWD) and cardiac index are analyzed in IPAH. There were 21 males and 55 females in IPAH and 8 males and 16 females in controls. Their mean ages were (31.5 ± 10.6) and (35.5 ± 6.4) years respectively. Significant differences (P = 0.000) existed between two groups in peak oxygen consumption ((12.7 ± 3.3) vs (25.6 ± 5.8) ml·min(-1)·kg(-1)), anaerobic threshold ((9.8 ± 2.5) vs (16.7 ± 3.9) ml·min(-1)·kg(-1)), peak oxygen pulse ((5.3 ± 1.6) vs (9.9 ± 2.5) ml/bpm) and ventilator efficiency (slope of minute ventilation in relation to CO2 produced) ((42.6 ± 2.0) vs (25.5 ± 3.5)). In IPAH, peak oxygen consumption was significantly correlated with NYHA class (r = -0.509, P = 0.000), 6 MWD (r = 0.443, P = 0.002) and NT-proBNP levels (r = -0.423, P = 0.011). And anaerobic threshold was significantly correlated with NYHA class (r = -0.362, P = 0.002), 6MWD (r = 0.343, P = 0.004) and NT-proBNP levels (r = -0.275, P = 0.017). Peak oxygen pulse and ventilator efficiency were both correlated well with total pulmonary vascular resistance. Partial correlation analysis demonstrated that there were significant correlations among peak oxygen consumption, anaerobic threshold, NYHA class, NT-proBNP levels and 6MWD after adjusting for age, gender and weight. Peak oxygen consumption and anaerobic threshold decrease ventilator efficiency in IPAH patients. Cardiopulmonary exercise testing is an invasive tool of assessing safely the function of IPAH patients.	\N	\N
24127735	Knee osteoarthritis (OA) is a major cause of pain, functional limitation, and reduced quality-of-life, particularly in older adults. This study evaluated the 'real world' NSAID-sparing effect of glucosamine (specifically Structoflex®) in patients with knee OA compared with a control population of patients who did not receive a slow-acting symptomatic anti-osteoarthritis agent. This analysis was conducted over a 1-year follow-up period. Data were sourced from the French Disease Analyzer (IMS Lifelink EMR™) database. The primary measure was the NSAID-sparing effect produced by Structoflex® compared with a matched control group. Secondary measures included an evaluation of the change in the number of general practitioner visits and use of other medicinal products related to knee OA. A total of 11,772 patients (67.66% female) were included in the analysis (436 and 11,336 patients in the Structoflex® and control groups, respectively). Most patients were aged 50-65 years (58.72%); 19.5% of patients were aged >76 years. At study inclusion, 51.61% of patients had experienced OA for <1 year. Prior to starting Structoflex®, 51.61% of patients had received an NSAID prescription. Significantly more patients who were receiving an NSAID at the time of starting Structoflex® discontinued their NSAID treatment during the follow-up period compared with patients in the control group (32% vs 23%; p = 0.0452). During the 1-year follow-up period, the total mean duration of NSAID prescription (30.39 ± 38.64 days vs 37.82 ± 54.62 days; p = 0.0109) and the mean number of days (calculated using Defined Daily Dose) on NSAID (45.12 ± 49.03 days vs 53.00 ± 71.14 days; p = 0.0333) was significantly lower in Structoflex®-treated patients compared with control group patients. This large 'real world' analysis demonstrated a significant NSAID-sparing effect of glucosamine in patients with knee OA.	\N	\N
24138892	I shall discuss the work of researchers at Harvard Medical School who came together in the early 1990s. Scattered across various Harvard-affiliated hospitals and research centers, these individuals were unified by their interest in ocular neovascularization. Together and separately, they investigated models of ocular neovascularization, exploring tumor angiogenesis in eye development and disease.	\N	\N
24141443	To validate the Clinical Gait and Balance Scale (GABS) for a Brazilian population of patients with Parkinson's disease (PD) and to compare it to the Berg Balance Scale (BBS). One hundred and seven PD patients were evaluated by shortened UPDRS motor scale (sUPDRSm), Hoehn and Yahr (HY), Schwab and England scale (SE), Falls Efficacy Scale International (FES-I), Freezing of Gait Questionnaire (FOG-Q), BBS and GABS. The internal consistency of the GABS was 0.94, the intra-rater and inter-rater reliability were 0.94 and 0.98 respectively. The area under the receiver operating characteristic (ROC) curve was 0.72, with a sensitivity of 0.75 and specificity of 0.6, to discriminate patients with a history of falls in the last twelve months, for a cut-off score of 13 points. Our study shows that the Brazilian version of the GABS is a reliable and valid instrument to assess gait and balance in PD.	\N	\N
24144148	Pompe disease is a rare, progressive and often fatal neuromuscular disorder. It is caused by a deficiency of the lysosomal alpha-glucosidase. Among glycogen storage disorders, it is one of the most common. Its clinical manifestations can start at any moment of life, with a very variable symptomatology. In this article, we show an extended revision of the literature in regards to the main medical aspects of Pompe disease: etiology, psychopathology, epidemiology, clinical variants, pathological diagnosis, and enzyme replacement therapy. With this information, we created a diagnostic and therapeutic guide, which is addressed to specialists and to first-level physicians, in order to let them identify both the classic and the late forms of this disease. We describe as well the best, timely, multidisciplinary treatment in use. Also, we show some suggestions to the proper functioning of health institutions, and routes to diagnosis. We conclude that Pompe disease may be properly diagnosed and treated if health care professionals follow the internationally approved recommendations.	\N	\N
24151631	Cystic echinococcosis (CE) is a chronic, clinically complex, and neglected disease. Its prevalence in Italy, a country of medium to high endemicity, remains poorly defined, as notification has long ceased to be mandatory. We set up a retrospective cohort study involving all CE patients followed at our institute between January 2005 and December 2012. Demographical and clinical features were recorded and analyzed. CE was found in 28 patients (64.3%), mostly Italians from the central regions (50%), followed by subjects from the islands (33.3%) and Southern Italy (16.7%). Their median age was 45 years (IQR: 38.5-66.5), with Eastern Europeans being significantly younger (28 years, IQR: 19-39) than other patients (P ≤ 0.0001). A total of 149 cysts, mostly with hepatic localization (96%), were described. Based on the WHO classification, the cysts were mainly small (80.5%) and active (CE1 (73.8%); CE2 (7.4%)). Active cysts were more common in Eastern Europeans (85.7%) than Italians (66.7%). Our data confirm CE occurrence in Italy. We emphasize the importance to have a national CE registry, opportunely recently introduced. This is essential to assess CE prevalence in this country, implement appropriate control measures, and improve patient management.	\N	\N
24152546	Pre-diagnosis oophorectomy and estrogen therapy could impact mortality due to breast cancer and cardiovascular disease (CVD) among breast cancer survivors. Elective bilateral oophorectomy at the time of hysterectomy for benign conditions is not uncommon among US women. We examined the association between pre-diagnosis total abdominal hysterectomy with bilateral salpingooophorectomy (TAHBSO) and both overall and cause-specific mortality in the Collaborative Breast Cancer Studies cohort. Medical history and prior estrogen use were collected during standardized telephone interviews. Vital status, including date and cause of death, was obtained by linkage with the National Death Index. Multivariate hazard ratios (HR) and 95% confidence intervals (CI) for cause-specific mortality were calculated using Cox proportional hazards regression. Seventeen percent (N = 1,778) of breast cancer survivors (mean age at diagnosis = 63.5) reported pre-diagnosis TAHBSO. During follow-up (mean = 9.5 years), 2,856 deaths occurred, including 1,060 breast cancer deaths and 459 CVD deaths. Breast cancer deaths occurred a median of 5.1 years after diagnosis; CVD deaths occurred further from diagnosis (median = 9.7 years). Women who reported pre-diagnosis TAHBSO had a 16% decrease in all-cause mortality (HR = 0.84; 95% CI: 0.76, 0.92) compared to those with an intact uterus and ovaries. This overall decrease reflected a 27% lower breast cancer mortality among women who never used postmenopausal hormones (HR = 0.73; CI: 0.55, 0.96) and 43% lower CVD risk among women who reported using estrogen (HR = 0.57; CI: 0.39, 0.83) after TAHBSO. Information on prior TAHBSO and estrogen use can inform risk of death fromboth breast cancer and cardiovascular disease among breast cancer survivors.	\N	\N
24152582	The Ca(2+) channel-binding domain 3 (CBD3) peptide, derived from the collapsin response mediator protein 2 (CRMP-2), is a recently discovered voltage-gated Ca(2+) channel (VGCC) blocker with a preference for CaV2.2. Rodent administration of CBD3 conjugated to cell penetrating motif TAT (TAT-CBD3) has been shown to reduce pain behavior in inflammatory and neuropathic pain models. However, TAT-CBD3 analgesia has limitations, including short half-life, lack of cellular specificity and undesired potential off-site effects. We hypothesized that these issues could be addressed by expressing CBD3 encoded by high-expression vectors in primary sensory neurons. We constructed an adeno-associated viral (AAV) vector expressing recombinant fluorescent CBD3 peptide and injected it into lumbar dorsal root ganglia (DRGs) of rats before spared nerve injury (SNI). We show that selective expression of enhanced green fluorescent protein (EGFP)-CBD3 in lumbar 4 (L4) and L5 DRG neurons and their axonal projections results in effective attenuation of nerve injury-induced neuropathic pain in the SNI model. We conclude that AAV-encoded CBD3 delivered to peripheral sensory neurons through DRG injection may be a valuable approach for exploring the role of presynaptic VGCCs and long-term modulation of neurotransmission, and may also be considered for development as a gene therapy strategy to treat chronic neuropathic pain.	\N	\N
24157515	While undernutrition and infectious diseases are still persistent in developing countries, overweight, obesity, and associated comorbidities have become more prevalent. Uganda, a developing sub-Saharan African country, is currently experiencing the public health paradox of undernutrition and overnutrition. We utilized the 2011 Uganda Demographic and Health Survey (DHS) to examine risk factors and hot spots for underweight, overweight, and obesity among adult females (N = 2,420) and their children (N = 1,099) using ordinary least squares and multinomial logit regression and the ArcGIS Getis-Ord Gi* statistic. Overweight and obese women were significantly more likely to have overweight children, and overweight was correlated with being in the highest wealth class (OR = 2.94, 95% CI = 1.99-4.35), and residing in an urban (OR = 1.76, 95% CI = 1.34-2.29) but not a conflict prone (OR = 0.48, 95% CI = 0.29-0.78) area. Underweight clustered significantly in the Northern and Northeastern regions, while overweight females and children clustered in the Southeast. We demonstrate that the DHS can be used to assess geographic clustering and burden of disease, thereby allowing for targeted programs and policies. Further, we pinpoint specific regions and population groups in Uganda for targeted preventive measures and treatment to reduce the burden of overweight and chronic diseases in Uganda.	\N	\N
24169298	Morbidity and mortality from preventable, noncommunicable chronic disease (NCD) threatens the health of our populations and our economies. The accumulation of vast amounts of scientific knowledge has done little to change this. New and innovative thinking is essential to foster new creative approaches that leverage and integrate evidence through the support of big data, technology, and design thinking. The purpose of this paper is to summarize the results of a consensus meeting on NCD prevention sponsored by the International Olympic Committee (IOC) in April 2013. Within the context of advocacy for multifaceted systems change, the IOC's focus is to create solutions that gain traction within health care systems. The group of participants attending the meeting achieved consensus on a strategy for the prevention and management of chronic disease that includes the following: 1. Focus on behavioral change as the core component of all clinical programs for the prevention and management of chronic disease. 2. Establish actual centers to design, implement, study, and improve preventive programs for chronic disease. 3. Use human-centered design (HCD) in the creation of prevention programs with an inclination to action, rapid prototyping and multiple iterations. 4. Extend the knowledge and skills of Sports and Exercise Medicine (SEM) professionals to build new programs for the prevention and treatment of chronic disease focused on physical activity, diet, and lifestyle. 5. Mobilize resources and leverage networks to scale and distribute programs of prevention. True innovation lies in the ability to align thinking around these core strategies to ensure successful implementation of NCD prevention and management programs within health care. The IOC and SEM community are in an ideal position to lead this disruptive change. The outcome of the consensus meeting was the creation of the IOC Non-Communicable Diseases ad hoc Working Group charged with the responsibility of moving this agenda forward.	\N	\N
24171516	The efficacy of autologous stem-cell transplantation during the first remission in patients with diffuse, aggressive non-Hodgkin's lymphoma classified as high-intermediate risk or high risk on the International Prognostic Index remains controversial and is untested in the rituximab era. We treated 397 patients who had disease with an age-adjusted classification of high risk or high-intermediate risk with five cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP plus rituximab. Patients with a response were randomly assigned to receive three additional cycles of induction chemotherapy (control group) or one additional cycle of induction chemotherapy followed by autologous stem-cell transplantation (transplantation group). The primary efficacy end points were 2-year progression-free survival and overall survival. Of 370 induction-eligible patients, 253 were randomly assigned to the transplantation group (125) or the control group (128). Forty-six patients in the transplantation group and 68 in the control group had disease progression or died, with 2-year progression-free survival rates of 69 and 55%, respectively (hazard ratio in the control group vs. the transplantation group, 1.72; 95% confidence interval [CI], 1.18 to 2.51; P=0.005). Thirty-seven patients in the transplantation group and 47 in the control group died, with 2-year overall survival rates of 74 and 71%, respectively (hazard ratio, 1.26; 95% CI, 0.82 to 1.94; P=0.30). Exploratory analyses showed a differential treatment effect according to risk level for both progression-free survival (P=0.04 for interaction) and overall survival (P=0.01 for interaction). Among high-risk patients, the 2-year overall survival rate was 82% in the transplantation group and 64% in the control group. Early autologous stem-cell transplantation improved progression-free survival among patients with high-intermediate-risk or high-risk disease who had a response to induction therapy. Overall survival after transplantation was not improved, probably because of the effectiveness of salvage transplantation. (Funded by the National Cancer Institute, Department of Health and Human Services, and others; SWOG-9704 ClinicalTrials.gov number, NCT00004031.).	\N	\N
24172078	Many symptomatic patients with severe aortic stenosis (AS) and preserved left ventricular ejection fraction (LVEF) are denied surgery and have a grim prognosis with medical management. Between 2003 and 2012, among 550 patients with severe isolated AS and preserved LVEF on transthoracic echocardiography, 241 did not undergo aortic valve replacement (mean age, 83.2±7.6 years; 54% female; aortic valve area index, 0.40±0.13cm(2)/m(2); mean LVEF, 64.8±7.6%) and 67% presented with cardiac symptoms. At a mean follow-up of 25.5±25.1 months, 134 patients (56%) had died. Survival at 1, 5 and 9.5 years was 71%, 28% at 12%, respectively. Median survival was 36.3 months (95% confidence interval [CI]: 27.2-42.4 months). In unadjusted analyses, age, heart failure, hypertension, renal insufficiency, left atrial size, pulmonary artery systolic pressure (PASP), relative wall thickness and LV mass/LV end diastolic volume ratio were associated with mortality. On multivariate analysis adjusted for all significant univariate predictors, age ≥78 years, history of hypertension, left atrial diameter ≥40mm and PASP ≥42mmHg gave a joint area under the curve of 0.80 (95% CI: 0.73-0.86) for mortality. In medically treated patients with severe isolated AS and preserved LVEF, older age, history of hypertension, and echo-Doppler variables reflecting LV diastolic dysfunction are independent predictors of death.	\N	\N
24203705	Microbial genome sequencing is one of the longest-standing areas of biological database development, but high-throughput, low-cost technologies have increased its throughput to an unprecedented number of new genomes per year. Several thousand microbial genomes are now available, necessitating new approaches to organizing information on gene function, phylogeny and microbial taxonomy to facilitate downstream biological interpretation. MetaRef, available at http://metaref.org, is a novel online resource systematically cataloguing a comprehensive pan-genome of all microbial clades with sequenced isolates. It organizes currently available draft and finished bacterial and archaeal genomes into quality-controlled clades, reports all core and pan gene families at multiple levels in the resulting taxonomy, and it annotates families' conservation, phylogeny and consensus functional information. MetaRef also provides a comprehensive non-redundant reference gene catalogue for metagenomic studies, including the abundance and prevalence of all gene families in the >700 shotgun metagenomic samples of the Human Microbiome Project. This constitutes a systematic mapping of clade-specific microbial functions within the healthy human microbiome across multiple body sites and can be used as reference for identifying potential functional biomarkers in disease-associate microbiomes. MetaRef provides all information both as an online browsable resource and as downloadable sequences and tabular data files that can be used for subsequent offline studies.	\N	\N
24206993	Ulnar impaction syndrome generally occurs with positive ulnar variance. The solution to the problem is to unload the ulnocarpal joint. Effective surgical options include diaphyseal ulnar shortening osteotomy, open wafer osteotomy, and arthroscopic wafer osteotomy. Recently, Slade and Gillon described an open procedure of ulnar shortening in the osteochondral region of the ulnar head. The procedure minimizes the risk of hemarthrosis and does not require hardware removal, which are problems with other surgical options. This article introduces a new arthroscopic technique of distal metaphyseal ulnar shortening osteotomy for ulnar impaction syndrome. This technique offers the advantages of minimizing surgical injury to the dorsal capsule of the distal radoulnar joint and so protects its stability.	\N	\N
24211848	Crimean-Congo hemorrhagic fever virus (CCHFV) etiology was detected in a family cluster (nine cases, including two deaths) in the village of Karyana, Amreli District, and also a fatal case in the village of Undra, Patan District, in Gujarat State, India. Anti-CCHFV IgG antibodies were detected in domestic animals from Karyana and adjoining villages. Hyalomma ticks from households were found to be positive for CCHF viral RNA. This confirms the emergence of CCHFV in new areas and the wide spread of this disease in Gujarat State.	\N	\N
24218343	Regional body-fat distribution is one of the key variables that explains the metabolic heterogeneity of obesity and its related cardiovascular risks. According to the ectopy concept, the inability of subcutaneous adipose tissue to store surplus triglycerides may lead to the development of fat in ectopic sites, such as the heart. Epicardial adipose tissue is a metabolically active endocrine organ that produces numerous factors that can modulate cardiac structure and function. The development of in vivo noninvasive imaging has made it possible to quantify its thickness and volume with increasing accuracy. In this review, we discuss the local interaction and cross-talk between epicardial fat and neighboring structures, such as coronary arteries and myocardium, and its relevance to cardiac diseases, such as coronary-artery disease or atrial fibrillation. Beneficial and harmful effects of epicardial adipose tissue are described and analyzed. What leads to an imbalance between protective and deleterious actions has to be further explored. We believe that epicardial fat, which has been neglected for years, plays a key role in cardiovascular disease pathophysiology and represents a "new world" exploration for therapeutic targets, which will be addressed in future clinical and research studies. Elucidating the mechanisms that drive the deposition or mobilization of cardiac adiposity between other ectopic-fat stores needs to be accomplished within the next few years.	\N	\N
24223459	We evaluated whether the methylenetetrahydrofolate reductase (MTHFR) 677C>T marker influences the risk and severity of Alzheimer's disease (AD) and whether AD is associated with homocysteine, vitamin B12, and cholesterol levels in Egypt. Forty-three Alzheimer's cases and 32 non-AD controls were genotyped for the 677C>T polymorphism. Clinical characteristics and levels of homocysteine, vitamin B12, and cholesterol were assessed. No significant differences in the frequencies of the MTHFR alleles or genotypes between AD cases and controls (P = 0.14) were identified. The 677T mutant allele was significantly overrepresented in AD cases compared to controls (OR = 2.22; P = 0.03). The 677T/T frequency was three times higher in AD patients than in controls, which could increase plasma homocysteine levels. Severe cases of AD were the most frequent in patients with the T/T genotype (11.6%). The effect of the MTHFR polymorphism on the risk of AD may be independent of homocysteine, vitamin B12, or even cholesterol levels. The MTHFR 677C>T polymorphism--especially the presence of one copy of the T allele--appears to confer a potential risk for the development of AD. The T/T genotype may contribute to hypercysteinemia as a sensitive marker.	\N	\N
24226095	Sterol 12α-hydroxylase (CYP8B1) is required for cholic acid synthesis and plays a critical role in intestinal cholesterol absorption and pathogenesis of cholesterol gallstone, dyslipidemia, and diabetes. In this study we investigated the underlying mechanism of fasting induction and circadian rhythm of CYP8B1 by a cholesterol-activated nuclear receptor and core clock gene retinoic acid-related orphan receptor α (RORα). Fasting stimulated, whereas restricted-feeding reduced expression of CYP8B1 mRNA and protein. However, fasting and feeding had little effect on the diurnal rhythm of RORα mRNA expression, but fasting increased RORα protein levels by cAMP-activated protein kinase A-mediated phosphorylation and stabilization of the protein. Adenovirus-mediated gene transduction of RORα to mice strongly induced CYP8B1 expression, and increased liver cholesterol and 12α-hydroxylated bile acids in the bile acid pool and serum. A reporter assay identified a functional RORα response element in the CYP8B1 promoter. RORα recruited cAMP response element-binding protein-binding protein (CBP) to stimulate histone acetylation on the CYP8B1 gene promoter. In conclusion, RORα is a key regulator of diurnal rhythm and fasting induction of CYP8B1, which regulates bile acid composition and serum and liver cholesterol levels. Antagonizing RORα activity may be a therapeutic strategy for treating inflammatory diseases such as non-alcoholic fatty liver disease and type 2 diabetes.	\N	\N
24226419	IL-32 is a pro-inflammatory cytokine expressed by activated natural killer cells, T cells, keratinocytes, and fibroblasts. In this study, we examined the role of IL-32 in cutaneous T-cell lymphoma (CTCL), including mycosis fungoides (MF) and Sézary syndrome (SS). IL-32 mRNA expression levels in lesional skin of MF patch, plaque, and tumor were increased compared with those of normal skin, which positively correlated with CCL17 and CCL18 mRNA expression levels. Serum IL-32 levels positively correlated with disease activity within each patient. Immunostaining showed that keratinocytes expressed IL-32 in the lesional skin of MF patch and plaque, whereas in MF tumor, atypical T cells in the dermis strongly expressed IL-32. We also showed that IL-32 dose-dependently accelerated the proliferation of MF and SS cell lines in vitro, which was inhibited by blocking mitogen-activated protein kinase and NF-κB-mediated signaling. The addition of anti-IL-32 antibodies in culture decreased the proliferation of SS cells and the viability of MF cells, suggesting that IL-32 serves as an autocrine growth factor. In conclusion, our results suggest that IL-32 has a role in the formation and maintenance of CTCL lesions, providing a possible therapeutic target for patients with this disease.	\N	\N
24240787	To assess the efficacy of pirfenidone in patients with advanced-stage idiopathic pulmonary fibrosis (IPF), we conducted a retrospective study of patients who received pirfenidone therapy. In addition, the combined effects of inhaled N-acetylcysteine (NAC) and pirfenidone were evaluated. Eligible patients had a clinical and radiologic diagnosis of advanced-stage IPF (stages of severity III&IV). Patients who exhibited a relative decline in forced vital capacity (FVC) of 10% or more within the preceding six (±2) months were enrolled. The outcome was evaluated from the date of the 6-month follow-up PFT. Relative declines in FVC of more than 10% were defined as progressive disease (ineffective group), while those less than 10% were defined as stable disease (effective group). The clinical features were compared between the two groups. We also compared the efficacy of the combined therapy with inhaled NAC and pirfenidone (n=11) with that of pirfenidone alone (n=7). Eighteen patients 59-82 years of age with IPF who received pirfenidone therapy were reviewed. Pirfenidone stabilized declines in FVC by 10% at six months in eight of the 18 cases (44%). The median changes in FVC at six months were +120 mL in the effective group and -590 mL in the ineffective group. The number of NAC users was significantly higher in the effective group (7/8=87.5%) than in the ineffective group (3/10=30%) (p=0.02). Furthermore, the use of combined NAC therapy was correlated with a favorable outcome. The median change in FVC at six months was 0 mL in the NAC group and -290 mL in the non-NAC group. The median survival period was 557 ± 66 days in the NAC group and 196 ± 57 days in the non-NAC group (p=0.03). Among the advanced-stage IPF patients with a more progressive status, pirfenidone decreased the rate of decline in FVC. In addition, patients treated with pirfenidone combined with NAC therapy exhibited favorable outcomes. Additional studies are needed to confirm the efficacy of this combined therapy for IPF.	\N	\N
24246538	The use of "chimney" stents to augment the proximal landing zone for endovascular aneurysm repair has been increasingly reported. Despite mounting enthusiasm for this technique, the durability of this type of repair and capability to preserve perfusion to target branches remains a paramount concern. Here, we report management of a patient presenting with acute bilateral renal chimney stent thrombosis and a type Ia endoleak.	\N	\N
24252129	Favre-Racouchot syndrome (FRS) is both disfiguring and difficult to treat. Available medical and surgical therapies are of variable efficacy. Most treatments do not achieve complete resolution and do not show maintenance of therapeutic response. To assess the response to a novel two-step treatment using the CO2 laser in patients with FRS. Seven patients with FRS were treated with the CO2 laser in resurfacing mode with manual expression of comedones under infiltrative local anaesthesia. The procedure was completed in one treatment session lasting 30 min and the wound was left to heal by secondary intention. A topical antibiotic was applied to treated areas, which were covered with a nonadherent dressing. All patients were assessed 3 months postoperatively by the operating laser surgeon and a visual assessment of clinical response to treatment in comparison with pretreatment photographs was made. Patient satisfaction was also recorded. All patients achieved complete resolution of FRS. The follow-up duration for our cohort ranged from 8 months to 3 years. Two patients required further treatment within a 2-3-year period from initial treatment. Disease relapse was noted over 1 year after the primary treatment; both these cases were smokers and repeat treatment with similar laser parameters maintained reproducible results. Our longest disease-free follow-up duration was 3 years postprimary treatment. The laser surgeons and patients reported high levels of therapeutic benefit and satisfaction with the results. This two-step treatment of FRS (CO2 laser resurfacing and manual pressure-induced expression of comedones) is an effective and durable treatment for FRS with an excellent cosmetic outcome. Long-term follow-up beyond 3 years is planned to determine whether later recurrence occurs with this technique.	\N	\N
24263779	Over recent decades, the prevalence of high blood pressure (BP) has increased among children. Several risk factors are involved in the genesis of high BP during childhood, and their early identification can prevent the development of that disease. To assess the prevalence of high BP and associated factors in children. Cross-sectional, population-based study, carried out at the household. This study included 276 two- to five-year-old children in the city of Goiânia, state of Goiás, and assessed their BP, sociodemographic characteristics, birth weight, high BP family history, passive smoking, maternal breastfeeding, dietary habits, sedentary lifestyle and nutritional status. Poisson regression was used to assess the association between risk factors and high BP. Their mean age was 3.1 ± 0.79 years, and high BP and overweight were observed in 19.9% and 11.2% of the children, respectively. Direct association of high BP was identified with age [prevalence ratio (PR) = 2.3; 95%CI: 1.2 - 4.8; p = 0.017] and overweight (PR = 2.0; 95%CI: 1.2 - 3.6; p = 0.014). No other variable associated with high BP. The prevalence of high BP in children was high. Overweight and younger children had greater prevalence of high BP.	\N	\N
24264509	According to 1981-2009 data, homicide accounts for 16,000-26,000 deaths annually in the United States and ranks within the top four leading causes of death among U.S. residents aged 1-40 years. Homicide can have profound long-term emotional consequences on families and friends of victims and on witnesses to the violence, as well as cause excessive economic costs to residents of affected communities. For years, homicide rates have been substantially higher among certain populations. Previous reports have found that homicides are higher among males, adolescents and young adults, and certain racial/ethnic groups, such as non-Hispanic blacks, non-Hispanic American Indian/Alaska Natives (AI/ANs), and Hispanics. The 2011 CDC Health Disparities and Inequalities Report (CHDIR) described similar findings for the year 2007. For example, the 2011 report showed that the 2007 homicide rate was highest among non-Hispanic blacks (23.1 deaths per 100,000), followed by AI/ANs (7.8 deaths per 100,000), Hispanics (7.6 deaths per 100,000), non-Hispanic whites (2.7 deaths per 100,000), and Asian/Pacific Islanders (A/PIs) (2.4 deaths per 100,000). In addition, non-Hispanic black men aged 20-24 years were at greatest risk for homicide in 2007, with a rate that exceeded 100 deaths per 100,000 population. Other studies have reported that community factors such as poverty and economic inequality and individual factors such as unemployment and involvement in criminal activities can play a substantial role in these persistent disparities in homicide rates. Public health strategies are needed in communities at high risk for homicide to prevent violence and save lives.	\N	\N
24269993	To report on unexpected findings in 4 patients with chronic paraplegia who underwent the laparoscopic implantation of neuroprosthesis procedure in the pelvic lumbosacral nerves. Observational case series. Tertiary referral unit specialized in advanced gynecological surgery and neuropelveology. Three patients with incomplete American Spinal Injury Association (ASIA) Impairment Scale (AIS) grade B (n=2) and AIS grade C (n=1) spinal cord injury (SCI) and 1 patient with flaccid complete chronic SCI (AIS grade A) (n=1). Functional electrical stimulation (FES)-assisted locomotor training and continuous low-frequency pelvic-lumbosacral neuromodulation. Change in ASIA Lower Extremity Motor Scores, ASIA sensory scores for light touch and pinprick sensation, and Walking Index for Spinal Cord Injury scores. All 4 patients developed progressive recovery of some sensory and voluntary motor functions below the lesions. Three are currently capable of voluntary weight-bearing standing and walking a few meters with a walker without FES. The first patient with the longest follow-up is even capable of electrically assisted standing/walking with 2 crutches without braces or assistance for a distance of about 900 meters, and of weight-bearing standing and walking for 30 meters with a walker without stimulation. We report unexpected sensory and locomotor recovery in 4 people with paraplegia with SCI. Our findings suggest that FES-assisted locomotor training with continuous low-frequency pelvic nerve stimulation in patients with SCI may induce changes that affect the central pattern generator and allow supra- and infraspinal inputs to engage residual spinal pathways.	\N	\N
24274981	DMD gene which is composed of 79 exons is the largest known gene located on X chromosome (Xp21). Point mutations in the dystrophin gene are responsible for 30-35% of cases with DMD/BMD. Mutation analysis of all the exons of the DMD gene is costly in developing countries, therefore, a few of the exons are selected to be analyzed routinely in clinical laboratories. In this study, direct sequencing was used for detection of point mutations in 10 exons of dystrophin gene in patients affected with DMD without detectable large rearrangements. Freely available programs were used to predict the damaging effects of the mutations. Point mutations were successfully detected in three patients. Three novel mutations, two missense mutations located on nonconservative domains and a single nucleotide deletion, were detected. Missense mutations were predicted to change splicing efficiency. Detection of point mutations by DNA analysis followed by prediction of the pathogenecity by using bioinformatic tool might be an asset to provide proper diagnosis or genetic counseling to patients and their family.	\N	\N
24276026	Early detection and improved (neo)-adjuvant treatment has extended survival of breast cancer over the last decades. It remains controversial whether a survival benefit is achieved once metastases have occurred. This study investigates survival trends in metastatic breast cancer (MBC) looking at the distribution of prognostic factors and the time period of the diagnosis of the primary and metastatic disease. In this retrospective study, 1635 patients, diagnosed with MBC and treated at three German cancer centers, were included. For the survival analysis, patients were grouped into three time periods [1980-1994 (a), 1995-1999 (b) and 2000-2009 (c)], which were chosen according to the availability of new antineoplastic drugs for the treatment of MBC. Additionally, patients were divided into three risk groups using the simultaneously published prognostic score. The analysis of overall survival according to the date of primary diagnosis demonstrated a significant decline compared with the reference (a): (a versus b) hazard ratio (HR) = 1.37; P < 0.001; (a versus c) HR = 2.45; P < 0.001. Considering the time of first occurrence of metastasis, survival remains unchanged over the three periods (a versus b): HR = 0.94 P = 0.436; (a versus c): HR = 0.95; P = 0.435. However, a significant shift towards more unfavorable risk factors was seen. Although survival in MBC remains unchanged over time, patients developing metastatic disease have a more aggressive disease that is presumably compensated by more effective treatment. This alteration of tumor biology in MBC may be explained by a negative selection of patients with adverse risk profiles due to the advantages of the adjuvant therapy.	\N	\N
24280762	Helicobacter pylori infections can induce pathologies ranging from chronic gastritis, peptic ulceration to gastric cancer. Bacterial isolates harbor numerous well-known adhesins, vacuolating cytotoxin VacA, protease HtrA, urease, peptidoglycan, and type IV secretion systems (T4SS). It appears that H. pylori targets more than 40 known host protein receptors on epithelial or immune cells. A series of T4SS components such as CagL, CagI, CagY, and CagA can bind to the integrin α 5β 1 receptor. Other targeted membrane-based receptors include the integrins αvβ 3, αvβ 5, and β 2 (CD18), RPTP-α/β, GP130, E-cadherin, fibronectin, laminin, CD46, CD74, ICAM1/LFA1, T-cell receptor, Toll-like receptors, and receptor tyrosine kinases EGFR, ErbB2, ErbB3, and c-Met. In addition, H. pylori is able to activate the intracellular receptors NOD1, NOD2, and NLRP3 with important roles in innate immunity. Here we review the interplay of various bacterial factors with host protein receptors. The contribution of these interactions to signal transduction and pathogenesis is discussed.	\N	\N
24281461	Pediatric-onset Crohn disease is more aggressive than adult-onset disease, has high rates of resistance to existing drugs, and can lead to permanent impairments. Few trials have evaluated new drugs for refractory Crohn disease in children. To determine whether thalidomide is effective in inducing remission in refractory pediatric Crohn disease. Multicenter, double-blind, placebo-controlled, randomized clinical trial of 56 children with active Crohn disease despite immunosuppressive treatment, conducted August 2008-September 2012 in 6 pediatric tertiary care centers in Italy. Thalidomide, 1.5 to 2.5 mg/kg per day, or placebo once daily for 8 weeks. In an open-label extension, nonresponders to placebo received thalidomide for an additional 8 weeks. All responders continued to receive thalidomide for an additional minimum 52 weeks. Primary outcomes were clinical remission at week 8, measured by Pediatric Crohn Disease Activity Index (PCDAI) score and reduction in PCDAI by ≥25% or ≥75% at weeks 4 and 8. Primary outcomes during the open-label follow-up were clinical remission and 75% response. Twenty-eight children were randomized to thalidomide and 26 to placebo. Clinical remission was achieved by significantly more children treated with thalidomide (13/28 [46.4%] vs 3/26 [11.5%]; risk ratio [RR], 4.0 [95% CI, 1.2-12.5]; P = .01; number needed to treat [NNT], 2.86). Responses were not different at 4 weeks, but greater improvement was observed at 8 weeks in the thalidomide group (75% response, 13/28 [46.4%] vs 3/26 [11.5%]; RR, 4.0 [95% CI, 1.2-12.5]; NNT = 2.86; P = .01; and 25% response, 18/28 [64.2%] vs 8/26 [30.8%]; RR, 2.1 [95% CI, 1.1-3.9]; NNT = 2.99; P = .01). Of the nonresponders to placebo who began receiving thalidomide, 11 of 21 (52.4%) subsequently reached remission at week 8 (RR, 4.5 [95% CI, 1.4-14.1]; NNT = 2.45; P = .01). Overall, 31 of 49 children treated with thalidomide (63.3%) achieved clinical remission, and 32 of 49 (65.3%) achieved 75% response. Mean duration of clinical remission in the thalidomide group was 181.1 weeks (95% CI, 144.53-217.76) vs 6.3 weeks (95% CI, 3.51-9.15) in the placebo group (P < .001). Cumulative incidence of severe adverse events was 2.1 per 1000 patient-weeks, with peripheral neuropathy the most frequent severe adverse event. In children and adolescents with refractory Crohn disease, thalidomide compared with placebo resulted in improved clinical remission at 8 weeks of treatment and longer-term maintenance of remission in an open-label follow-up. These findings require replication to definitively determine clinical utility of this treatment. clinicaltrials.gov Identifier: NCT00720538.	\N	\N
24284613	The aim of this review was to identify, evaluate and summarize all relevant studies reporting on the clinical response to gluten challenge by adult or pediatric patients with suspected or diagnosed coeliac disease (CD) on a gluten-free diet. We evaluated the effect of gluten challenge on changes in symptoms, intestinal mucosa histology, and serum antibodies. A systematic electronic search was performed for studies published as of 1966 using PubMed and Scopus databases. In the reviewed studies, doses ranged from 0.2 to 30 g/day of wheat gluten or comprised a gluten-containing diet. The onset of symptoms upon gluten intake varied largely from days to months and did not parallel serum antibody or histological changes. Within 3 months of gluten challenge, 70%-100% of pediatric CD patients became positive for AGA-IgA and EMA-IgA antibodies and 50%-70% for AGA-IgG. A limited number of trials suggest that no more than half of adult patients developed positive AGA-IgA, EMA-IgA, tTG-IgA or DGP-IgA/IgG titers. Approximately 50%-100% of pediatric and adult patients experienced mucosal relapse of gluten provocation within 3 months, which was preceded by increased mucosal intra-epithelial lymphocytes within several days of challenge. A 3-month high-dose gluten challenge should be suitable to diagnose the majority of CD patients. In some cases prolonged challenge may be needed to verify diagnosis. Combination testing for antibodies and mucosal histology may fasten the diagnosis.	\N	\N
24286024	Brain changes reminiscent of Alzheimer disease (AD) have been previously reported in a substantial portion of elderly cognitive healthy (HC) subjects. The major aim was to evaluate the accuracy of MRI assessed regional gray matter (GM) volume, 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), and neuropsychological test scores to identify those HC subjects who subsequently convert to mild cognitive impairment (MCI) or AD dementia. We obtained in 54 healthy control (HC) subjects a priori defined region of interest (ROI) values of medial temporal and parietal FDG-PET and medial temporal GM volume. In logistic regression analyses, these ROI values were tested together with neuropsychological test scores (free recall, trail making test B (TMT-B)) as predictors of HC conversion during a clinical follow-up between 3 and 4 years. In voxel-based analyses, FDG-PET and MRI GM maps were compared between HC converters and HC non-converters. Out of the 54 HC subjects, 11 subjects converted to MCI or AD dementia. Lower FDG-PET ROI values were associated with higher likelihood of conversion (p = 0.004), with the area under the curve (AUC) yielding 82.0% (95% CI = (95.5%, 68.5%)). The GM volume ROI was not a significant predictor (p = 0.07). TMT-B but not the free recall tests were a significant predictor (AUC = 71% (95% CI = 50.4%, 91.7%)). For the combination of FDG-PET and TMT-B, the AUC was 93.4% (sensitivity = 82%, specificity = 93%). Voxel-based group comparison showed reduced FDG-PET metabolism within the temporo-parietal and prefrontal cortex in HC converters. In conclusion, medial temporal and-parietal FDG-PET and executive function show a clinically acceptable accuracy for predicting clinical progression in elderly HC subjects.	\N	\N
24286594	Optimal management of colon cancer (CC) requires detailed assessment of extent of disease. This study prospectively investigates the diagnostic accuracy of 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography/computed tomography (PET/CT) for staging and detection of recurrence in primary CC. PET/CT for preoperative staging was performed in 66 prospectively included patients with primary CC. Diagnostic accuracy for PET/CT and CT was analyzed. In addition to routine follow up, 42 stages I-III CC patients had postoperative PET/CT examinations every 6 months for 2 years. Serological levels of tissue inhibitor of metalloproteinase-1 (TIMP-1), carcinoembryonic antigen, and liberated domain I of urokinase plasminogen activator receptor were analyzed. Accuracy for tumor, nodal, and metastases staging by PET/CT were 82% (95% confidence interval [CI]: 70; 91), 66% (CI: 51; 78), and 89% (CI: 79; 96); for CT the accuracy was 77% (CI: 64; 87), 60% (CI: 46; 73), and 69% (CI: 57; 80). Cumulative relapse incidences for stages I-III CC at 6, 12, 18, and 24 months were 7.1% (CI: 0; 15); 14.3% (CI: 4; 25); 19% (CI: 7; 31), and 21.4% (CI: 9; 34). PET/CT diagnosed all relapses detected during the first 2 years. High preoperative TIMP-1 levels were associated with significant hazards toward risk of recurrence and shorter overall survival. This study indicates PET/CT as a valuable tool for staging and follow up in CC. TIMP-1 provided prognostic information potentially useful in selection of patients for intensive follow up.	\N	\N
24292183	Pulmonary arterial hypertension (PAH) is a rare, progressive, and fetal disease. The five-year survival rate after diagnosis is ～50%. In Japan, PAH is listed in the Specified Rare and Intractable Diseases. Pulmonary vascular remodeling and sustained pulmonary vasoconstriction are the major causes for the elevated pulmonary vascular resistance (PVR) in PAH. The pathogenic mechanisms involved in the pulmonary vascular abnormalities in PAH remain unclear. Sustained vasoconstriction and vascular remodeling owing to proliferation of pulmonary arterial smooth muscle cells (PASMCs) are key pathogenic events that lead to early morbidity and mortality. These events have been closely linked to Ca(2+) mobilization and signaling in PASMCs. An increase in cytosolic Ca(2+) concentration ([Ca(2+)]cyt) in PASMCs is an important stimulus for pulmonary vasoconstriction and cell proliferation which subsequently cause pulmonary vascular wall thickening followed by the increase in PVR. Increased resting [Ca(2+)]cyt and enhanced Ca(2+) influx have been implicated in PASMCs from PAH patients, but precise therapeutic targets to interrupt these signal pathways have not been identified. We recently found that the extracellular Ca(2+)-sensing receptor (CaSR), a G protein-coupled receptor (GPCR), is upregulated in PASMCs from patients with idiopathic pulmonary arterial hypertension (IPAH). In addition, blockage of the CaSR with an antagonist (NPS2143) prevents the development of pulmonary hypertension and right ventricular hypertrophy in animal models of pulmonary hypertension. The functionally upregulated CaSR in PASMCs is a novel pathogenic mechanism contributing to the augmented Ca(2+) signaling and excessive cell proliferation in IPAH. Targeting CaSR in PASMCs may help develop novel therapeutic approach for PAH.	\N	\N
24298283	In January 2012, Boström and colleagues identified a new muscle tissue secreted peptide, which they named irisin, to highlight its role as a messenger that comes from skeletal muscle to other parts of the body. Irisin is a cleaved and secreted fragment of FNDC5 (also known as FRCP2 and PeP), a member of fibronectin type III repeat containing gene family. Major interest in this protein arose because of its great therapeutic potential in diabetes and perhaps also therapy for obesity. Here we review the most important aspects of irisin's action and discuss its involvement in energy and metabolic homeostasis and whether the beneficial effects of exercise in these disease states could be mediated by this protein. In addition the effects of irisin at the central nervous system (CNS) are highlighted. It is concluded that although current and upcoming research on irisin is very promising it is still necessary to deepen in several aspects in order to clarify its full potential as a meaningful drug target in human disease states.	\N	\N
24299152	Patients with systemic lupus erythematosus (SLE) have persistent platelet activation and an increased risk of thrombotic events, which cannot be accounted for by traditional cardiovascular risk factors. Factor (F)XII has a potentially important role in thrombus formation and is triggered by activated platelets. We therefore asked whether the contact system is involved in inflammation and vascular disease (VD) in SLE. Fibrin clots were incubated with purified FXII or whole blood, and the activation and regulation of FXII were studied. Plasma from SLE patients with (n = 31) or without (n = 38) previous VD and from matched healthy controls (n = 68) were analyzed for the presence of complexes formed between contact system enzymes and antithrombin (AT) or C1 inhibitor (C1INH) and evaluated with regard to clinical data and laboratory parameters. Fibrin clots elicited FXII activation and acted as co-factors for AT. In clotting plasma, the levels of FXIIa-AT increased, and FXIIa-C1INH decreased. A similar reciprocal relationship existed in SLE patients. FXIIa-AT was elevated in the SLE patients with a history of VD, while the corresponding levels of factor FXIIa-C1INH were significantly decreased. FXIIa-AT correlated strongly with platelet parameters. The odds ratio for VD among the SLE patients was 8.9 if they had low levels of FXIIa-C1INH, 6.1 for those with high levels of FXIIa-AT, and increased to 23.4 for those with both decreased levels of FXIIa-C1INH and increased levels of FXIIa-AT. Activation of FXII is elicited by fibrin during thrombotic reactions in vitro and in vivo, and fibrin acts as a heparin-like co-factor and regulates AT. Patients with SLE had altered levels of FXIIa-serpin complexes, supporting that the contact system is involved in this disease. FXIIa-serpin complexes are strongly associated with previous VD in SLE patients, suggesting that these complexes are potential biomarkers for monitoring and assessing the risk of thrombotic events in SLE.	\N	\N
24305931	Intense postoperative monitoring has resulted in increasing detection of patients with recurrent papillary thyroid cancer (PTC). Our goals included quantifying successful reoperation, and analyzing surgical complications and reasons for relapse. From 1999 to 2008, a total of 410 patients underwent reoperation for PTC relapse. We analyzed post-reoperative disease outcomes, reasons for relapse, and complications. Bilateral reoperative thyroidectomy was performed in 13 (3 %) patients; lobectomy, 34 (8 %); central neck (VI) soft tissue local recurrence excision, 47 (11.5 %); bilateral VI node dissection, 107 (26 %); unilateral VI dissection, 112 (27 %); levels II-V dissection, 93 (23 %); levels III-V, 86 (21 %); lateral single- or two-compartment dissection, 51 (12 %); and node picking, 20 (5 %) of level VI and 53 (13 %) lateral neck. Complications occurred in 6 %; including hypoparathyroidism, 3 %; unintentional recurrent laryngeal nerve (RLN) paralysis, 3 %; phrenic nerve injury, 0.5 %; spinal accessory nerve injury, 0.5 %; and chyle leak in 1.6 %. Of 380 (93 %) patients with follow-up (mean 5.2 years); 274 (72 %) patients are alive with no structural evidence of disease, 38 % developed disease relapse (mean 2.1 years), 42 (11 %) died from PTC, and 55 (14 %) are alive with disease. The reason for relapse was a false negative pre-reoperative ultrasound (US) in 18 (5 %), nodal recurrence in the operative field in 37 (10 %), a combination of these two reasons in 10 (3 %), and disease virulence (local or systemic recurrence) in 81 (21 %). Although 72 % of patients were rendered structurally disease free after reoperation, nearly 40 % suffered additional relapse. Improved surgical technique or preoperative localization might positively affect 15-20 %; at least 20 % reflect the biologic aggressiveness of the disease.	\N	\N
24319959	To study the clinical characteristics of pediatric Kawasaki disease complicating mycoplasma pneumoniae pneumonia. Retrospective analysis was conducted on 11 children who had been diagnosed with Kawasaki disease with Mycoplasma pneumoniae pneumonia. The 11 cases presented with varying degrees of fever, conjunctival congestion, skin rashes, lymphadenectasis, distal extremities lesions, heart and lung lesions. 8 of them were standartly treated with azithromycin, while 3 of them were treatad with azithromycin and erythromycin. 2 patients with pleural effusion complicated by lobar pneumonia consolidation were treated with gamma globulin combined aspirin. All of the 11 patients were healed. Infections are common at the diagonosis of KD. Reasonable examination and antibiotics is useful to cure KD with MPP.	\N	\N
24321203	Data from surveillance networks help epidemiologists and public health officials detect emerging diseases, conduct outbreak investigations, manage epidemics, and better understand the mechanics of a particular disease. Surveillance networks are used to determine outbreak intensity (i.e., disease burden) and outbreak timing (i.e., the start, peak, and end of the epidemic), as well as outbreak location. Networks can be tuned to preferentially perform these tasks. Given that resources are limited, careful site selection can save costs while minimizing performance loss. We study three different site placement algorithms: two algorithms based on the maximal coverage model and one based on the K-median model. The maximal coverage model chooses sites that maximize the total number of people within a specified distance of a site. The K-median model minimizes the sum of the distances from each individual to the individual's nearest site. Using a ground truth dataset consisting of two million de-identified Medicaid billing records representing eight complete influenza seasons and an evaluation function based on the Huff spatial interaction model, we empirically compare networks against the existing Iowa Department of Public Health influenza-like illness network by simulating the spread of influenza across the state of Iowa. We show that it is possible to design a network that achieves outbreak intensity performance identical to the status quo network using two fewer sites. We also show that if outbreak timing detection is of primary interest, it is actually possible to create a network that matches the existing network's performance using 59% fewer sites. By simulating the spread of influenza across the state of Iowa, we show that our methods are capable of designing networks that perform better than the status quo in terms of both outbreak intensity and timing. Additionally, our results suggest that network size may only play a minimal role in outbreak timing detection. Finally, we show that it may be possible to reduce the size of a surveillance system without affecting the quality of surveillance information produced.	\N	\N
24326825	Lymph node metastasis (LNm), local recurrence (LR), and second primary tumor (SPT) after primary surgery for oral squamous cell carcinoma (OSCC) have been considered poor prognostic entities in terms of survival rate. The purpose of this study was to identify the clinicopathologic parameters significantly related to LNm, LR, and SPT. Records from 180 patients who underwent radical surgery for OSCC were retrospectively reviewed. Perineural invasion was significantly related to LNm (18% vs 8%) and LR (15% vs 5%), while the status of the surgical margin (10% in case of clear margins, 18% close margins, and 24% involved margins), namely epithelial precursor lesions (43%) was an independent factor influencing SPT. Perineural invasion proved a good prognostic factor for early events, either LNm or LR, while a surgical margin width less than 5 mm or with epithelial precursor lesions may be considered a risk factor for late events such as SPT.	\N	\N
24342581	To evaluate the efficacy of plasma-rich growth factor (PRGF) in improving socket healing after tooth extraction in diabetic patients. This was a split-mouth study in which each patient also served as the control: the study socket was treated with PRGF, whereas the control socket underwent natural healing. The outcome variables were the Healing Index, residual socket volume, visual analog scale score, postsurgical complications, and outcome of a patient questionnaire. The investigation considered the impact of hyperglycemia, glycated hemoglobin, End Organ Disease Score, and smoking habits. Follow-up included 4 postextraction checkups over a 21-day period. Pairs of correlated continuous variables were analyzed with the Wilcoxon test, independent continuous variables with the Mann-Whitney test, and categorical variables with the χ(2) test or Fisher test. From January 2012 to December 2012, 34 patients affected by insulin-dependent diabetes mellitus underwent contemporary bilateral extractions of homologous teeth. The treatment-versus-control postoperative comparison showed that PRGF resulted in significantly smaller residual socket volumes and better Healing Indices from days 3 to 14. The patients' questionnaire outcomes were unanimously in favor of PRGF treatment. The small sample of patients with glycemia values of at least 240 mg/dL showed worse Healing Index and minor socket decreases. PRGF application after extraction improved the healing process in diabetic patients by accelerating socket closure (epithelialization) and tissue maturation, proving the association between PRGF use and improved wound healing in diabetic patients.	\N	\N
24349495	Panton-Valentine leukocidin (PVL; gene designation lukF/S-PV) is likely an important virulence factor for Staphylococcus aureus (S. aureus), as qualitative expression of the protein correlates with severity for specific clinical presentations, including skin and soft tissue infections (SSTIs). Development of genetic approaches for risk-assessment of patients with S. aureus infections may prove clinically useful, and whether lukF/S-PV gene expression correlates with specific clinical presentations for S. aureus has been largely unexplored. In the present study, we quantified lukS-PV mRNA among 96 S. aureus isolates to determine whether expression levels correlated with specific clinical presentations in adults and children. Expression level of lukS-PV mRNA among isolates from skin and soft tissue infections (SSTIs) was significantly greater than among isolates from blood stream infection (BSIs), and expression level of lukS-PV mRNA among BSI isolates from children was significantly greater than for BSI isolates among adults. Moreover, expression level of lukS-PV mRNA among community-acquired (CA) isolates was significantly greater than for hospital-acquired (HA) isolates. These data justify additional studies to determine the potential clinical utility for lukS-PV mRNA quantification as a predictive tool for severity of S. aureus infection.	\N	\N
24352112	This report contains CDC guidance that augments the 2011 recommendations of the Advisory Committee on Immunization Practices (ACIP) for evaluating hepatitis B protection among health-care personnel (HCP) and administering post-exposure prophylaxis. Explicit guidance is provided for persons working, training, or volunteering in health-care settings who have documented hepatitis B (HepB) vaccination years before hire or matriculation (e.g., when HepB vaccination was received as part of routine infant [recommended since 1991] or catch-up adolescent [recommended since 1995] vaccination). In the United States, 2,890 cases of acute hepatitis B were reported to CDC in 2011, and an estimated 18,800 new cases of hepatitis B occurred after accounting for underreporting of cases and asymptomatic infection. Although the rate of acute hepatitis B virus (HBV) infections have declined approximately 89% during 1990-2011, from 8.5 to 0.9 cases per 100,000 population in the United States, the risk for occupationally acquired HBV among HCP persists, largely from exposures to patients with chronic HBV infection. ACIP recommends HepB vaccination for unvaccinated or incompletely vaccinated HCP with reasonably anticipated risk for blood or body fluid exposure. ACIP also recommends that vaccinated HCP receive postvaccination serologic testing (antibody to hepatitis B surface antigen [anti-HBs]) 1-2 months after the final dose of vaccine is administered (CDC. Immunization of health-care personnel: recommendations of the Advisory Committee on Immunization Practices [ACIP]. MMWR 2011;60 [No. RR-7]). Increasing numbers of HCP have received routine HepB vaccination either as infants (recommended since 1991) or as catch-up vaccination (recommended since 1995) in adolescence. HepB vaccination results in protective anti-HBs responses among approximately 95% of healthy-term infants. Certain institutions test vaccinated HCP by measuring anti-HBs upon hire or matriculation, even when anti-HBs testing occurs greater than 2 months after vaccination. This guidance can assist clinicians, occupational health and student health providers, infection-control specialists, hospital and health-care training program administrators, and others in selection of an approach for assessing HBV protection for vaccinated HCP. This report emphasizes the importance of administering HepB vaccination for all HCP, provides explicit guidance for evaluating hepatitis B protection among previously vaccinated HCP (particularly those who were vaccinated in infancy or adolescence), and clarifies recommendations for postexposure management of HCP exposed to blood or body fluids.	\N	\N
24355565	The pancreas consists of two major divisions, the exocrine and the endocrine pancreas. Recent data from our laboratory have shown that the functions of the two divisions are under modulatory regulation by separate neurocircuits that originate in the dorsal motor nucleus of the vagus (DMV). Metabotropic glutamate receptors (mGluRs) are expressed throughout the central nervous system and have been implicated in the modulation of synaptic transmission. mGluRs consist of three groups of receptors, which can be distinguished based on their pharmacological properties and second messenger systems. Group I mGluRs predominantly increase, whereas group II and III mGluRs decrease synaptic transmission. Group II and group III mGluRs are present on excitatory and inhibitory synaptic terminals impinging on pancreas-projecting DMV neurons. We have shown that group II mGluRs regulate both exocrine pancreatic secretions and insulin release, whereas group III mGluRs only regulate insulin release. Several mGluR agonists and antagonists have been shown to have clinical uses for disorders accompanied by abnormal synaptic transmission, including anxiety and Parkinson's disease. Moreover, a negative allosteric modulator of Group I mGluRs is effective in alleviating symptoms of gastro-esophageal reflux disease (GERD). Since the role of the three mGluR groups in mediating different gastrointestinal (GI) functions appears to be highly specific, the use of agonists or antagonists directed at a single receptor group could potentially provide highly selective targets for the treatment of GI disorders including GERD, functional dyspepsia and acute pancreatitis.	\N	\N
24361034	The integration of body, mind, and spirit has become a key dimension of health education and disease prevention and treatment; however, our health care system remains primarily disease centered. Finding simple steps to help each of us find our own balance can improve our lives, our work, and our relationships. On the basis of interviews with health care experts at the leading edge of the new model of medicine, this article identifies simple tools to improve the health of patients and caregivers.	\N	\N
24362818	Follicular lymphoma is an incurable malignancy, with transformation to an aggressive subtype representing a critical event during disease progression. Here we performed whole-genome or whole-exome sequencing on 10 follicular lymphoma-transformed follicular lymphoma pairs followed by deep sequencing of 28 genes in an extension cohort, and we report the key events and evolutionary processes governing tumor initiation and transformation. Tumor evolution occurred through either a 'rich' or 'sparse' ancestral common progenitor clone (CPC). We identified recurrent mutations in linker histone, JAK-STAT signaling, NF-κB signaling and B cell developmental genes. Longitudinal analyses identified early driver mutations in chromatin regulator genes (CREBBP, EZH2 and KMT2D (MLL2)), whereas mutations in EBF1 and regulators of NF-κB signaling (MYD88 and TNFAIP3) were gained at transformation. Collectively, this study provides new insights into the genetic basis of follicular lymphoma and the clonal dynamics of transformation and suggests that personalizing therapies to target key genetic alterations in the CPC represents an attractive therapeutic strategy.	\N	\N
24368549	Hugh Henry Bentall, the inventor of the surgical procedure that enabled concomitant replacement of the aortic valve and ascending aorta, died on September 2012 at the age of 92. He was the first Professor of Cardiothoracic Surgery in the United Kingdom, at the Hammersmith Hospital, and carried out the first open-heart operations with a heart-lung machine in London in 1953. Besides cardiac surgery, he paid particular attention to cardiac anatomy and embryology, which he enriched even following retirement. He leaves three sons and a daughter.	\N	\N
24369205	Extracorporeal irradiation (ECI) is relatively a rare method used in the management of malignant bone tumors (MBT). It consists of en-bloc removal of the tumor bearing bone segment, removal of the tumor from the bone, irradiation, and re-implantation back in the body. We report our preliminary experience of using ECI for management of MBT. From year 2009 to 2010, 14 patients with primary MBT were enrolled into this study. The eligibility criteria included histopathological proof of malignancy, no evidence of distant metastases, and suitability for limb preservation therapy. Surgery was performed about 4 weeks after completion of neoadjuvant chemotherapy. The affected bone segment was resected, irradiated extracorporeally with a dose of 50 Gy and reimplanted. Local control, complications and short-term survival were studied. Functional outcome was assessed by Musculoskeletal Tumor Society (MSTS) scoring system. There were 10 males and four females with median age of 14 years. Histopthologically, nine patients had osteosarcoma (OS) and five had Ewing's sarcoma family of tumors (ESFT). Distribution of primary site was as follows: Femur eight patients, tibia five patients and humerus one patient. At a median follow-up was 22 months, three patients (two OS, one ESFT) had local recurrence. Two patients (14%) developed wound infection in the perioperative period. The 2 year local recurrence free survival was 73% and mean MSTS score was 88. Results of our study suggest that ECI is technically feasible in the management of MBT and provides decent local control and short-term survival rates.	\N	\N
24377187	Optimal nutrition, immunological state and psychological condition play an important role in the process of chronic wound healing. Infections caused by pathogens resistant to commonly used antibiotics additionally complicate and disturb regeneration of wounds. As part of the treatment, modern wound dressings are used, for example designed on the basis of alginates, dextranomers, hydrogels, hydrofiber, polyurethanes foams, hydrocolloids and liquids for wound debridement such us 0.9% NaCl, the PWE liquid, Ringer's liquid, octenidine. Owing to their features, treatment in accordance with TIME concept could be realized, because they provide moisture wound bed, protection against contamination, gas exchange, protection of wound edges and infection control. Repairing process in chronic wounds is dependent on blood flow in tissues, which may be insufficient. The result is a permanent hypoxia. Natural occurring antioxidants are becoming more crucial in chronic wound treatment. They decrease oxygen radical concentration, increase angiogenesis, reduce inflammatory response, stimulate fibroblasts and keratinocytes proliferation, possess antibacterial properties against chemotherapeutic resistant strains. There are a lot of antioxidants in honey, papaya fruit (Carrica papaia L.), transgenic flax (Linum usitatissimum), and in orange oil (Citrus sinensis), stem of acanthus (Acanthus ebracteatus), leafs of tea (Camellia sinensis). Application of biologically active, natural derived compounds is nowadays a direction of intense in vitro and in vivo research focused on the chronic wound treatment. Results suggest beneficial influence of antioxidant on wound repairing process. Clinical research are needed to state effective influence of natural compound in the chronic wound treatment.	\N	\N
24382893	Pathological inflammation and autoimmune disease frequently involve elevated neutrophil activity in the absence of infectious agents. Tumor necrosis factor-α (TNF-α) contributes to many of the problems associated with autoimmune diseases. We investigated the ability of serum α-1 antitrypsin (AAT) to control TNF-α biosynthesis and signaling in neutrophils and assessed whether AAT deficiency (AATD) is a TNF-α-related disease. In vitro studies demonstrate that serum AAT coordinates TNF-α intracellular signaling and neutrophil degranulation of tertiary and secondary granules via modulation of ligand-receptor interactions. AATD patients homozygous for the Z allele were characterized by increased activation of the TNF-α system, as demonstrated by increased membrane TNF-α levels and increased plasma concentrations of TNF receptor 1 and neutrophil-released secondary and tertiary granule proteins. The incidence of autoantibodies directed against degranulated lactoferrin and surface protein accessible to these antibodies was increased in ZZ-AATD, leading to an enhanced rate of neutrophil reactive oxygen species production. Treatment of ZZ-AATD individuals with AAT augmentation therapy resulted in decreased membrane TNF-α expression and plasma levels of granule antigenic proteins and immunoglobulin G class autoantibodies. These results provide a mechanism by which AAT augmentation therapy affects TNF-α signaling in the circulating neutrophil, indicating promising potential of this therapy for other TNF-α-related diseases.	\N	\N
24390521	Patients with atrial fibrillation (AF) have an increased risk of congestive heart failure (CHF) as well as ischemic stroke. The aim of this study was to investigate the clinical predictors of CHF in patients with non-valvular AF (NVAF). Three hundred and forty-seven patients (derivation cohort) with NVAF were retrospectively evaluated between 2004 and 2005. The associations between potential risk factors and CHF were tested using a Cox proportional hazards analysis, and a risk score for predicting CHF was created. The model was then validated in 161 patients (validation cohort) enrolled between 2008 and 2010. During the follow-up period, 41 patients in the derivation cohort developed CHF requiring hospitalization due to New York Heart Association (NYHA) class III or IV disease. Four independent risk factors were identified, each of which was assigned a number of points as follows: Age ≥72 years (1 point), heart rate ≥80 bpm (1 point), hypertension (1 point), and a previous history of congestive heart failure (2 points). The patients were grouped into one of three risk categories according to the calculated risk score (ARC2H score): low risk (0 points), intermediate risk (1-3 points) and high risk (4-5 points). In the derivation cohort, the annual rates of CHF in these risk categories were 0%, 2.5% and 18% per year respectively. In the validation cohort, the corresponding rates were 0.8%, 8% and 35% per year respectively. A simple clinical risk score, the ARC2H score, was developed to predict CHF in patients with NVAF and validated in an independent cohort.	\N	\N
24395633	Although Hodgkin's lymphoma (HL) was one of the first human cancers to be cured by chemotherapy, no new agents other than brentuximab vedotin (Adcetris®, CD 30 directed antibody drug conjugate) have received US Food and Drug Administration (FDA) approval for HL since 1977. Subsets of young adult patients with HL continue to relapse, even after stem cell transplantation, warranting new approaches. Against this background, we report a dramatic response in a young patient with advanced HL refractory to the standard treatment who responded to the combination of a pan-histone deacetylase inhibitor (vorinostat, suberoylanilide hydroxamic acid, SAHA) and mammalian target of rapamycin (mTOR) inhibitor therapy (sirolimus,rapamume). In-depth immunohistochemical and morphoproteomic analyses of this exceptional responder to targeted therapy have yielded potential insights into the biology of advanced HL. The PI3K/AKT/mTOR pathway is a commonly activated pathway in multiple tumor types including HL. The patient was treated using therapy based on mechanistic in vitro data demonstrating that combined histone deacetylase (HDAC) and mTOR inhibition act together on this pathway, resulting in inhibition of reciprocal feedback networks, leading to better anti-proliferative activity. The in vivo response signature from this patient's tissue sample sheds light on immune dysregulation in HL. We describe the response signature achieved from targeting immune dysregulation in addition to targeting the key oncogenic PI3K/AKT/mTOR pathway. We also expand on the role of rapamycin analogs in oncology. This study supports a role for an immune-type pathogenesis that is amenable to immune modulating targeted therapy in refractory HL. We report an exceptional responder to molecularly targeted and immune modulator therapy in advanced Hodgkin's lymphoma. The morphoproteomic/morphometric findings in this "unusual responder" patient's relapsed HL that correlate best, as a response signature with the subsequent clinical remission following rapamycin (sirolimus) and vorinostat (SAHA) therapies, center on an immune dysregulation involving an imbalance between effector and functional T regulatory cells in addition to targeting the mTOR pathway. This underscores the need for an approach illustrated in our study--namely of focusing on pathogenetic mechanisms and combinatorial therapies that target both the pathogenesis and adaptive responses to contemplated therapies.	\N	\N
24395648	Information on the chimpanzee nasopharygeal colonization in captive sanctuaries and in the wild is rare. This study was undertaken to establish the nasopharygeal colonization and potential bacterial pathogens in sanctuary chimpanzees as a basis for improving chimpanzee and employee health. Nasopharygeal colonization of 39 healthy chimpanzees were analyzed by microbiological cultivation method and polymerase chain reaction (PCR) targeting the bacterial 16S rRNA gene. We report four major phyla dominated by Proteobacteria (50%), Fermicutes (35.7%), Bacteriodes (7.1%), and Cynobacteria (7.1%) in healthy semi-captive chimpanzees. Further classification based on 7-base oligomers revealed the following genera: Streptococcus, Veillonella, Neisseria, Prevotella, Kingella and unclassified Cynobacteria, Actinobacillus, Bacteriodes and Pasteurellaceae. On microbiological cultivation we were able to identify and characterize some of the bacteria to species level as Klebsiella pneumonie and Pseudomonas aeruginosa being dominant bacteria with 54.7% and 50% colonization, respectively. Of these, Streptococcus, Neisseria, Klebsiella, and Haemophillus have representatives known to potentially cause severe respiratory disease. Our data present important information on chimpanzee nasopharygeal colonization as a guide to understanding disease processes and pharmaceutical therapies required for improving the health of chimpanzees. The results from this study will guide the processes to improve procedures for routine management of sanctuary chimpanzees and use it as a basis for evaluation of future reintroduction possibilities.	\N	\N
24418861	Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma and is mostly represented by the embryonal (ERMS) and alveolar (ARMS) histotypes. Whereas ERMS shows variable genetic alterations including TP53, RB1, and RAS mutations, ARMS carries a gene fusion between PAX3 or PAX7 and FOXO1. Epithelioid RMS is a morphologic variant of RMS recently described in adults. Five cases of epithelioid RMS were identified after histologic review of 85 cases of ARMS enrolled in Italian therapeutic protocols. Immunostaining analyses (muscle-specific actin, desmin, myogenin, AP-2β, EMA, cytokeratins, INI-1) and reverse transcription polymerase chain reaction assays to detect MyoD1, myogenin, and PAX3/7-FOXO1 transcripts were performed. In 4 cases DNA sequencing of TP53 was performed; and RB1 allelic imbalance and homozygous deletion were analyzed by quantitative real-time polymerase chain reaction. Histologically, epithelioid RMS displayed sheets of large cells without rhabdomyoblastic differentiation or anaplasia in 3 and prominent rhabdoid cells in 2; necrosis was evident in 4, often with a geographic pattern. Immunostainings for INI, desmin, myogenin (scattered cells in 4, diffuse in 1) were positive in all; EMA and MNF116 were positive in 2; AP-2β was negative. PAX3/7-FOXO1 transcripts were absent. In all cases RB1 was wild type, and a TP53 mutation at R273H codon was found in 1. All patients are in complete remission, with a median follow-up of 6 years. Epithelioid RMS may occur in children and is probably related to ERMS, as suggested by lack of fusion transcripts, weak staining for myogenin, negative AP-2β, evidence of TP53 mutation (although only in 1 case), and a favorable clinical course.	\N	\N
24424075	Hyperphosphataemia, a common biochemical abnormality in chronic kidney disease, poses significant management challenges. This study aims to determine whether the reasons for this are multifactorial; including poor dietary knowledge, poor adherence to a low phosphate diet and phosphate-binding medications and the impact of age on these parameters. In order to compare serum phosphate and other associated parameters to the UK Renal Association Clinical Practice Guidelines 2010 an audit and service evaluation questionnaire was carried out in May 2011 on 130 haemodialysis outpatients attending the Plymouth Dialysis Unit. Fifty-three percent of patients had serum phosphate within the target range of 1.1-1.7 mmol/l, 77% and 85% had serum calcium and parathyroid hormone within target ranges, respectively. Younger patients (18-45 years) were significantly less likely to have serum phosphate within range χ(2) (2, n=124)=18.77, P<0.001. Despite better knowledge of their own phosphate levels (P=0.005), phosphorus-rich foods (P<0.001), symptoms of hyperphosphataemia (P<0.001) and increased use of Renal Patient View (P=0.002), <65 years old had significantly higher phosphate levels than those >65 years (P<0.001). No significant associations were found between phosphate control and the following factors: gender, timing of dialysis shift, years on dialysis or dialysis adequacy. In this population, despite better knowledge, younger patients have worse phosphate control than older patients. Using the same dietary education techniques may not be suitable for all ages, more innovative approaches supported by skilled health professionals are needed to motivate and engage with younger patients to promote self-management and adherence.	\N	\N
24424629	To evaluate the long-term efficacy of pain reduction by two dose fractionation schedules used for low-dose radiotherapy of painful elbow syndrome. Between February 2006 and February 2010, 199 evaluable patients were recruited for this prospective trial. All patients received low-dose orthovoltage radiotherapy. One course consisted of 6 fractions in 3 weeks. In the case of insufficient pain remission after 6 weeks, a second course was administered. Patients were randomly assigned to one of two groups to receive single doses of either 0.5 or 1.0 Gy. Endpoint was pain reduction. Pain was measured before radiotherapy, as well as immediately after (early response), 6 weeks after (delayed response) and approximately 3 years after (long-term response) completion of radiotherapy using a questionnaire-based visual analogue scale (VAS) and a comprehensive pain score (CPS). Median follow-up was 35 months (range 9-57 months). The overall early, delayed and long-term response rates for all patients were 80, 90 and 94 %, respectively. The mean VAS scores before treatment and those for early, delayed and long-term response in the 0.5- and 1.0-Gy groups were 59.6 ± 20.2 and 55.7 ± 18.0 (p = 0.46); 32.1 ± 24.5 and 34.4 ± 22.5 (p = 0.26); 27.0 ± 27.7 and 23.5 ± 21.6 (p = 0.82) and 10.7 ± 15.0 and 21.5 ± 26.9 (p = 0.12), respectively. The mean CPS values before treatment and those for early, delayed and long-term response were 8.7 ± 2.9 and 8.1 ± 3.1 (p = 0.21); 4.5 ± 3.2 and 5.0 ± 3.4 (p = 0.51); 3.9 ± 3.6 and 2.8 ± 2.8 (p = 0.19) and 1.5 ± 2.3 and 2.4 ± 3.5 (p = 0.27), respectively. No significant differences in the quality of the long-term response were found between the 0.5- and 1.0-Gy arms (p = 0.28). Low-dose radiotherapy is an effective treatment for the management of benign painful elbow syndrome. For radiation protection reasons, the dose for a radiotherapy series should not exceed 3.0 Gy.	\N	\N
24436152	L-Asparaginase is an integral component of standard chemotherapy regimens for the treatment of acute lymphoblastic leukemia (ALL). Clinical hypersensitivity, a common reason for treatment discontinuation, has been reported in 10-30% of patients receiving Escherichia coli-derived asparaginase. After hypersensitivity, E. coli-derived asparaginase should be discontinued and an alternative asparaginase preparation, such as asparaginase Erwinia chrysanthemi, may be initiated. We conducted a compassionate-use study to collect additional safety information on asparaginase Erwinia chrysanthemi and to support FDA approval of the product. Patients with ALL or lymphoblastic lymphoma (LBL; N = 1368) who developed a hypersensitivity reaction (grade ≥2) to an E. coli-derived asparaginase participated in this trial. The recommended asparaginase Erwinia chrysanthemi dose was 25,000 IU/m(2) three days per week (Monday/Wednesday/Friday) for two consecutive weeks for each missed pegylated E. coli-derived asparaginase dose and 25,000 IU/m(2) for each missed nonpegylated asparaginase dose for the completion of their planned asparaginase treatment. Adverse event reports and/or case report forms were completed for 940 patients. The most common adverse event (AE) was hypersensitivity (13.6%). Eighteen patients (1.9%) died during the study. Most patients (77.6%) completed their planned asparaginase treatment with asparaginase Erwinia chrysanthemi. There was no apparent difference in the incidence of the most commonly reported AEs with asparaginase treatment by age, administration, or disease state. This study further established the safety profile of asparaginase Erwinia chrysanthemi in patients with ALL or LBL who had a hypersensitivity reaction to an E. coli-derived asparaginase.	\N	\N
24437400	The development of culture-independent techniques has revolutionized our understanding of how our human cells interact with the even greater number of microbial inhabitants of our bodies. As part of this revolution, data are increasingly challenging the old dogma that in health, the lung mucosa is sterile. To understand how the lung microbiome may play a role in human health, we identified five major questions for lung microbiome research: (1) Is the lung sterile? (2) Is there a unique core microbiome in the lung? (3) How dynamic are the microbial populations? (4) How do pulmonary immune responses affect microbiome composition? and (5) Are the lungs influenced by the intestinal immune responses to the gut microbiome? From birth, we are exposed to continuous microbial challenges that shape our microbiome. In our changing environment, perturbation of the gut microbiome affects both human health and disease. With widespread antibiotic use, the ancient microbes that formerly resided within us are being lost, for example, Helicobacter pylori in the stomach. Animal models show that antibiotic exposure in early life has developmental consequences. Considering the potential effects of this altered microbiome on pulmonary responses will be critical for future investigations.	\N	\N
24446993	With an estimated 12.1% of children aged 2-5 years already obese, prevention efforts must target our youngest children. One of the best places to reach young children for such efforts is the early care and education setting (ECE). More than 11 million U.S. children spend an average of 30 hours per week in ECE facilities. Increased attention at the national, state, and community level on the ECE setting for early obesity prevention efforts has sparked a range of innovative efforts. To assist these efforts, CDC developed a technical assistance and training framework - the Spectrum of Opportunities for Obesity Prevention in the ECE setting - which also served as the organizing framework for the Weight of the Nation ECE track. Participants highlighted their efforts at national, state, and local levels pursuing opportunities on the Spectrum, the standards and best practices that had been the emphasis of their efforts, and common steps for developing, implementing, and evaluating initiatives. Strong leadership and collaboration among a broad group of stakeholders; systematic assessment of needs, opportunities and resources; funding sources; and training and professional development were reported to be integral for successful implementation of standards and best practices, and sustainability.	\N	\N
24447640	Fungal endophthalmitis is a rare but serious infection. In March 2012, several cases of probable and laboratory-confirmed fungal endophthalmitis occurring after invasive ocular procedures were reported nationwide. We identified 47 cases in 9 states: 21 patients had been exposed to the intraocular dye Brilliant Blue G (BBG) during retinal surgery, and the other 26 had received an intravitreal injection containing triamcinolone acetonide. Both drugs were produced by Franck's Compounding Lab (Ocala, FL, USA). Fusarium incarnatum-equiseti species complex mold was identified in specimens from BBG-exposed case-patients and an unopened BBG vial. Bipolaris hawaiiensis mold was identified in specimens from triamcinolone-exposed case-patients. Exposure to either product was the only factor associated with case status. Of 40 case-patients for whom data were available, 39 (98%) lost vision. These concurrent outbreaks, associated with 1 compounding pharmacy, resulted in a product recall. Ensuring safety and integrity of compounded medications is critical for preventing further outbreaks associated with compounded products.	\N	\N
24449063	Psychotic symptoms have previously been reported following right hemisphere brain injury. We sought to identify the specific neuroanatomical basis of delusions following stroke by studying a series of patients with post-stroke psychosis. Lesion overlap analysis was conducted on three individuals with delusions following right hemisphere stroke. These cases were compared with a control group of patients with similar anatomical damage. The main outcome measures were presence of delusions and presence of behavioural susceptibility. The right inferior frontal gyrus and underlying white matter, including the superior longitudinal fasciculus and anterior corona radiata, were involved in all three cases. All three had a preexisting untreated psychiatric disorder. In contrast, only one of nine control cases with equivalent lesions had evidence of previous psychiatric disorder (p = 0.0182, Fisher's exact test), and this was being treated at the time of stroke. We provide clinical evidence from patients with structural brain lesions implicating damage to the right inferior frontal lobe in the generation of persistent psychosis following stroke. We suggest that preexisting psychiatric disease provided a behavioural susceptibility to develop delusions in these individuals.	\N	\N
24449064	The logopenic variant of primary progressive aphasia (lvPPA) strongly associates with Alzheimer's disease, but can also associate with frontotemporal lobar degeneration. We aimed to assess the frequency of lvPPA in patients with speech and language disorders without β-amyloid deposition, and to perform detailed neuroimaging and genetic testing in such lvPPA patients. Seventy-six patients with a neurodegenerative speech and language disorder and Pittsburgh compound B (PiB) PET imaging demonstrating no β-amyloid deposition were analyzed. Six lvPPA patients (8 %) were identified. All six underwent progranulin (GRN) gene testing. Structural abnormality index maps and Cortex ID analysis were utilized to assess individual patterns of grey matter atrophy on MRI and hypometabolism on 18-F fluorodeoxyglucose (FDG) PET. Statistical parametric mapping was used to perform MRI and FDG-PET group comparisons between those with (GRN-positive) and without (GRN-negative) progranulin mutations. All six lvPPA patients showed left temporoparietal atrophy and hypometabolism. Three patients (50 %) were GRN-positive. Speech, language, and neurological and neuropsychological profiles did not differ between GRN-positive and negative patients, although GRN-positive patients had family histories, were on average 8 years younger, and had lower PiB-PET ratios. All six patients showed similar patterns of atrophy and hypometabolism, although, as a group, GRN-positive patients had more severe abnormalities, particularly in anteromedial temporal lobes. Logopenic PPA accounts for a small minority of neurodegenerative speech and language disorders not associated with β-amyloid deposition. Identification of such patients, however, should prompt testing for GRN mutations, since GRN-positive patients do not have distinctive features, yet account for 50 % of this patient population.	\N	\N
24449169	Low-frequency, bilateral stimulation of the subthalamic nucleus can improve axial symptoms of advanced Parkinson's disease (PD), but it is not particularly effective for segmental symptoms. The optimal contacts for low-frequency (60 Hz) and high-frequency (130 Hz) single monopolar stimulation were determined. Then, in a randomized, double-blind, prospective crossover manner, 60-Hz and 130-Hz stimulations via the respective optimal contacts were compared for immediate efficacy in improving the motor function of patients with PD. The optimal contacts for 60-Hz stimulation were situated more ventrally than those for 130-Hz stimulation (P = 0.038). Under the respective optimal, single monopolar stimulation, 60 Hz provided superior efficacy over 130 Hz in improving the total Unified Parkinson's Disease Rating Scale motor score (P < 0.001) and the akinesia (P = 0.011) and axial motor signs (P = 0.012) subscores without compromising the therapeutic effect on tremor and rigidity. Low-frequency stimulation via the optimal contacts is effective in improving overall motor function of patients with PD.	\N	\N
24450996	Routine annual influenza vaccination is primarily recommended for all persons aged 60 and above and for people with underlying chronic conditions in Germany. Other countries have already adopted additional childhood influenza immunisation programmes. The objective of this study is to determine the potential epidemiological impact of implementing paediatric influenza vaccination using intranasally administered live-attenuated influenza vaccine (LAIV) in Germany. A deterministic age-structured model is used to simulate the population-level impact of different vaccination strategies on the transmission dynamics of seasonal influenza in Germany. In our base-case analysis, we estimate the effects of adding a LAIV-based immunisation programme targeting children 2 to 17 years of age to the existing influenza vaccination policy. The data used in the model is based on published evidence complemented by expert opinion. In our model, additional vaccination of children 2 to 17 years of age with LAIV leads to the prevention of 23.9 million influenza infections and nearly 16 million symptomatic influenza cases within 10 years. This reduction in burden of disease is not restricted to children. About one third of all adult cases can indirectly be prevented by LAIV immunisation of children. Our results demonstrate that vaccinating children 2-17 years of age is likely associated with a significant reduction in the burden of paediatric influenza. Furthermore, annual routine childhood vaccination against seasonal influenza is expected to decrease the incidence of influenza among adults and older people due to indirect effects of herd protection. In summary, our model provides data supporting the introduction of a paediatric influenza immunisation programme in Germany.	\N	\N
24459296	Huntington disease (HD) is a debilitating neurodegenerative disease characterized by the loss of motor control and cognitive ability that ultimately leads to death. It is caused by the expansion of a polyglutamine tract in the huntingtin (HTT) protein, which leads to aggregation of the protein and eventually cellular death. Both the wild-type and mutant form of the protein are highly regulated by post-translational modifications including proteolysis, palmitoylation and phosphorylation. We now demonstrate the existence of a new post-translational modification of HTT: the addition of the 14 carbon fatty acid myristate to a glycine residue exposed on a caspase-3-cleaved fragment (post-translational myristoylation) and that myristoylation of this fragment is altered in a physiologically relevant model of mutant HTT. Myristoylated HTT553-585-EGFP, but not its non-myristoylated variant, initially localized to the ER, induced the formation of autophagosomes and accumulated in abnormally large autophagolysosomal/lysosomal structures in a variety of cell types, including neuronal cell lines under nutrient-rich conditions. Our results suggest that accumulation of myristoylated HTT553-586 in cells may alter the rate of production of autophagosomes and/or their clearance through the heterotypic autophagosomal/lysosomal fusion process. Overall, our novel observations establish a role for the post-translational myristoylation of a caspase-3-cleaved fragment of HTT, highly similar to the Barkor/ATG14L autophagosome-targeting sequence domain thought to sense, maintain and/or promote membrane curvature in the regulation of autophagy. Abnormal processing or production of this myristoylated HTT fragment might be involved in the pathophysiology of HD.	\N	\N
24460750	In patients with essential thrombocythemia (ET), vascular complications contribute to both morbidity and mortality. To better predict the occurrence of thrombotic events, an International Prognostic Score of thrombosis for ET (IPSET-thrombosis) was recently developed. We hereby presented an external validation and analysis of this model in a large Cohort of Chinese Patients. We retrospectively evaluated the characteristics and risk factors for thrombosis in 970 Chinese patients with ET and estimated the clinical implications of the IPSET-thrombosis model. The median follow-up was 49 months (range, 0-360). Chinese ET patients had similar clinical characteristics as Caucasian patients. Similar to the IPSET-thrombosis study, our multivariate analysis revealed age >60 (HR = 1.949), previous thrombosis (HR = 2.484), JAK2V617F mutation (HR = 1.719), and cardiovascular risk factors (HR = 1.877) as independent risk factors for thrombosis. We confirmed that the above risk factors in IPSET-thrombosis, when compared with traditional risk factors (e.g., age ≥60 and previous thrombotic events), were more predictive of thrombotic events (C-index 0.714 vs. 0.647). Classification by IPSET-thrombosis risk groups revealed different cumulative thrombosis-free survival (P < 0.001). For treatment, patients in the intermediate- and high-risk group derived clinical benefit from cytoreductive agents (P < 0.05), but those in the low-risk group did not (P = 0.446). The lower risk of thrombosis on cytoreductive therapy was related to decrease in leukocyte count during the disease course. We validate the reproducibility of IPSET-thrombosis in Chinese ET patients and provide key clinical implications.	\N	\N
24467498	alcohol use disorders are associated with a greater incidence of certain comorbidities in patients with celiac disease. Currently there is no available information about the impact that these disorders may have on length of hospital stays, overexpenditures during hospital stays, and excess mortality in these patients. a case-control study was conducted with a selection of patients 18 years and older hospitalized during 2008-2010 in 87 hospitals in Spain. Estimations of excess length of stays, costs, and attributable mortality were calculated using a multivariate analysis of covariance, which included age, gender, hospital group, alcohol use disorders, tobacco related disease and 30 other comorbidities. patients who had both celiac disease and alcohol use disorders had an increased length of hospital stay, an average of 3.1 days longer in women, and 1.7 days longer in men. Excess costs per stay ranged from 838.7 euros in female patients, to 389.1 euros in male patients. Excess attributable mortality was 15.1 % in women, 12.2 % in men. apart from a gluten-free diet and other medical measures, the prevention of alcohol abuse is indicated in these patients. Patients hospitalized who present these disorders should receive specialized attention after leaving the hospital. Early detection and treatment should be used to prevent the appearance of organic lesions and should not be solely focused on male patients.	\N	\N
24469423	The molecular epidemiology of group B Streptococcus (GBS) in Ireland was investigated. Invasive (n = 132) and non-invasive (n = 45) isolates, collected in 2007-2011, were analysed by multilocus locus sequence typing, capsular polysaccharide (CPS) serotyping, profiling of surface proteins, pilus islands (PI), and antimicrobial susceptibility. Isolates grouped into 45 sequence types and five main clonal complexes (CC). CC1, CC17 and CC23 represented 67.2 % of isolates and the most prevalent serotypes Ia, III and V. Serotype and surface protein genes were largely predictive of CC. Accordingly, CPS V/alp3, CPS Ib/CPS II/bca + bac, and CPS Ia/eps predominated in CC1, CC12 and CC23, respectively, and CPS III/rib in CC17 and CC19. Supporting their vaccine potential, all isolates harboured at least one PI, of which the PI-1 + PI-2a combination was most prevalent. Macrolide resistance was found in 18.6 % of isolates. erm(B) and the globally disseminated CC1/CPS V were the most common resistance mechanism and CC/CPS type, respectively. CC17, significantly associated with neonatal disease, was also prevalent in pregnant adults, but was underrepresented among non-pregnant adults. Two of 46 CC17 isolates (typically CPS III) were CPS IV. Sequence analysis confirmed capsular switching and their relatedness to CC17/CPS IV strains recently characterized in France. CPS IV, detected only in invasive isolates (6.8 %), was most prevalent in adults (12 %) and showed an increase in prevalence to that reported (1.4 %) for invasive isolates in Ireland 1997-1999. Increases in serotype IV and evidence of capsular switching in CC17 highlights the importance of ongoing surveillance of GBS and may have implications for vaccine development strategies.	\N	\N
24478094	Evidence from clinical trials of malaria vaccine candidates suggests that both cell-mediated and humoral immunity to pre-erythrocytic parasite stages can provide protection against infection. Novel pre-erythrocytic antibody (Ab) targets could be key to improving vaccine formulations, which are currently based on targeting antigens such as the circumsporozoite protein (CSP). However, methods to assess the effects of sporozoite-specific Abs on pre-erythrocytic infection in vivo remain underdeveloped. Here, we combined passive transfer of monoclonal Abs (MAbs) or immune serum with a luciferase-expressing Plasmodium yoelii sporozoite challenge to assess Ab-mediated inhibition of liver infection in mice. Passive transfer of a P. yoelii CSP MAb showed inhibition of liver infection when mice were challenged with sporozoites either intravenously or by infectious mosquito bite. However, inhibition was most potent for the mosquito bite challenge, leading to a more significant reduction of liver-stage burden and even a lack of progression to blood-stage parasitemia. This suggests that Abs provide effective protection against a natural infection. Inhibition of liver infection was also achieved by passive transfer of immune serum from whole-parasite-immunized mice. Furthermore, we demonstrated that passive transfer of a MAb against P. falciparum CSP inhibited liver-stage infection in a humanized mouse/P. falciparum challenge model. Together, these models constitute unique and sensitive in vivo methods to assess serum-transferable protection against Plasmodium sporozoite challenge.	\N	\N
24501382	It has been established that bimanual coordination with augmented feedback (FB) versus no augmented feedback (NFB) is associated with activity in different brain regions. It is unclear however, whether this distinction remains after practice comprising both these conditions. Functional magnetic resonance imaging was used in humans to compare visual FB versus NFB conditions for a bimanual tracking task, and their differential evolution across learning. Scanning occurred before (Pre) and after 2 weeks (Post) of mixed FB and NFB training using an event-related design, allowing differentiation between the planning and execution phase of the task. Activations at the whole-brain level initially differed for FB versus NFB movements but this differentiation diminished with training for the movement execution phase. Specifically, in right dorsal premotor cortex and right dorsolateral prefrontal cortex activation increased for NFB and decreased for FB trials to converge toward the end of practice. This suggests that learning led to a decreased need to adjust the ongoing movement on the basis of FB, whereas online monitoring became more pronounced in NFB trials as discrepancies between the required and the produced motor output were detected more accurately after training, due to a generic internal reference of correctness supporting movement control under varying conditions.	\N	\N
24505382	Public health surveillance systems provide valuable data for reliable predication of future epidemic events. This paper describes a study that used nine types of infectious disease data collected through a national public health surveillance system in mainland China to evaluate and compare the performances of four time series methods, namely, two decomposition methods (regression and exponential smoothing), autoregressive integrated moving average (ARIMA) and support vector machine (SVM). The data obtained from 2005 to 2011 and in 2012 were used as modeling and forecasting samples, respectively. The performances were evaluated based on three metrics: mean absolute error (MAE), mean absolute percentage error (MAPE), and mean square error (MSE). The accuracy of the statistical models in forecasting future epidemic disease proved their effectiveness in epidemiological surveillance. Although the comparisons found that no single method is completely superior to the others, the present study indeed highlighted that the SVMs outperforms the ARIMA model and decomposition methods in most cases.	\N	\N
24507376	Human infections with different avian influenza viruses--eg, H5N1, H9N2, and H7N9--have raised concerns about pandemic potential worldwide. We report the first human infection with a novel reassortant avian influenza A H10N8 virus. We obtained and analysed clinical, epidemiological, and virological data from a patient from Nanchang City, China. Tracheal aspirate specimens were tested for influenza virus and other possible pathogens by RT-PCR, viral culture, and sequence analyses. A maximum likelihood phylogenetic tree was constructed. A woman aged 73 years presented with fever and was admitted to hospital on Nov 30, 2013. She developed multiple organ failure and died 9 days after illness onset. A novel reassortant avian influenza A H10N8 virus was isolated from the tracheal aspirate specimen obtained from the patient 7 days after onset of illness. Sequence analyses revealed that all the genes of the virus were of avian origin, with six internal genes from avian influenza A H9N2 viruses. The aminoacid motif GlnSerGly at residues 226-228 of the haemagglutinin protein indicated avian-like receptor binding preference. A mixture of glutamic acid and lysine at residue 627 in PB2 protein--which is associated with mammalian adaptation--was detected in the original tracheal aspirate samples. The virus was sensitive to neuraminidase inhibitors. Sputum and blood cultures and deep sequencing analysis indicated no co-infection with bacteria or fungi. Epidemiological investigation established that the patient had visited a live poultry market 4 days before illness onset. The novel reassortant H10N8 virus obtained is distinct from previously reported H10N8 viruses. The virus caused human infection and could have been associated with the death of a patient. Emergency Research Project on human infection with avian influenza H7N9 virus, the National Basic Research Program of China, and the National Mega-projects for Infectious Diseases.	\N	\N
24508287	Ghrelin is an endogenous ligand of the growth hormone (GH) secretagogue receptor and is closely associated with chronic heart failure (CHF). We undertook this study to investigate the relevance of ghrelin in CHF prognosis. A total of 145 in-patients with CHF in NYHA class II, III or IV despite optimized therapy were prospectively included in the study, grouped according to NYHA class and compared with 55 healthy control subjects. Ghrelin and N-terminal pro-B-type natriuretic peptide (Nt pro-BNP) were measured in plasma by ELISA. Echocardiographic information was also measured, including left atrial dimension, left ventricular end-diastolic diameter, LV volume and left ventricular ejection fraction (LVEF). Patients were followed for 2 years or until major adverse cardiac events. Plasma ghrelin levels were significantly lower in patients with CHF than in control subjects (p = 0.014). In addition, plasma ghrelin levels differed significantly with the severity of CHF. Notably, survival analysis showed that high ghrelin levels were an indicator of a favorable prognosis for CHF. Our results also showed that ghrelin correlated inversely with plasma Nt pro-BNP levels (r = -0.562, p <0.001) and positively with LVEF (r = 0.620, p <0.001) in patients with CHF. Furthermore, multivariate analysis showed that ghrelin levels were independently associated with adverse cardiac events (hazard ratio: 0.72; 95% CI: 0.64-0.81, p = 0.03). Ghrelin is a new biomarker of CHF severity as well as a new prognostic predictor for patients with CHF. Future experimental and clinical studies are warranted to evaluate ghrelin as a novel prognostic tool and for its therapeutic potential in patients with CHF.	\N	\N
24512284	To perform psychometric testing an owner self-administered questionnaire, the Canine Orthopedic Index (COI), designed to assess outcome in dogs with orthopedic disease. Original study. Owners (n = 20) of dogs with osteoarthritis (OA) for item (question) pretesting, and 80 owners of dogs with OA for reliability and validity testing. Standard methodology for the stepwise development and testing of instruments designed to assess subjective states was followed. Items generated in previous studies were pretested for readability, ambiguity, and inter-item correlations; poorly performing items were removed; and the reduced set of items subjected to factor analysis, reliability, and validity testing. Four factors were identified and named on the basis of the items contained in them: "Stiffness," "Gait," "Function," and "Quality of Life." Cronbach's α ranged from 0.76 to 0.86, suggesting the items in each factor could be assessed as a group to compute factor scores (i.e., stiffness, gait, function, and quality of life scores). The test-retest analysis revealed κ values from 0.68 to 0.80. Overall, the scores amongst the 4 factors correlated moderately well (r = 0.52-0.58), with a mild correlation (r = 0.35) between gait and function scores. The COI is a psychometrically sound owner completed instrument that can assess 4 domains in dogs with OA: Stiffness, Gait, Function, and Quality of Life.	\N	\N
24513795	Blood sample and placenta were taken from a 37-week pregnant woman; serologic results indicated acute toxoplasmosis. Placenta was inoculated into mice. Seropositive mice were sacrificed and tissue cysts from brain were inoculated into new mice. Specific DNA was detected by PCR, and the isolate was characterized as Type II by nPCR-RFLP for nSAG2, SAG3, BTUB, GRA6, c29-2, c22-8, L358, PK1 and Apico markers. This is the first isolation and molecular characterization of Toxoplasma gondii from humans in Argentina.	\N	\N
24517642	Salvage liver transplantation (SLT) is an attractive sequential strategy which combines liver resection (LR) for hepatocellular carcinoma (HCC), followed by liver transplant (LT) in the event of HCC recurrence or progressive liver deterioration. To compare the long-term results of SLT with primary liver transplant (PLT). Between 2000 and 2011, 125 patients (72 transplantable) underwent LR and 226 underwent LT in our unit. The outcome of SLT was analysed in a two-step fashion: firstly, SLT (n = 28) was compared with PLT (n = 198), secondly an intention-to-treat analysis was performed on all transplantable HCC patients who underwent LR (LRT group = 72) compared to PLT (n = 198). The five-year overall survival (OS) was 65.4% vs. 49.2% (P = 0.63), and disease-free survival (DFS) was 89.7% vs. 80.6% (P = 0.31) for PLT and SLT respectively. Predictive factors for DFS after LT included HCC total diameter [hazard ratio (HR) 1.29 P = 0.003], alpha-foetoprotein (HR 1.002 P < 0.001) and number of HCC nodules (HR 1.317 P = 0.035), whereas viral hepatitis C positivity (HR 1.911 P = 0.03) and outside Up-to-seven criteria (HR 2.652 P < 0.001) were negative independent prediction factors of OS. Intention-to-treat analysis showed that OS at 5 years was improved in PLT vs. LRT (LRT n = 72 including SLT plus LR group) and was 69.4% vs. 42.2% (P < 0.004), with an additional increase in DFS (89.2% vs. 54.5% respectively P < 0.001). Salvage liver transplantation is a safe treatment strategy, as it does not impair long-term survival. At intention-to-treat analysis, PLT showed improved survival compared with LRT.	\N	\N
24519340	Mental health is a human right and fundamental to good personal health. Developing, planning, and implementing mental health programs is a key part of health policies worldwide. This paper uses the perspective of "mental health mainstreaming" to define mental health and explore its relationship with mental illness and psychiatric disease. Further, we apply this perspective to Taiwan's three-tiered community mental illness prevention strategy as a reference for mental health promotion and rehabilitation programs in hopes that all healthcare providers help facilitate holistic community health.	\N	\N
24524071	Heat shock protein 72 (Hsp72) exhibits a protective role during times of increased risk of pathogenic challenge and/or tissue damage. The aim of the study was to ascertain Hsp72 protective effect differences between animal and human studies in sepsis using a hypothetical "comparative study" model. Forty-one in vivo (56.1%), in vitro (17.1%), or combined (26.8%) animal and 14 in vivo (2) or in vitro (12) human Hsp72 studies (P < 0.0001) were enrolled in the analysis. Of the 14 human studies, 50% showed a protective Hsp72 effect compared to 95.8% protection shown in septic animal studies (P < 0.0001). Only human studies reported Hsp72-associated mortality (21.4%) or infection (7.1%) or reported results (14.3%) to be nonprotective (P < 0.001). In animal models, any Hsp72 induction method tried increased intracellular Hsp72 (100%), compared to 57.1% of human studies (P < 0.02), reduced proinflammatory cytokines (28/29), and enhanced survival (18/18). Animal studies show a clear Hsp72 protective effect in sepsis. Human studies are inconclusive, showing either protection or a possible relation to mortality and infections. This might be due to the fact that using evermore purified target cell populations in animal models, a lot of clinical information regarding the net response that occurs in sepsis is missing.	\N	\N
24529770	When tried in court, mothers accused of neonaticide may claim that the umbilical cord just broke during birth and the newborn child bled to death accordingly. To evaluate the possibility of a breakage of the umbilical cord is the goal of this work. Therefore 25 umbilical cords from neonates of both sexes born at term were stretched using an electrically operated material testing machine and the energy necessary to break them was measured. This experimental set-up equals a static strain, not a dynamic one. The maximum force endured (F max) ranged from 37.24 N to 150.04 N. The average force endured was 79.87 N with a standard deviation of 27.39. The elongation at break varied from 13.24% to a maximum of 119.93%. We found no relationship between the force endured and any of the following parameters: birth weight, pH of the venous umbilical blood, diameter of cord, free length under testing, duration of pregnancy or the mother's age. We performed a literature research and tried to define the circumstances in which a break is more likely to occur, these being malformations, entanglement or disease, e.g. inflammation.	\N	\N
24550581	Levosimendan is a calcium sensitizer drug which has been used in cardiac surgery for the prevention of postoperative low cardiac output syndrome (LCOS) and in difficult weaning from cardiopulmonary bypass (CPB). This study aims to evaluate perioperative hemodynamic effects of levosimendan pretreatment in patients for off-pump coronary artery bypass graft (OPCABG) surgery with low left ventricular ejection fractions (LVEF < 30%). Fifty patients undergoing OPCABG surgery with low LVEF (<30%) were enrolled in the study. Patients were randomly divided in two groups: Levosimendan pretreatment (Group L) and placebo pretreatment (Group C) of 25 each. Group L, patients received levosimendan infusion 200 μg/kg over 24 h and in Group C Patients received placebo. The clinical parameters measured before and after the drug administration up to 48 h were heart rate (HR; for the hour after drug infusion), cardiac index (CI), and pulmonary capillary wedge pressure (PCWP). The requirement of inotropes, intraaortic balloon pump (IABP), CPB, intensive care unit (ICU) stay, and hospital stay were also measured. The patients in group L exhibited higher CI and PCWP during operative in early postoperative period as compared to control group C. Group L also had a less requirement for inotropes, CPB support and IABP with shorter ICU stay as well as hospital stay. Levosimendan pretreatment (24 h infusion) in patient for OPCABG with poor LVEF shows better outcomes and hemodynamics in terms of inotropes, CPB and IABP requirements. It also reduces ICU stay.	\N	\N
24554437	The ER is the largest cellular compartment and a major storage site for lipids and ions. In recent years, much attention has focused on contacts between the ER and other organelles, and one particularly intimate relationship is that between the ER and the endosomal system. ER-endosome contacts intensify when endosomes mature, and the ER participates in endosomal processes, such as the termination of surface receptor signaling, multi-vesicular body formation, and transport and fusion events. Cholesterol and Ca(2+) are transferred between the ER and endosomes, possibly acting as messengers for ER-endosome crosstalk. Here, we summarize different types of ER-endosomal communication and discuss membrane contact sites that might facilitate this crosstalk. We review the protein pairs that interact at the ER-endosome interface and find that many of these have a role in cholesterol exchange. We also summarize Ca(2+) exchange between the ER and endosomes, and hypothesize that ER-endosome contacts integrate several cellular functions to guide endosomal maturation. We post the hypothesis that failure in ER-endosome contacts is an unrecognized but important contributor to diseases, such as Niemann-Pick type C disease, Alzheimer's disease and amyotrophic lateral sclerosis.	\N	\N
24555602	This article will describe the elements of performing a thorough venous ultrasound evaluation of the lower extremity in patients with manifestations of chronic venous disorder. The emphasis will be on the evaluation of superficial venous reflux. Only the specific aspects of the evaluation of the deep system pertaining to chronic venous disease will be discussed. Duplex ultrasound requires the examiner to solve a puzzle to explain the patient's clinical manifestations. Patients who have been treated with surgery, thermal ablation, or ultrasound-guided sclerotherapy will require duplex ultrasound after treatment to identify complications, gauge the extent of treatment success, and evaluate the cause for any recurrence.	\N	\N
24557586	The survival of patients with axial skeletal or pelvic osteosarcoma (OS) remains poor, and the management of these patients is challenging. The object of this study is a cohort of unselected patients aged < 19 years with primary high-grade pelvic/axial OS. Patients were treated with high-dose methotrexate, doxorubicin, cisplatin, ifosfamide followed or preceded by local treatment (surgery and/or radiotherapy). Twenty patients aged 3-19 years were treated. Eight patients had pelvic OS, 8 axial OS and 4 mandible/maxilla OS. All patients received chemotherapy, after which necrosis was evaluable in 9 patients (≥ 90% in 3). Sixteen patients underwent surgery. Radiotherapy was administered to 8 patients (total dose 34-60 Gy). The median follow-up was 35 months (8-276), and the 5-year disease-free survival and overall survival rates were 37 and 40%, respectively. Six patients were alive at the time of this report: 2 with pelvic OS (both responded well to chemotherapy, one underwent hemipelvectomy and the other had non-radical surgery plus radiotherapy); 1 with axial and multicentric OS (with a good histological response and radical surgery); 3 with mandible/maxilla OS. Two patients died of secondary tumors (one bone and one breast cancer). It is worth noting that 4 patients had a p53 mutation: 1 is alive, 2 died of their OS, 1 of breast cancer. Adequacy of local treatment and pathological response influenced the prognosis for axial OS, which remained dismal. A high incidence of p53 mutation emerged in our series of patients.	\N	\N
24560191	In this issue of Immunity, Funabiki et al. (2014) have identified in mice a mutation of the IFIH1 gene, encoding the viral receptor MDA5 that causes constitutive IFN production and fatal autoimmune disease. The authors show that the autoimmune disease-associated variant of human MDA5 is permanently switched on.	\N	\N
24566636	In the current open society and with the growth of human rights, people are more and more concerned about the privacy of their information and other important data. This study makes use of electrocardiography (ECG) data in order to protect individual information. An ECG signal can not only be used to analyze disease, but also to provide crucial biometric information for identification and authentication. In this study, we propose a new idea of integrating electrocardiogram watermarking and compression approach, which has never been researched before. ECG watermarking can ensure the confidentiality and reliability of a user's data while reducing the amount of data. In the evaluation, we apply the embedding capacity, bit error rate (BER), signal-to-noise ratio (SNR), compression ratio (CR), and compressed-signal to noise ratio (CNR) methods to assess the proposed algorithm. After comprehensive evaluation the final results show that our algorithm is robust and feasible.	\N	\N
24568610	The generation of induced pluripotent stem cells (iPSCs) from somatic cells by expressing ectopic reprogramming transcriptional factors such as Oct3/4, Sox2, Klf4, c-Myc, and Nanog is one of the cutting-edge discoveries in stem cell and cancer research. This discovery has raised several safety issues regarding the use of iPSC technology for human disease research. Tumorigenesis is the major obstacle observed for iPSC-mediated transplantation therapy. Recently, a new method to generate human iPSCs either by a chemical method or by direct delivery of reprogramming factors has become a promising approach for future customized cell therapy of human disorders. These reprogramming transcriptional factors play critical roles in diverse cellular functions such as transactivation, cellular proliferation, differentiation, apoptosis, and tumorigenesis. Posttranslational modifications (PTMs) (phosphorylation, ubiquitination, acetylation, sumoylation, and so on) of these proteins act as a regulatory signal to control protein activity, expression, and stability in a wide variety of cellular processes. We attempt to summarize the accumulated evidence to address the role of PTMs of Oct3/4, Sox2, Klf4, c-Myc, and Nanog in regulating their biological functions. This review allows us to understand the importance of PTMs and their application in developing an efficient and safe reprogramming method without cancer development for cell therapy. Finally, we discuss the importance of PTMs of reprogramming factors in tumor pathogenesis.	\N	\N
24574413	Interferons (IFNs) are cytokines produced by host cells in response to the infection with pathogens. By binding to the corresponding receptors, IFNs trigger different pathways to block intracellular replication and growth of pathogens and to impede the infection of surrounding cells. Due to their key role in host defense against viral infections, as well as for clinical therapies, the IFN responses and regulation mechanisms are well studied. However, studies of type I IFNs have mainly focused on alpha interferon (IFN-α) and IFN-β subtypes. Knowledge of IFN-κ and IFN-ω is limited. Moreover, most studies are performed in humans or mouse models but not in the original host of zoonotic pathogens. Bats are important reservoirs and transmitters of zoonotic viruses such as lyssaviruses. A few studies have shown an antiviral activity of IFNs in fruit bats. However, the function of type I IFNs against lyssaviruses in bats has not been studied yet. Here, IFN-κ and IFN-ω genes from the European serotine bat, Eptesicus serotinus, were cloned and functionally characterized. E. serotinus IFN-κ and IFN-ω genes are intronless and well conserved between microchiropteran species. The promoter regions of both genes contain essential regulatory elements for transcription factors. In vitro studies indicated a strong activation of IFN signaling by recombinant IFN-ω, whereas IFN-κ displayed weaker activation. Noticeably, both IFNs inhibit to different extents the replication of different lyssaviruses in susceptible bat cell lines. The present study provides functional data on the innate host defense against lyssaviruses in endangered European bats. We describe here for the first time the molecular and functional characterization of two type I interferons (IFN-κ and -ω) from European serotine bat (Eptesicus serotinus). The importance of this study is mainly based on the fact that very limited information about the early innate immune response against bat lyssaviruses in their natural host serotine bats is yet available. Generally, whereas the antiviral activity of other type I interferons is well studied, the functional involvement of IFN-κ and -ω has not yet been investigated.	\N	\N
24579399	Patients with chronic kidney disease (CKD) who are treated with dialysis have impaired physical functioning that is associated with poor outcomes. Gait speed is an important measure of mobility that predicts adverse events and mortality in older people. Gait speed is low in patients with CKD, and those treated with hemodialysis average below cut-points known to indicate increased risk of reduced survival and adverse health events. Measurement of gait speed in patients with CKD may be valuable in identifying those at risk for adverse events, including disability and mortality.	\N	\N
24583421	Magnetic resonance imaging has been shown to be a powerful tool for diagnosing multiple sclerosis (MS) and evaluating surrogate markers of the disease activity. However, biomarkers may provide more accurate information regarding ongoing immune responses leading to demyelination and treatment effects in MS patients. Although serum biomarkers are easily accessible, they do not provide clear-cut results, whereas cerebrospinal fluid (CSF) biomarkers provide unequivocal information, although samples cannot be repeatedly obtained. For diagnosis, the presence of oligoclonal IgG bands remains important. In addition, measuring the levels of adhesion molecules, matrix metalloproteinase-9 and complement regulator factor H in the serum and evaluating the proportion of Th1/Th2 cells in the blood may be clinically feasible for monitoring the disease activity. In CSF samples, increased IL-8, IL-12, IL-17, CCL3, CCL5 and CXCL10 levels indicate active disease, and the flow cytometry findings of CSF cells can be used to detect increases in Th1 and CD4(+)CD25(+) cells during relapse. Biomarkers closely linked to the disease activity may be informative of the pathogenesis of MS, while those associated with tissue damage or repair may be targets of new treatment strategies. Establishing the latter will be a primary point of research in the near future.	\N	\N
24583589	A 76-year-old woman was admitted to our hospital because of convulsions that developed after a 1-month history of progressive right-leg palsy. MRI showed thickening of the meninges with gadolinium enhancement in the left parietal lobe and it revealed pia-subarachnoid space pattern. A lumbar puncture was performed, and cerebrospinal fluid analysis revealed no abnormality. Her serum adenosine deaminase level was elevated (28.7 IU/l). The results of serum cultures were normal. To differentially diagnose collagen disease, infection, malignancy, and inflammation of uncommon causes, we conducted brain and meningeal biopsies on the 15th hospital day. Histopathological examination of the brain tissue showed mainly necrosis and inflammation. There was severe pachymeningeal thickening without necrosis. Although it was difficult to reach a definitive diagnosis, a tissue sample taken from under the leptomeninges tested positive for mycobacterium on Ziehl-Neelsen staining. The results of polymerase chain reaction for mycobacterium were negative in the meningeal tissue. The patient received anti-tuberculous drugs, anti-nontuberculous mycobacteriosis drugs, and corticosteroids to treat Mycobacterium tuberculosis and nontuberculous mycobacterium. After starting treatment, the findings on magnetic resonance imaging improved dramatically, and no convulsions occurred during hospitalization. She was discharged on the 153rd hospital day without any neurological deficit. Because previous studies have reported that isolated mycobacterium meningitis is a diagnostically challenging condition, brain and meningeal biopsies should be considered in patients with gadolinium enhancement in the meninges.	\N	\N
24585436	The development of fully automated and high-throughput systems for proteomics is now in demand because of the need to generate new protein-based disease biomarkers. Unfortunately, it is difficult to identify protein biomarkers that are low abundant when in the presence of highly abundant proteins, especially in complex biological samples such as serum, cell lysates, and other biological fluids. Membrane proteins, which are in many cases of low abundance compared to the cytosolic proteins, have various functions and can provide insight into the state of a disease and serve as targets for new drugs making them attractive biomarker candidates. Traditionally, proteins are identified through the use of gel electrophoretic techniques, which are not always suitable for particular protein samples such as membrane proteins. Microfluidics offers the potential as a fully automated platform for the efficient and high-throughput analysis of complex samples, such as membrane proteins, and do so with performance metrics that exceed their bench-top counterparts. In recent years, there have been various improvements to microfluidics and their use for proteomic analysis as reported in the literature. Consequently, this review presents an overview of the traditional proteomic-processing pipelines for membrane proteins and insights into new technological developments with a focus on the applicability of microfluidics for the analysis of membrane proteins. Sample preparation techniques will be discussed in detail and novel interfacing strategies as it relates to MS will be highlighted. Lastly, some general conclusions and future perspectives are presented.	\N	\N
24588669	Tumour hypoxia is increasingly recognized as a major deleterious factor in cancer therapies, as it compromises treatment and drives malignant progression. This review seeks to clarify the oxygen levels that are pertinent to this issue. It is argued that normoxia (20% oxygen) is an extremely poor comparator for "physoxia", i.e. the much lower levels of oxygen universally found in normal tissues, which averages about 5% oxygen, and ranges from about 3% to 7.4%. Importantly, it should be recognized that the median oxygenation in untreated tumours is significantly much lower, falling between approximately 0.3% and 4.2% oxygen, with most tumours exhibiting median oxygen levels <2%. This is partially dependent on the tissue of origin, and it is notable that many prostate and pancreatic tumours are profoundly hypoxic. In addition, therapy can induce even further, often unrecognized, changes in tumour oxygenation that may vary longitudinally, increasing or decreasing during treatment in ways that are not always predictable. Studies that fail to take cognizance of the actual physiological levels of oxygen in tissues (approximately 5%) and tumours (approximately 1%) may fail to identify the real circumstances driving tumour response to treatment and/or malignant progression. This can be of particular importance in genetic studies in vitro when comparison to human tumours is required.	\N	\N
24590608	Iron is an essential mineral in many proteins and enzymes in human physiology, with limited means of iron elimination to maintain iron balance. Iron accrual incurs various pathological mechanisms linked to cardiovascular disease. In atherosclerosis, iron catalyzes the creation of reactive oxygen free radicals that contribute to lipid modification, which is essential to atheroma formation. Inflammation further fuels iron-related pathologic processes associated with plaque progression. Given iron's role in atherosclerosis development, in vivo detection techniques sensitive iron are needed for translational studies targeting iron for earlier diagnosis and treatment. Magnetic resonance imaging is uniquely able to quantify iron in human tissues noninvasively and without ionizing radiation, offering appealing for longitudinal and interventional studies. Particularly intriguing is iron's complementary biology vs. calcium, which is readily detectable by computed tomography. This review summarizes the role of iron in atherosclerosis with considerable implications for novel diagnostic and therapeutic approaches.	\N	\N
24603533	Telomere biology is frequently associated with disease evolution in human cancer and dysfunctional telomeres have been demonstrated to contribute to genetic instability. In BCR-ABL(+) chronic myeloid leukemia (CML), accelerated telomere shortening has been shown to correlate with leukemia progression, risk score and response to treatment. Here, we demonstrate that proliferation of murine CML-like bone marrow cells strongly depends on telomere maintenance. CML-like cells of telomerase knockout mice with critically short telomeres (CML-iG4) are growth retarded and proliferation is terminally stalled by a robust senescent cell cycle arrest. In sharp contrast, CML-like cells with pre-shortened, but not critically short telomere lengths (CML-G2) grew most rapidly and were found to express a specific 'telomere-associated secretory phenotype', comprising secretion of chemokines, interleukins and other growth factors, thereby potentiating oncogene-driven growth. Moreover, conditioned supernatant of CML-G2 cells markedly enhanced proliferation of CML-WT and pre-senescent CML-iG4 cells. Strikingly, a similar inflammatory mRNA expression pattern was found with disease progression from chronic phase to accelerated phase in CML patients. These findings demonstrate that telomere-induced senescence needs to be bypassed by leukemic cells in order to progress to blast crisis and provide a novel mechanism by which telomere shortening may contribute to disease evolution in CML.	\N	\N
24610167	The aim of this study was to evaluate the diagnostic accuracy of postnatal multidetector computed tomography (MDCT) compared with prenatal ultrasound (US), surgical findings, and histology, in 33 patients with congenital cystic lung disease. Thirty-three patients, 17 males and 16 females, were evaluated by MDCT. Twenty-seven of these patients underwent prenatal US between week 18 and 22, and between week 32 and 35 of gestation. Lung lobectomy, segmentectomy, atypical resection, lesion resection were performed in 31 patients and surgical specimens were analysed. Prenatal US and MDCT correctly diagnosed 76.9 and 94 % of the lesions, respectively. Disagreement occurred in six lesions with prenatal US and in two lesions with MDCT. No statistically significant differences were observed between the two techniques (P = 0.122). As most surgeons consider the surgical resection of these lesions mandatory, our study underscores the essential role of imaging, in particular CT, in providing invaluable preoperative information on congenital cystic lung diseases recognised in uterus.	\N	\N
24611185	To investigate factors associated with 30-day perioperative complications (POC) after aorto-iliac (AI) stenting, and to compare follow-up cardiovascular prognosis between patients with and without POC. This was a retrospective multicenter study. We used a multicenter database of 2012 consecutive patients who successfully underwent AI stenting for peripheral arterial disease in 18 centers in Japan from January 2005 to December 2009 to analyze independent predictors of POC and impact of POC on prognosis by logistic regression and a Cox proportional hazard regression model, respectively. Mean age was 71 ± 9 years (median: 72 years; range: 37-98 years), and 1,636 patients (81%) were men. POC occurred in 126 patients (6.3%). In multivariate logistic regression analysis, old age (≥80 years), critical limb ischemia (CLI), and Trans Atlantic Inter-Societal Consensus (TASC) II class C/D were independently associated with POC with adjusted odds ratios and 95% confidence intervals (CI) of 1.9 (1.3-2.9), 2.3 (1.5-3.4), and 2.4 (1.6-3.4), respectively. Out of 2012 patients, 1995 were followed up for more than 30 days (mean: 2.6 ± 1.5 years; range: 2-2,393 days). In a Cox hazard regression model adjusted for baseline clinical characteristics, POC was positively and independently associated with follow-up major adverse cardiac events (adjusted hazard ratio [HR]: 1.9; 95% CI: 1.3-2.8; p = .002), but not with major adverse limb events and target lesion revascularization (adjusted HR: 1.4; 95% CI: 0.7-2.7; p = .25; and adjusted HR: 1.2; 95% CI 0.6-2.6; p = .568), respectively. Age >80 years, CLI, and TASC C/D lesion were positively associated with POC after AI stenting. Occurrence of POC appears to adversely affect follow-up cardiovascular, but not limb and vessel prognosis.	\N	\N
24614649	The microsatellite instability (MSI) pathway is one of the important mutational pathways that play a critical role in colorectal carcinogenesis. About 15% of colorectal cancers (CRCs) are characterized by MSI. MSI tumors usually arise because of a genetic defect in mismatch repair (MMR) genes, one of the main DNA-repairing systems. MMR is a highly conserved biological pathway that plays a key role in maintaining genomic stability by correcting the base-base mismatches and insertion/deletion mispairs generated during DNA replication and recombination. Escherichia coli MutS and MutL and their eukaryotic homologs, MutSα and MutLα, respectively, are key players in MMR-associated genome maintenance. Mutations in at least five pivotal genes of MMR, namely, in those encoding mutS homolog 2 (MSH2), mutL homolog 1 (MLH1), mutS homolog 6 (MSH6), postmeiotic segregation increased 1 (PMS1), and postmeiotic segregation, increased 2 (PMS2) have been found in CRC, highlighting the importance of understanding the basic structure and functions of the essential molecules that make up the MMR system. In this review, we have attempted to focus on this aspect, that is, the role that MMR molecules play in CRC carcinogenesis.	\N	\N
24617559	Exaggerated postprandial lipemia has been reported after spinal cord injury (SCI). We examined metabolite and accompanying pro-inflammatory biomarker responses to repeat feeding of typical high-fat meals in individuals with chronic paraplegia. Descriptive trial. Metabolites (triglycerides, glucose, and insulin) and inflammatory biomarkers (interleukin-6 and high-sensitivity C-reactive protein (hsCRP)) were measured under fasting conditions in 11 recreationally active individuals with chronic (>1 year) paraplegia. Subjects received high-fat meals at time point 0 and again at minute 240. Antecubital venous blood was obtained at time points -30 (fasting), 0 (first meal), 30, 60, 90, 120, 240 (second meal), 360, and 480 minutes. Correlations were examined among the study variables. Exploratory subgroup analysis was performed for subjects with levels of postprandial glucose greater than >200 mg/dl. Triglycerides showed a significant rise 4 hours after eating. Basal inflammatory markers were elevated, and did not undergo additional change during the testing. Additionally, subjects with excessive postprandial glucose responses showed higher hsCRP levels than those having typical glucose responses both for fasting (11.8 ± 6.5 vs. 2.9 ± 2.7 mg/l, P = 0.064) and postprandial (11.1 ± 4.9 vs. 3.7 ± 3.8 mg/l, P = 0.018) values. Despite elevations in metabolic response markers, inflammatory markers did not change significantly after consumption of population-representative (i.e. hypercaloric) mixed-nutrient meals. Levels of fasting CRP in the high-risk range are consistent with other reports in persons with SCI and continue to pose concern for their cardiovascular disease risk. The possible association between postprandial metabolic responses and inflammatory states warrants further investigation to identify individual component risks for this secondary health hazard.	\N	\N
24619118	The northward spread of leishmaniasis from Mediterranean to Continental Europe affects our area where it is typically associated with Leishmania infantum infection. In this study a 22-year survey was performed in patients (including both patients with and without history of travel through endemic areas other than Italy) attending the University Hospital of Parma, Northern Italy, in order to make a contribution to describe the cases of the visceral leishmaniasis (VL) and cutaneous leishmaniasis (CL) diagnosed in this area. One hundred fifty-six samples from 134 patients with clinical suspicion of leishmaniasis (96 suspected of having VL, 37 CL and one both VL and CL) were analyzed in our laboratory during 1992-2013 by microscopy, culture and, from 2005, also by real-time PCR. Leishmania spp. were detected in 23 samples of 15 patients (seven with VL and eight with CL), representing an infection rate of 11.2%. The figure of the cases of leishmaniasis herein reported, even if not comparable to that described for Italian areas other than Parma, underlines that suitable tools are mandatory for correct diagnosis. Moreover, the severity of this disease, particularly VL with its documented northward spread, requires physicians of continental Europe to increase their attention about the possibility of suspecting leishmaniasis in patients reporting related signs and symptoms and/or risk factors.	\N	\N
24626438	Cardiovascular risk factors have different impact on different arterial territories. Diseases with elevated circulating parathyroid hormone (PTH) such as primary hyperparathyroidism and chronic renal failure have been shown to be associated with an increased risk of cardiovascular disease, predominantly heart or cerebrovascular diseases. However, data on the associations between circulating PTH and peripheral atherosclerosis are limited. Two prospective, community-based studies were used. In 306 men and women, who were 70 years old, from the Prospective investigation of the vasculature in Uppsala seniors (PIVUS) study, cross-sectional relations between PTH and atherosclerotic burden assessed by whole-body magnetic resonance angiography were investigated. In 998 men, who were 71 years old, from the Uppsala longitudinal study of adult men (ULSAM) study, the association between PTH concentration and risk of subsequent nonfatal atherosclerotic disease (excluding coronary or cerebrovascular disease) was investigated. Adjusting for established vascular risk factors, PTH was associated with burden of atherosclerosis (increase in total atherosclerotic score per SD PTH increase: 0.04, 0.003-0.08; P=0.03) in the PIVUS study. During follow-up in the ULSAM study (median 16.7 years), 89 men were diagnosed with nonfatal atherosclerotic disease. In Cox-regression analyses adjusting for established vascular risk factors and mineral metabolism, higher PTH was associated with an increased risk of nonfatal atherosclerotic disease (hazard ratio for 1 SD increase of PTH: 1.55, 1.33-1.88; P<0.0001). Results were similar when including fatal atherosclerotic disease in the outcome. In 2 independent community-based cohorts, PTH was associated to the degree of atherosclerosis and risk of clinically overt atherosclerotic disease, respectively. Our data confirm and extend previous studies supporting a role for PTH in the development of atherosclerotic disease.	\N	\N
24628295	Imatinib (Glivec(®)/Gleevec(®)) has shown long-term efficacy and safety in randomized trials. No large-scale studies have prospectively assessed the benefit-risk profile of an imatinib copy drug. We prospectively evaluated the response of patients with chronic myeloid leukemia in chronic phase in one institution. Patients with a complete hematologic response (n = 126) switched from branded imatinib to an imatinib copy drug. Subsequently, all patients switched back to the branded imatinib. Many patients in this study had a loss of hematologic response and tolerability issues with the imatinib copy drug. Hematologic response and tolerability improved upon retreatment with branded Glivec.	\N	\N
24628740	Pentraxin 3 (PTX3) is probably a specific marker of vascular inflammation. However, associations of PTX3 with cardiovascular disease (CVD) risk have not been well studied in healthy adults or multi-ethnic populations. We examined associations of PTX3 with CVD risk factors, measures of subclinical CVD, coronary artery calcification (CAC) and CVD events in the Multi-Ethnic Study of Atherosclerosis. Two thousand eight hundred and thirty-eight participants free of prevalent CVD with measurements of PTX3 were included in the present study. After adjustment for age, sex, and ethnicity, PTX3 was positively associated with age, obesity, insulin, systolic blood pressure, C-reactive protein (CRP), and carotid intima-media thickness (all P < 0.045). A one standard deviation increase in PTX3 level (1.62 ng mL(-1) ) was associated with the presence of CAC in fully adjusted models including multiple CVD risk factors (relative risk of 1.05; 95% confidence interval [CI] 1.01-1.08). In fully adjusted models, a standard deviation higher level of PTX3 was associated with an increased risk of myocardial infarction (hazard ratio [HR] 1.51; 95% [CI] 1.16-1.97), combined CVD events (HR 1.23; 95% [CI] 1.05-1.45), and combined CHD events (HR 1.33; 95% [CI] 1.10-1.60), but not stroke, CVD-related mortality, or all-cause death. In these apparently healthy adults, PTX3 was associated with CVD risk factors, subclinical CVD, CAC and incident coronary heart disease events independently of CRP and CVD risk factors. These results support the hypothesis that PTX3 reflects different aspects of inflammation than CRP, and may provide additional insights into the development and progression of atherosclerosis.	\N	\N
24631511	The aim of this study was to report the frequency, patient and lesion-related characteristics, and outcomes of subclinical, nonculprit plaque ruptures in the PROSPECT (Providing Regional Observations to Study Predictors of Events in the Coronary Tree) study. Plaque rupture and subsequent thrombosis is the most common cause of acute coronary syndrome (ACS). Secondary, subclinical, nonculprit plaque ruptures have been seen in both stable patients and patients with ACS; however, reports of the natural history of these secondary plaque ruptures are limited. After successful stenting in 697 patients with ACS, 3-vessel grayscale and intravascular ultrasound virtual histology (IVUS-VH) was performed in the proximal-mid segments of all 3 coronary arteries as part of a prospective multicenter study. Among 660 patients with complete IVUS data, 128 plaque ruptures were identified in 105 nonculprit lesions in 100 arteries from 93 patients (14.1%). Although the minimum lumen area (MLA) was similar, the plaque burden was significantly greater in nonculprit lesions with a plaque rupture compared with nonculprit lesions without a plaque rupture (66.0% [95% confidence interval: 64.5% to 67.4%] vs. 56.0% [95% confidence interval: 55.6% to 56.4%]; p < 0.0001). IVUS-VH analysis revealed that a nonculprit lesion with a plaque rupture was more often classified as a fibroatheroma than a nonculprit lesion without a plaque rupture (77.1% vs. 51.4%; p < 0.0001). Independent predictors of a plaque rupture were lesion length (per 10 mm; odds ratio: 1.30; p < 0.0001), plaque burden at the MLA site (per 10%; odds ratio: 2.56; p < 0.0001), vessel area at the MLA site (per 1 mm(2); odds ratio: 1.13; p < 0.0001), and VH-thin-cap fibroatheroma (odds ratio: 1.80; p = 0.016). During 3 years of follow-up, the incidence of overall major adverse cardiac events did not differ significantly between the patients with and patients without subclinical, nonculprit plaque ruptures. Secondary, nonculprit plaque ruptures were seen in 14% of patients with ACS and were associated with a fibroatheroma phenotype with a residual necrotic core but not with adverse outcomes if patients were treated with optimal medical therapy as part of a multicenter study. (Providing Regional Observations to Study Predictors of Events in the Coronary Tree [PROSPECT]; NCT00180466).	\N	\N
24634197	The redox-active transition metal copper is an essential trace element for growth and development and serves as a structural or catalytic cofactor for many enzymes in a range of physiological processes. Mammalian copper homeostasis is tightly regulated, and an imbalance in copper metabolism is implicated in various pathological disorders. Radioactive copper isotopes, in particular (64) Cu (t1/2  = 12.7 h) and (67) Cu (t1/2  = 62.01 h), have made important contributions to the understanding of copper metabolism in health and disease. This review gives a brief account of how radiolabelled copper(II) salts and bioreductive copper complexes have been used to trace copper uptake, transport and efflux in vitro and in vivo. Recently, positron emission tomography (PET) has emerged as a noninvasive tool to image copper metabolism in living subjects and (64) Cu-PET is investigated for the study of copper-related neurological disorders, genetic diseases and cancer.	\N	\N
24642005	Every year about 2500 patients in Sweden undergo surgery due to heart valve disease. A mechanical heart valve prosthesis causes risk of thromboembolic stroke or thrombus formation in the valve while anticoagulant treatment increases the risk of bleeding. Treatment quality with warfarin is crucial for patients with mechanical valve prostheses. It has previously been shown that poorly controlled warfarin treatment increases mortality in this patient group. TTR (Time in Therapeutic Range) on warfarin has been shown to affect the risk of complications in atrial fibrillation, but has not been studied in patients with mechanical heart valves. Our aim is to evaluate the impact of TTR on the risk of complications in this patient group. A non-randomized, prospective study of 534 adults with mechanical heart valve prostheses from Malmö and Sundsvall registered in the Swedish National Quality Registry Auricula between 01.01.2008 and 31.12.2011. Quartiles regarding individual TTR levels were compared regarding risk of complications. The risk of complications was significantly higher at lower TTR levels for all complications (p=0.005), bleeding (p=0.01) and death (p=0.018) but not for thromboembolism. In multivariate analysis the risk was significantly increased at lower TTR levels for bleeding and all complications but not for death or thromboembolism. Patients with a lower warfarin treatment quality measured by TTR have a higher risk of complications such as severe bleeding or death. A TTR of 83% or higher at the individual level should be obtained for best outcome.	\N	\N
24653575	There are various models of health care, such as the epidemiological, psychosocial, sociological, economic, systemic of Neuman, cognitive medicine or ecological, ayurvedic, supraparadigmatic among others. All of them are seeking to combine one or more elements to integrate a model of health care. The article presents a systemic approach to health care with complementary medicines such as rehabilitative acupuncture, homeopathy and chiropractic through the application of a method of holistic care and integrated approach. There was a participatory action research in January 2012 to January 2013, with a comprehensive approach in 64 patients using the clinical method. We included the environmental aspects, biological, emotional, and behavioral to identify, recognize and integrate the form of manifestation of the disease. Later, it was ordered in a coherent way the etiologic factors, precipitating factors and identified the vulnerability of the patients as well as the structural alterations, classifying them in immediate, mediate and late. Referred to the three disciplines: rehabilitative acupuncture, homeopathy and chiropractic to be seen doing references and against-references between them, evaluating the current state of health and each meeting by noting the clinical and behavioral changes submitted and thus the area of attention to which would be forwarded to continue their treatment. 64 patients rotated by the 3 areas taking an average of 30 meetings with rehabilitative acupuncture, 12 with homeopathy and 10 with chiropractic. The changes were submitted clinical attitudinal, behavioral, clinical and organic. The model of care was multifaceted and interdisciplinary with a therapeutic approach of individualization and a holistic view to carry out a comprehensive diagnosis and provide quality health care to the population.	\N	\N
24654676	To identify the frequency of disc hyperfluorescence, and to use optical coherence tomography to look for vitreopapillary traction as a possible underlying cause. Eight patients with presumed Fuchs uveitis syndrome were included. A complete ocular examination, fundus fluorescein angiography, and spectral-domain optical coherence tomography for optic nerve head were performed. There were 4 males and 4 female patients, and the mean age at diagnosis was 41.7 years. The most common ocular symptom was floaters (5/9). The range of initial visual acuity was 6/5-6/12. The most frequent clinical sign was inflammatory cells in the anterior chamber (9/9). Fundus fluorescein angiography showed disc hyperfluorescence in all but 1 patient. Optical coherence tomography did not show evidence of vitreopapillary traction in all eyes but one eye. We think that the high frequency of disc hyperfluorescence on fundus fluorescein angiography is an indication of an inflammatory process rather than a mechanical one.	\N	\N
24655021	Gliomas are highly vascular and rich in VEGF, which promotes angiogenesis. Bevacizumab is a monoclonal antibody against VEGF, inhibiting angiogenesis by preventing receptor activation. Early Phase II clinical trials using bevacizumab in both newly diagnosed and recurrent high-grade gliomas (HGG) showed promising results, but these have not been confirmed in recent Phase III trials. This review is an update including recently reported Phase II and III study results. This is a review of clinical trials investigating bevacizumab in newly diagnosed and recurrent HGG with a focus on outcome results. A future perspective about the expected future role of bevacizumab is given. Bevacizumab efficacy, safety and tolerability, the combination of radiation and bevacizumab, as well as the use of bevacizumab to treat pseudoprogression are discussed. Further criteria of response evaluation needed to be adjusted in the age of antiangiogenic therapy are also discussed. Bevacizumab has been shown to be safe and tolerable in HGG. In the recurrent disease setting, bevacizumab might offer clinical benefits and is currently approved as a single agent for this indication. Although clinical trials demonstrate a prolonged progression-free survival (PFS) in bevacizumab-treated HGG, a benefit on overall survival has not been demonstrated. Research so far shows that bevacizumab appears to prolong PFS in newly diagnosed glioblastoma. Available data do not demonstrate a survival benefit in newly diagnosed patients. In the recurrent setting, there is no adequately powered randomized clinical trial to address whether there is a PFS or survival benefit with bevacizumab. Bevacizumab has also been introduced into other settings in neuro-oncology, including concurrent administration with re-irradiation for recurrent HGG.	\N	\N
24659875	Hepatitis C virus (HCV) is one of the main causes of liver disease worldwide, and alterations of glucose metabolism have reached pandemic proportions in western countries. However, the frequent coexistence between these two conditions is more than simply coincidental, since HCV can induce insulin resistance through several mechanisms. Indeed, the virus interferes with insulin signaling both directly and indirectly, inducing the production of pro-inflammatory cytokines. Furthermore, the entire viral life cycle has strict interconnections with lipid metabolism, and HCV is responsible for a "viral" steatosis which is frequently superimposed to a "metabolic" one. Several evidences suggest that HCV-induced metabolic disorders contribute both to the evolution of liver fibrosis and, likely, to the progression of the other disorders which are typically associated with altered metabolism, in particular atherosclerosis. In the present review, we will examine in depth the links between HCV infection and insulin resistance, liver steatosis and diabetes, and analyze the impact of these interactions on the progression of liver fibrosis and atherosclerosis. Special attention will be focused on the highly debated topic of the relationship between HCV infection and cardiovascular disease. The available clinical literature on this item will be broadly reviewed and all the mechanisms possibly implied will be discussed.	\N	\N
24669569	Nasopharyngeal carcinoma (NPC) has the propensity to develop distant metastases at a high rate and with poor prognosis. The metastatic sites are usually multifocal and involve the bones, lungs, liver and distant lymph nodes. The management of metastatic disease is essenti- ally palliative and is based on radiochemotherapy. A 50-year old man with a huge hematoma in the liver derived from a diagnosed NPC was treated with intermittent drainage of the hepatic hematoma for abdominal decompression, and the cavity was packed with omentum. In addition, 2 suspected metastatic lesions were excised. Neoadjuvant radiochemotherapy followed by concurrent chemotherapy was administered. After surgical treatment of the huge hematoma, the suspect sites in the liver were diagnosed as metastatic carcinoma, similar to the primary tumor. Several months later, bone metastatic lesions in the vertebra and oss iliaca dextra were detected due to distant metastasis. Treatment of metastatic NPC is essentially palliative and survival is usually poor.	\N	\N
24670466	To evaluate the feasibility of monitoring clopidogrel resistance with flow cytometric analysis of platelet vasodilator stimulated phosphoprotein (VASP) phosphorylation. Twenty patients with coronary heart disease (CHD) and 17 healthy volunteers were examined for platelet aggregation rate and phosphorylation of VASP (calculated as platelet reactivity index, PRI) using traditional optical nephelometry and flow cytometry before and after concurrent therapy of clopidogrel and aspirin. No significant differences were found in PRI between CHD group and healthy control group [(89.45∓5.22)% vs (86.58∓4.35)%] before treatment. The PRI in CHD group was significantly lowered after treatment to (67.66∓19.77)% (P<0.05). Clopidogrel resistance was found in 6 (30%) cases in CHD group by flow cytometric analysis, which showed a higher sensitivity than optical nephelometry (10%). Flow cytometric analysis of VASP phosphorylation is a more reliable test to specifically evaluate clopidogrel resistance.	\N	\N
24670932	The second leading cause of cancer-related deaths (both genders combined) in the United States is colorectal cancer (CRC). This emphasizes the need to develop both effective therapies for CRC patients and pre-clinical models mimicking human disease that carry translational potential in drug-development. Notably, at present there are no in situ models of CRC metastasis to lung. In our azoxymethane-induced colon tumorigenesis study in A/J mice assessing grape seed extract (GSE) efficacy, during necropsy we also found multiple lung nodules suggestive of colon tumor metastasis to lung that were significantly inhibited in GSE fed group. Both histopathological and molecular studies were performed to characterize and establish the origin of these lesions in lung. Histologically these nodules were determined as adenocarcinoma of mucin origin. Molecular analyses by immunohistochemistry (IHC) and RT-PCR revealed strong protein and transcript levels of colon specific markers CDX2 and CK20 in these lung nodules compared to uninvolved control lung tissue. Vis-à-vis, these nodules also showed minimally expressed lung specific biomarkers, specifically surfactant D and TTF-1, in IHC analysis. Additionally, 0.25% GSE supplementation in diet (w/w) decreased the incidence of these lung nodules by 53% and their total number by 66%. Together, the characterization of this unique in situ mouse model of CRC metastasis to lung provides translational opportunities in developing effective therapies to clinically manage and treat CRC at the advanced stage. Moreover, GSE efficacy in inhibiting CRC metastasis to lung in this model further supports its translational potential in controlling CRC growth, progression and metastasis in patients.	\N	\N
24671083	Determining the composition and function of subgingival dental plaque is crucial to understanding human periodontal health and disease, but it is challenging because of the complexity of the interactions between human microbiomes and human body. Here, we examined the phylogenetic and functional gene differences between periodontal and healthy individuals using MiSeq sequencing of 16S rRNA gene amplicons and a specific functional gene array (a combination of GeoChip 4.0 for biogeochemical processes and HuMiChip 1.0 for human microbiomes). Our analyses indicated that the phylogenetic and functional gene structure of the oral microbiomes were distinctly different between periodontal and healthy groups. Also, 16S rRNA gene sequencing analysis indicated that 39 genera were significantly different between healthy and periodontitis groups, and Fusobacterium, Porphyromonas, Treponema, Filifactor, Eubacterium, Tannerella, Hallella, Parvimonas, Peptostreptococcus and Catonella showed higher relative abundances in the periodontitis group. In addition, functional gene array data showed that a lower gene number but higher signal intensity of major genes existed in periodontitis, and a variety of genes involved in virulence factors, amino acid metabolism and glycosaminoglycan and pyrimidine degradation were enriched in periodontitis, suggesting their potential importance in periodontal pathogenesis. However, the genes involved in amino acid synthesis and pyrimidine synthesis exhibited a significantly lower relative abundance compared with healthy group. Overall, this study provides new insights into our understanding of phylogenetic and functional gene structure of subgingival microbial communities of periodontal patients and their importance in pathogenesis of periodontitis.	\N	\N
24674299	Erdheim-Chester disease is a rare systemic disease. The diagnosis is difficult due to significant clinical and morphological polymorphism. Orbital involvement is rare, but constitutes a classic means of detection. We report the case of a 60-year-old man, who consulted for evaluation of bilateral retro-orbital tumors. These tumors had been discovered on head CT two years previously during work-up of proptosis. Two biopsies were performed. The first one revealed polymorphous inflammatory tissue. The second one revealed intense granulomatous reaction, rich in non-specific foamy histiocytes. Thoracic-abdominal-pelvic CT scan detected peri-aortic and retroperitoneal infiltration. The association of these signs pointed to a diagnosis of Erdheim-Chester disease, confirmed by the re-examination of the histological samples. Erdheim-Chester disease is a rare non-Langerhans histiocytosis with a specific tropism for perivascular and fatty connective tissue. The cause is not known. The diagnosis of this systemic disease is histological. In the case of bilateral intra-orbital tumors, the diagnosis of Erdheim-Chester disease must be considered.	\N	\N
24674770	Excessive daytime sleepiness (EDS) is common in Parkinson's Disease (PD). Actigraphy uses periods of immobility as surrogate markers of nighttime sleep but there are no examples of its use in assessing EDS of PD. A commercial wrist worn system for measuring bradykinesia and dyskinesia also detects 2 min periods of immobility, which have a 85.2% concordance with the detection of sleep by ambulatory daytime polysomnography, (p < 0.0001 Chi Squared). High Epworth Sleepiness Scores (ESS) were associated with a proportion of time immobile (PTI) (p = 0.01 Mann-Whitney U). The median PTI between 0900 and 1800 h w in 30 age matched control subjects was 2%, representing 10 min and PTI at or above the 75th percentile (5% or 27 min) was taken as a high level. PD patients had higher PTI (median 4.8%) than controls (p < 0.0001, Mann-Whitney U). PD subjects with a high PTI had more bradykinesia, less dyskinesia and higher PDQ39 scores than those with low PTI. There was no relationship between PTI and dose or type of PD medications. However, in 53% of subjects, PTI increased in the 30-60 min after levodopa confirming that in some subjects levodopa results in increased sleepiness. In summary, immobility is a surrogate marker of daytime sleep in PD, confirmed by correlation with PSG and ESS. PD subjects measured this way are more likely to be sleepy and sleepy PD subjects are more likely to be bradykinetic and have a higher PDQ39. Levodopa leads to an increase in sleepiness in more than half of subjects post dosing.	\N	\N
24677192	Donor factors influence hepatitis C virus (HCV) disease severity in liver transplant (LT) recipients. Living donors, because they are typically young and have short cold ischemic times, may be advantageous for HCV-infected patients. Among HCV-infected patients in the Adult-to-Adult Living Donor Liver Transplantation Cohort Study (A2ALL) surviving >90 days and followed for a median 4.7 years, advanced fibrosis (Ishak stage ≥3) and graft loss were determined. The 5-year cumulative risk of advanced fibrosis was 44% and 37% in living donor LT (LDLT) and deceased donor LT (DDLT) patients (P = 0.16), respectively. Aspartate aminotransferase (AST) activity at LT (hazard ratio [HR] = 1.38 for doubling of AST, P = 0.005) and biliary strictures (HR = 2.68, P = 0.0001) were associated with advanced fibrosis, but LDLT was not (HR = 1.11, 95% confidence interval [CI] 0.73-1.69, P = 0.63). The 5-year unadjusted patient and graft survival probabilities were 79% and 78% in LDLT, and 77% and 75% in DDLT (P = 0.43 and 0.32), with 27% and 20% of LDLT and DDLT graft losses due to HCV (P = 0.45). Biliary strictures (HR = 2.25, P = 0.0006), creatinine at LT (HR = 1.74 for doubling of creatinine, P = 0.0004), and AST at LT (HR = 1.36 for doubling of AST, P = 0.004) were associated with graft loss, but LDLT was not (HR = 0.76, 95% CI: 0.49-1.18, P = 0.23). Donor type does not affect the probability of advanced fibrosis or patient and graft survival in HCV-infected recipients. Thus, while LDLT offers the advantage of shorter wait times, there is no apparent benefit for HCV disease progression. Biliary strictures have a negative effect on HCV fibrosis severity and graft survival, and a high AST at LT may be an important predictor of fibrosis risk post-LT.	\N	\N
24684672	Rheumatoid arthritis (RA) is an autoimmune disease of unknown cause and a chronic and progressive inflammatory disorder ensuing in genetically predisposed subjects, characterized by synovitis causing joint destruction, as well as inflammation in body organ systems, leading to anatomical alteration and functional disability. Immune competent cells, deregulated synoviocytes and cytokines play a key role in the pathophysiological mechanisms. The immune system function shows time-related variations related to the influence of the neuroendocrine system and driven by the circadian clock circuitry. Immune processes and symptom intensity in RA are characterized by oscillations during the day following a pattern of circadian rhythmicity. A cross-talk between inflammatory and circadian pathways is involved in RA pathogenesis and underlies the mutual actions of disruption of the circadian clock circuitry on immune system function as well as of inflammation on the function of the biological clock. Modulation of molecular processes and humoral factors mediating in RA the interplay between the biological clock and the immune response and underlying the rhythmic fluctuations of pathogenic processes and symptomatology could represent a promising therapeutic strategy in the future.	\N	\N
24685603	The effects of thymidylate synthase (TS) polymorphisms on susceptibility to colorectal cancer (CRC) have been investigated in many studies, but the results remain conflicting rather than conclusive. To resolve these conflicts, we performed a quantitative synthesis of the evidence on the association between these two polymorphisms and CRC risk. All eligible case-control studies published up to September 2013 were identified by searching PubMed, Web of Science and CNKI. Effect sizes of odds ratio (OR) and 95% confidence interval (95% CI) were calculated by using a fixed- or random-effect model. A total of 11 case-control studies were included, including 10 studies (3324 cases and 4622 controls) for TSER polymorphism and 9 studies (3223 cases and 3886 controls) for TS1494del6 polymorphism. Overall, no significant association between the TS polymorphisms and CRC risk was found. In the subgroup analysis by ethnicity, a significantly association were found among Caucasian populations for TSER polymorphism; but for TS1494del6 polymorphism, no significantly association was observed in both Asian and Caucasian populations. When stratifying by source of controls, we found there was a statistically significant association between TSER polymorphism and risk of CRC in the population-based population; however, we detected no association in both population-based and hospital-based populations for TS1494del6 polymorphism. This meta-analysis suggests that the TSER polymorphism in TS gene but not TS1494del6 polymorphism might be a protective factor for CRC among Caucasian populations.	\N	\N
24713244	To study the expression and clinicopathologic significance of cancer stem cell markers CD44v6 and CD24 in ovarian serous carcinoma tissues. One hundred and two cases of ovarian carcinoma diagnosed during the period from June, 2001 to December, 2010 were retrieved from archival files. The histology slides were reviewed and a two-tier system for grading of ovarian serous carcinoma was applied. The expression of CD44v6 and CD24 was detected by immunohistochemistry using EnVision method. The relationship between CD44v6/CD24 expression and various clinicopathologic parameters was analyzed. There were 46.1% (47/102) and 59.8% (61/102) cases expressing CD44v6 and CD24, respectively. Both CD44v6 and CD24 expression showed positive correlation with higher histopathologic grade (P = 0.003 and P < 0.05, respectively). CD24 expression also correlated with the presence of lymph node metastasis (P < 0.05). There was no statistically significant relationship between the expression of these two markers (χ(2) = 0.394, P = 0.530). The age of the patients, histopathologic grade, clinical stage and nodal status correlated with progression-free survival time (P < 0.05). CD44v6 expression and histopathologic grade correlated with the overall survival time (P < 0.05). Patient age was an independent poor prognostic factor by multivariate analysis. CD44v6 expression, age older than 50 years, high clinical stage and presence of lymph node metastasis are associated with poor prognosis in patients with ovarian serous carcinoma. The two-tier system for grading of ovarian serous carcinoma is useful in predicting survival; and high tumor grade represents an important poor prognostic indicator for ovarian serous carcinoma.	\N	\N
24713591	High-density-lipoprotein cholesterol (HDL-C) has been identified in population studies as an independent inverse predictor of cardiovascular events. Although the causal nature of this association has been questioned, HDL and its major protein, apolipoprotein (apo)A1, have been shown to prevent and reverse atherosclerosis in animal models. In addition, HDL and apoA1 have several putatively atheroprotective functions, such as the ability to promote efflux of cholesterol from macrophages in the artery wall, inhibit vascular inflammation, and enhance endothelial function. Therefore, HDL-C and apoA1 have been investigated as therapeutic targets for coronary heart disease. However, recent clinical trials with drugs that raise HDL-C, such as niacin and inhibitors of cholesteryl ester transfer protein, have been disappointing. Here, we review the current state of the science regarding HDL as a therapeutic target.	\N	\N
24715127	The objective of this study was to evaluate the 25-year outcome of patients with primary Sjögren's syndrome (pSS). One hundred and fifty-two patients diagnosed with pSS (American-European classification criteria) were retrospectively and descriptively analysed (1986-2011). Of all 152 patients, 55.9% were alive, 18.4% had died and 25.7% discontinued follow-up (mostly due to old age). Malignancy affected 28.3% and non-Hodgkin's lymphoma (NHL) affected 10.5%. The adjusted risk for development of NHL was an odds ratio (OR) of 10.5 (95% confidence interval [CI]: 3.05-36.42) in patients with vasculitis (p<0.001), and OR 3.4 (95% CI 1.05-11.2) in the presence of glandular complications (parotid swelling, lymphadenopathy) (p < 0.041). Seventy-five patients (49.3%) developed other autoimmune diseases (autoimmune thyroid disease [15.8%], pulmonary fibrosis [7.2%] and vasculitis [10.5%]). Although the course of pSS is relatively benign, over 25 years patients experience more clinical complications than previously described. In addition, vasculitis and glandular manifestations were significant predictors for NHL.	\N	\N
24720286	There is currently no cure for metastatic castration-resistant prostate cancer (CRPC). Chemoresistance and metastatic disease remain the main causes of treatment failure and mortality in CaP patients. Although several advances have been made in the control of CRPC with some newly developed drugs, there is still an urgent need to investigate the mechanisms and pathways of prostate cancer (CaP) metastasis and chemoresistance, identify useful therapeutic targets, develop novel treatment approaches, improve current therapeutic modalities and increase patients' survival. Cancer stem cells (CSCs), a minority population of cancer cells characterised by self-renewal and tumor initiation, have gained intense attention as they not only play a crucial role in cancer recurrence but also contribute substantially to chemoresistance. As such, a number of mechanisms in chemoresistance have been identified to be associated with CSCs. Therefore, a thorough and integral understanding of these mechanisms can identify novel biomarkers and develop innovative therapeutic strategies for CaP treatment. Our recent data have demonstrated CSCs are associated with CaP chemosensitivity. In this review, we discuss the roles of putative CSC markers in CaP chemoresistance and elucidate several CSC-associated signaling pathways such as PI3K/Akt/mTOR, Wnt/β-catenin and Notch pathways in the regulation of CaP chemoresistance. Moreover, we will summarize emerging and innovative approaches for the treatment of CRPC and address the challenging CRPC that is driven by CSCs. Understanding the link between CSCs and metastatic CRPC will facilitate the development of novel therapeutic approaches to overcome chemoresistance and improve the clinical outcomes of CaP patients.	\N	\N
24723322	The mitochondrial toxin 3-nitropropionic acid (3-NP) is an irreversible inhibitor of respiratory chain complex II. Chronic systemic administration of 3-NP to mice, rats, and non-human primates leads to preferential degeneration of the striatum, and produces motor and cognitive symptoms that are highly reminiscent of Huntington's disease (HD). HD is caused by a dominant inherited expansion of CAG repeats in the Huntington gene. Thus, many aspects of HD cannot be mimicked by 3-NP. However, recent research shows that mitochondrial defects and oxidative stress may play a key role in HD pathogenesis, further supporting the potential utility of the 3-NP model of striatal degeneration. First, a basic protocol to produce acute striatal lesions in rats using repeated intraperitoneal injection of 3-NP is described. Second, a more complex protocol that takes advantage of the use of osmotic minipumps to steadily release 3-NP leading to consistent lesions and motor symptoms in Lewis rats is presented. Curr. Protoc. Neurosci. 67:9.48.1-9.48.14. © 2014 by John Wiley & Sons, Inc.	\N	\N
24725410	Maintenance of a constant cell volume in response to extracellular or intracellular osmotic changes is critical for cellular homeostasis. Activation of a ubiquitous volume-regulated anion channel (VRAC) plays a key role in this process; however, its molecular identity in vertebrates remains unknown. Here, we used a cell-based fluorescence assay and performed a genome-wide RNAi screen to find components of VRAC. We identified SWELL1 (LRRC8A), a member of a four-transmembrane protein family with unknown function, as essential for hypotonicity-induced iodide influx. SWELL1 is localized to the plasma membrane, and its knockdown dramatically reduces endogenous VRAC currents and regulatory cell volume decrease in various cell types. Furthermore, point mutations in SWELL1 cause a significant change in VRAC anion selectivity, demonstrating that SWELL1 is an essential VRAC component. These findings enable further molecular characterization of the VRAC channel complex and genetic studies for understanding the function of VRAC in normal physiology and disease.	\N	\N
24726273	Central obesity represents the major factor responsible for NAFLD, but several immunological and endocrinological mechanisms are involved in fatty infiltration in the liver, inflammation and fibrosis. Gut microbiota and genetic factors were recently indicated as major players in liver injury. Loss of weight and physical activity represent till now the cornerstone of treatment, but they are very difficult to obtain and to maintain. Several pharamocotherapeutic approaches including insulin sensitizers, omega-3 fatty acids and vitamin E have been extensively studied in randomized trials, but final conclusions still could not be formulated. Therefore, new treatments based on pathogenetic mechanisms leading to NAFLD are under evaluation to establish the effective pharmacological therapy of this disorder.	\N	\N
24734429	In 2013 the main efforts of the Medical Service were aimed at the following tasks: optimization of management system of military medical service, improvement of medical evacuation system, medical service security for military contingents, assigned according to territory principle to military-medical facilities of the Ministry of Defence of the Russian Federation, implementation of innovations at all stages of medical evacuation in peace- and wartime, security of combat and mobilization readiness of regulatory bodies of the Medical Service, medical military units and military medical facilities, medical service of troops battle training, improvement of material and technical resources, security of regular pharmacy and equipment supply, activation of research work in the Medical Service interests. Lines of military medicine development in 2014 are: transfer of treatment facilities that are not used by the Ministry of Defence into the Federal Biomedical Agency till the end of 2014, prevention of pneumonia and meningitis in military personnel, improvement of early diagnosis system, medical service for military contingents according to territory principle, improvement of diagnostic and treatment work in military-medical units and subunits and military-medical facilities by means of development of material and technical resources, monitor the implementation of innovative diagnostic and treatment technologies, completion of construction projects of central military hospitals and etc.	\N	\N
24744504	Consumption of tomato fruits, like those of many other plant species that are part of the human diet, is considered to be associated with several positive effects on health. Indeed, tomato fruits are an important source of bioactive compounds with known beneficial effects including vitamins, antioxidants, and anticancer substances. In particular, antioxidant metabolites are a group of vitamins, carotenoids, phenolic compounds, and phenolic acid that can provide effective protection by neutralizing free radicals, which are unstable molecules linked to the development of a number of degenerative diseases and conditions. In this review, we will summarize the recent progress on tomatoes nutritional importance and mechanisms of action of different phytochemicals against inflammation processes and prevention of chronic noncommunicable diseases (e.g., obesity, diabetes, coronary heart disease, and hypertension). In addition, we will summarize the significant progress recently made to improve the nutritional quality of tomato fruits through metabolic engineering and/or breeding.	\N	\N
24748016	Food allergy is a common condition that plays an important role in the pathogenicity and maintenance of atopic dermatitis (AD), however, must be carefully investigated before imposing a restrictive diet. The aim of this study was to evaluate the sensitivity to foods in patients with AD, correlating it with the severity of the disease and other possible associated factors. One hundred and eleven children (6-180 months of age) with AD were evaluated and later followed up at the Allergy and Clinical Immunology Division, Department of Pediatrics at FMABC. The serum concentrations of specific IgE to cow's milk (CM), egg, soy, wheat, corn, peanut and fish were measured using an enzymatic fluorescence method (ImmunoCAP™). In order to identify the clinical reactivity, the open oral provocation test was performed when specific IgE was positive to CM, egg and wheat and in all those who related symptoms after the intake of such foods regardless of the presence or absence of sensitization. In total, 40.5 % of the studied population was sensitized to at least one food allergen, especially those between 73 and 180 months of age. There was a higher prevalence of sensitization in children with more severe AD, and foods like CM, egg and wheat were the most involved, but with low clinical reactivity. We observed increased severity of AD in cases that initiated symptoms earlier and who had shorter duration of exclusive breastfeeding as well as a linear increase in sensitization in the most serious cases. Serum-specific immunoglobulin E was the only factor associated with the relationship that showed sensitization. The occurrence of sensitization to foods was frequent, mainly in the age group of 6-9 years and in patients with severe AD; however, the validation of the clinical reactivity was negative in most of the provocations performed, which agrees with the need to prove the same before the imposition of restrictive diets, often unnecessary and complex.	\N	\N
24748137	This report describes the case of a 44-year-old Caucasian woman of Northern European descent with a medical history of pyoderma gangrenosum, chronic abdominal pain and erythema nodosum which required intermittent use of high-dose steroids that failed to improve her symptoms. The patient was initially diagnosed with Crohn's disease and most recently with sclerosing mesenteritis. She presented to the hospital with worsening abdominal pain. She was found to have recurrent painful aphthous oral, genital and perianal ulcers and a clinical diagnosis of Behçet's disease was made. Her hospitalisation was complicated by haemoptysis, and bronchoscopy revealed alveolar haemorrhage. Treatment was initiated with three days of pulse intravenous solumedrol 1 g/day and cyclophosphamide at 700 mg/m(2). The case had a favourable outcome despite the initial diagnostic challenges. This report emphasises that systemic diseases, including Behçet's disease, can have variable presentations and can be frequently misdiagnosed.	\N	\N
24751894	Both the diagnosis and treatment of Mycoplasma pneumoniae infections in children are currently facing two main challenges: a relatively high carriage in asymptomatic children, and a worldwide increase in macrolide-resistant M. pneumoniae (MRMP). This review focuses on the scientific and clinical implications of these crucial issues. Recent studies have indicated that the prevalence of M. pneumoniae in the upper respiratory tract is similar among asymptomatic, healthy children and children with a symptomatic respiratory tract infection, and that current diagnostic procedures for M. pneumoniae are unable to differentiate between bacterial carriage and infection. It is therefore possible that the burden of M. pneumoniae-associated disease is overestimated. Another phenomenon that has an important impact on the treatment of M. pneumoniae infections is the rapid worldwide emergence of MRMP isolates. The current diagnostic procedures for M. pneumoniae cannot discern between bacterial carriage and infection in a clinically relevant time frame. It is therefore imperative that these procedures be modified such as to unambiguously detect symptomatic M. pneumoniae infections. Moreover, the emergence of MRMP necessitates the application of methods to detect macrolide resistance as well as the implementation of restrictive policies regarding the use of macrolides.	\N	\N
24763465	Atrial fibrillation (AF) is the most common arrhythmia and is associated with increased morbidity. As the population ages and the prevalence of AF continues to rise, the socioeconomic consequences of AF will become increasingly burdensome. Although there are well-defined clinical risk factors for AF, a significant heritable component is also recognized. To identify the molecular basis for the heritability of AF, investigators have used a combination of classical Mendelian genetics, candidate gene screening, and genome-wide association studies. However, these avenues have, as yet, failed to define the majority of the heritability of AF. The goal of this review is to describe the results from both candidate gene and genome-wide studies, as well as to outline potential future avenues for creating a more complete understanding of AF genetics. Ultimately, a more comprehensive view of the genetic underpinnings for AF will lead to the identification of novel molecular pathways and improved risk prediction of this complex arrhythmia.	\N	\N
24782446	We aimed to evaluate whether a recent knee injury was associated with accelerated knee osteoarthritis (OA) progression. In the Osteoarthritis Initiative, we studied participants free of knee OA on their baseline radiographs (Kellgren/Lawrence [K/L] <2). We compared 3 groups as follows: 1) individuals with accelerated progression of knee OA: defined as having at least 1 knee that progressed to end-stage knee OA (K/L grade 3 or 4) within 48 months, 2) common knee OA progression: at least 1 knee increased in radiographic scoring within 48 months (excluding those defined as accelerated knee OA), and 3) no knee OA: no change in K/L grade in either knee. At baseline, participants were asked if their knees had ever been injured, and at each annual visit they were asked about injuries during the prior 12 months. We used multinomial logistic regressions to determine whether a new knee injury was associated with the outcome of accelerated knee OA or common knee OA progression, after adjusting for age, sex, body mass index, static knee malalignment, and systolic blood pressure. A knee injury during the total observation period was associated with accelerated knee OA progression (n = 54; odds ratio [OR] 3.14) but not common knee OA progression (n = 187; OR 1.08). Furthermore, a more recent knee injury (within a year of the outcome) was associated with accelerated (OR 8.46) and common knee OA progression (OR 3.12). Recent knee injuries are associated with accelerated knee OA. Most concerning is that certain injuries may be associated with a rapid cascade toward joint failure in less than 1 year.	\N	\N
24783461	Patients with established rheumatoid arthritis (RA) have a higher cardiovascular morbidity and mortality in comparison with the general population. It is considered to be an independent risk factor for cardiovascular disease. The purpose of this article is to describe the mechanisms responsible for accelerated atherogenesis in RA patients and to give an overview of the effects of different RA therapies (methotrexate, TNF antagonists and other biologicals).	\N	\N
24800540	To analyze the clinical features and treatment of tuberculous otitis media and mastoiditis. Thirteen patients with tuberculous otitis media and mastoiditis were retrospectively analyzed and the related literatures were reviewed. One case was treated by surgery only, and anti-tuberculosis treatment was given to another one patient, and surgical removal of disease lesions in combination with anti-tuberculosis treatment were given to 12 patients. One patient received surgery only was found to recur after follow-up for seven months. The patient did not recur after seven months' follow-up after antituberculosis therapy,and other patients did not recur. Although the regular anti-tuberculosis chemotherapy treatment was the main treatment for tuberculous otitis and mastoiditis, surgical treatment was helpful to achieved more rapid healing of the ear.	\N	\N
24804836	Non-melanoma skin cancers (NMSCs) are among the most common human malignancies. Current methods for their prevention include avoidance of natural and artificial sources of UV radiation and using photoprotective clothing and sunscreens. However, these methods have proven to be inadequate in stemming the rise in skin cancer incidence over the past several years. There is accumulating evidence that cyclooxygenase-2 (COX-2), an enzyme involved in prostaglandin synthesis, may be involved in the pathogenesis of NMSC. In preclinical studies, animals genetically deficient in the COX-2 enzyme or that have been treated with pharmacological inhibitors of COX-2 develop significantly fewer tumors when subjected to a UV-induced skin carcinogenesis protocol compared with control mice. Several epidemiological studies in humans support the concept that this enzyme is intimately involved in UV-induced skin cancer development, and UV radiation is known to augment COX-2 expression in human skin. Recent studies suggest that drugs that block COX-2 expression may prevent the development of NMSCs. Thus, pharmacologic agents that inhibit the enzyme COX-2 may be effective chemopreventive agents for NMSCs.	\N	\N
24806099	The use of liver retransplantation (ReLT) for hepatitis C virus (HCV) recurrence is controversial because of subsequent viral recurrence after ReLT. Case-control analysis between patients undergoing ReLT for HCV reinfection between 1993 and 2012 (ReLT group: 26 patients) and patients undergoing liver transplantation (LT) for HCV infection immediately before and after each ReLT (LT group: 52 patients). ReLT group had worse hepatocellular function, higher preoperative viral load, higher transfusion requirements, and increased number of postoperative complications than LT group. ReLT patients showed a trend toward worse graft survival compared with LT (five-yr graft survival: 42.3% vs. 64.3%, p = 0.145), but the rate of severe HCV recurrence and infection-free survival (IFS) was similar. The use of donors older than 60 yr led to a lower IFS and graft survival in both groups. Early severe HCV infection rate was similar in both groups, but it affected prognosis in ReLT more markedly than in LT (three-yr graft survival: 0% vs. 66.7%, p = 0.003). ReLT for HCV reinfection has acceptable results when strict selection policies of donor and recipient are applied. However, early severe recurrence more markedly impairs prognosis in ReLT patients than in LT.	\N	\N
24820120	Regardless of whether alone or in combination, cecal ligation and puncture (CLP) is the most commonly used model to emulate human polymicrobial sepsis. Numerous CLP studies have shown that female mice survive better than males. In adult mice, this effect may be partly due to the unequal cecum mass (larger in males), as cecum ligation is frequently not size standardized. Comparing two ligation approaches, we investigated whether cecum size influences gender-specific outcome differences. 15-month-old (middle-aged) female and male CD-1 mice underwent sublethal trauma/hemorrhage followed by CLP 48 h later. The evaluation of cecum size (in centimeters) and filling (score) was immediately followed by two ligation protocols: (1) ileocecal ligation (IC-L; n = 28/each gender) below the ileocecal valve, and (2) apex ligation (AP-L; n = 31 males, n = 24 females) 2 cm from the apex ceci - all followed by an identical double puncture and 10-day monitoring. Cecum length (3.4 cm in males vs. 2.65 cm in females) and filling (2.5 score points in males vs. 1.7 in females; both p < 0.05) were always greater in male than female mice (27 vs. 44%, respectively). Compared to AP-L, the 10-day CLP mortality was higher with IC-L (86% in males and 61% in females), and this exacerbation was similar in both genders (by 21% in male and 23% in female mice). Finally, the intergender comparison demonstrated that female mice displayed a significant and similar survival advantage regardless of the ligation approach: the difference reached 25% with IC-L and 24% with AP-L. Standardization by AP-L did not eliminate the gender-specific difference in mortality due to posttraumatic sepsis. The greater cecum length/filling in middle-aged male mice was not responsible for their inferior survival compared to females.	\N	\N
24821164	Nephronophthisis is an autosomal recessive disease that leads to end-stage renal disease. These days, molecular genetic analysis is used pre-emptively for making a definitive diagnosis in patients who have clinical and radiological data suggestive of the disease. Herein, we are reporting a 12-year-old girl who was genetically diagnosed to have juvenile nephronophthisis, which explained the mystery of the chronic kidney disease in her four affected siblings.	\N	\N
24821649	Hepatocellular carcinoma (HCC) is associated with a poor prognosis because of a lack of effective treatment options. The objective of this study was to examine a new strategy for HCC treatment, namely the use of poly (ADP-ribose) polymerase 1 (PARP-1) inhibitor (ABT-888) together with Temozolomide (TMZ) incorporated onto magnetic nanoparticles. Magnetic Fe3 O4 /Fe cores were encapsulated within a silica shell to facilitate the simultaneous incorporation of ABT-888 and TMZ. In vitro tests were performed with HepG2, Hep3B and PLC-PRF-5 liver tumoural cell lines and with WRL-68 liver non-tumoural cells. The magnetic nanocarriers were loaded simultaneously with ABT-888 and TMZ. High stability and extended release were achieved in culture medium. Confocal microscopy images showed that drug-loaded particles were uptaken and accumulated into the cytoplasm of liver tumoural cells, inducing the following effects: G2/M cell cycle arrest (P < 0.05), accumulation of DNA damage (P < 0.05), mitochondrial depolarization (P < 0.01), reduction in BCL-xL, FOS, JUND gene expression (P < 0.05), PARP-1 fragmentation, Caspase-3 activation and apoptotic cell death (P < 0.05). Interestingly, drugs loaded onto nanoparticles exhibited better efficiency than free drugs (cell death triggered by drug delivery nanosystem: 53.5% vs. 34.5% by free drugs, P = 0.01). These magnetic nanocompounds are able to incorporate both drugs simultaneously, enter the tumour cells and release them. ABT-888/TMZ/NPs decrease the transcription of key genes involved in tumour survival and induce apoptotic cell death in a more effective manner than is achieved by free drugs.	\N	\N
24821915	Only a small fraction of individuals exposed to Mycobacterium tuberculosis develop clinical tuberculosis (TB). Over the past century, epidemiological studies have shown that human genetic factors contribute significantly to this interindividual variability, and molecular progress has been made over the past decade for at least two of the three key TB-related phenotypes: (i) a major locus controlling resistance to infection with M. tuberculosis has been identified, and (ii) proof of principle that severe TB of childhood can result from single-gene inborn errors of interferon-γ immunity has been provided; genetic association studies with pulmonary TB in adulthood have met with more limited success. Future genetic studies of these three phenotypes could consider subgroups of subjects defined on the basis of individual (e.g. age at TB onset) or environmental (e.g. pathogen strain) factors. Progress may also be facilitated by further methodological advances in human genetics. Identification of the human genetic variants controlling the various stages and forms of TB is critical for understanding TB pathogenesis. These findings should have major implications for TB control, in the definition of improved prevention strategies, the optimization of vaccines and clinical trials and the development of novel treatments aiming to restore deficient immune responses.	\N	\N
24843888	The adaptive function of melanin located in the integument is well known. Although pigments are also deposited in various internal organs, their function is unclear. A review of the literature revealed that 'internal melanin' protects against parasites, pollutants, low temperature, oxidative stress, hypoxemia and UV light, and is involved in the development and function of organs. Importantly, several studies have shown that the amount of melanin deposited on the external body surface is correlated with the amount located inside the body. This finding raises the possibility that internal melanin plays more important physiological roles in dark than light-colored individuals. Internal melanin and coloration may therefore not evolve independently. This further emphasizes the major role played by indirect selection in evolutionary processes.	\N	\N
24845215	Over 5100 colorectal cancers (CRCs) are diagnosed in the United Kingdom in 85 years and older age group per year but little is known of cancer progression in this group. We assessed clinical, pathological and molecular features of CRC with early and late mortality in such patients. Data were analysed in relation to early mortality and long-term survival in 90 consecutive patients with CRC aged 85 years or older in a single hospital. Patients not undergoing operation, those with an ASA score of III or greater and those with advanced tumour stage were more likely to die within 30 days. Regression analysis showed that 30 day mortality was independently related to failure to undergo resection (odds ratio (O.R.), 10.0; 95% confidence interval [C.I.], 1.7-58.2; p=0.01) and an ASA score of III or greater (O.R. 13.0; 95% C.I., 1.4-12.6; p=0.03). All cause three and five year survival were 47% and 23% respectively for patients who are alive 30 days after diagnosis. Three and five year relative survivals were 64% and 54%, respectively. Long-term outcome was independently related to tumour stage (relative risk [R.R.], 2; 95% C.I., 1.3-3.1; p=0.001), presence of co-morbid diseases (R.R., 2.8; 95% C.I., 1.3-6.0; p=0.007) and lipid peroxidation status (R.R., 2.9; 95% C.I., 1.1-7.5; p=0.025). An active multidisciplinary approach to the care of patients with CRC at the upper extreme of life is reasonable. It also seems sensible to individualise care based upon the extent of disease at diagnosis and the presence of co-morbid conditions. Further studies to examine the role of lipid peroxidation are warranted.	\N	\N
24850149	Inflammasomes are specialized signaling platforms critical for the regulation of innate immune and inflammatory responses. Various NLR family members (i.e., NLRP1, NLRP3, and IPAF) as well as the PYHIN family member AIM2 can form inflammasome complexes. These multi-protein complexes activate inflammatory caspases (i.e., caspase-1) which in turn catalyze the maturation of select pro-inflammatory cytokines, including interleukin (IL)-1β and IL-18. Activation of the NLRP3 inflammasome typically requires two initiating signals. Toll-like receptor (TLR) and NOD-like receptor (NLR) agonists activate the transcription of pro-inflammatory cytokine genes through an NF-κB-dependent priming signal. Following exposure to extracellular ATP, stimulation of the P2X purinoreceptor-7 (P2X7R), which results in K(+) efflux, is required as a second signal for NLRP3 inflammasome formation. Alternative models for NLRP3 activation involve lysosomal destabilization and phagocytic NADPH oxidase and/or mitochondria-dependent reactive oxygen species (ROS) production. In this review we examine regulatory mechanisms that activate the NLRP3 inflammasome pathway. Furthermore, we discuss the potential roles of NLRP3 in metabolic and cognitive diseases, including obesity, type 2 diabetes mellitus, Alzheimer's disease, and major depressive disorder. Novel therapeutics involving inflammasome activation may result in possible clinical applications in the near future.	\N	\N
24851665	Self-efficacy, a central construct in health interventions, has been measured in various contexts. The absence of any published meta-review of self-efficacy instrumentation led to the current meta-synthesis that reports and evaluates the instrumentation processes. A systematic search resulted in 39 self-efficacy instrumentation studies, which were evaluated for the aspects of conceptual bases, health contexts, operational definition, instrumentation procedures, reliability and scale length, and item content. Primarily based in Bandura's social cognitive theory, these studies reported self-efficacy instrumentation for developing new scales and modifying/validating measures for illness management, healthy behavior adoption/maintenance, disease/risk prevention, and aging management. Trait-like, specific-domain, and situation approaches were used for generating item content. Problems in some studies include non-efficacy items, a lack of systematic instrumentation procedures, item content too general for specific-domain self-efficacy, and measurement inefficiency. The piecemeal fashion of self-efficacy instrumentation has resulted in incomparable self-efficacy measures of similar domains of health functioning. A trans-domain framework, thus, is warranted. Suggestions are provided for solving other problems in self-efficacy instrumentation.	\N	\N
24852869	The ABC-02 trial has defined the standard therapy for patients with advanced biliary tract cancer (ABC); however, outcome in an unselected patient population in the UK has not been described. We aimed to investigate the outcome of a series of patients with ABC from two large UK cancer networks. We retrospectively reviewed all cases of ABC presenting to two UK cancer networks over a nine-year period. Overall survival (OS) and factors influencing OS were assessed. Four hundred and two patients were available for analysis. The median OS was 6.2 months. On univariate analysis, age ≥70 years (P = 0.047), advanced disease stage (P <0.001), gall bladder primary (P = 0.033), poor performance status (P <0.001) and lack of chemotherapy (P <0.001) were associated with worse outcome. Survival was superior in the 36.4% of patients who received palliative chemotherapy (12.5 vs 4.3 months; P <0.001). On multivariate analysis of patients who had chemotherapy, those who did not receive fluoropyrimidine-based regimens (HR = 5.12; P = 0.022) or gemcitabine-based regimens (HR = 5.01; P = 0.021) had a higher mortality, whereas the effect of platinum-containing regimens was of borderline significance (HR = 2.23; P = 0.086). Sites, age, and multi-agent regimens were not significant. This is one of the largest retrospective studies reporting outcome of palliative chemotherapy for ABC. It confirms the benefit of palliative chemotherapy in an unselected group of patients. Fluoropyrimidine-based regimens appear to be as effective as gemcitabine-based treatments.	\N	\N
24853219	Epidermal growth factor receptor (EGFR) inhibitors are widely used in the treatment of many cancers, and the cutaneous toxicity profile associated with these agents has become prominent. In fact, dermatologic side effects have also been reported with other targeted agents, including both BRAF and mTOR inhibitors. During her presentation at the NCCN 19th Annual Conference, Dr. Barbara Burtness reviewed the array of skin complications caused by many targeted therapies, focusing on the more common culprits, the role of prophylactic versus reactive management strategies, the need to be attentive to potential infections, the importance of mastering local measures to improve quality of life and cosmetic issues, the therapeutic mainstays (oral and topical antibiotics and topical steroids), and the preference of improving these cutaneous complications over suspending anticancer treatment.	\N	\N
24861877	Vitamin D deficiency has been associated with hypertension, diabetes mellitus, and incident stroke. Little is known about the association between vitamin D and subclinical cerebrovascular disease. To examine the relationship of 25-hydroxyvitamin D (25[OH]D) levels with cerebrovascular abnormalities as assessed on brain magnetic resonance imaging (MRI) among participants of the Atherosclerosis Risk in Communities (ARIC) Brain MRI study. Participants were white and black adults aged 55 to 72 years with no history of clinical stroke who underwent a cerebral MRI at ARIC visit 3 (n = 1622) and a second cerebral MRI approximately 10 years later (n = 888). The 25(OH)D level was measured by mass spectrometry at visit 3, with levels adjusted for calendar month and categorized using race-specific quartiles. The cross-sectional and prospective associations of 25(OH)D levels with white matter hyperintensities (WMHs) and MRI-defined infarcts were investigated using multivariable regression models. The mean age of the participants was 62 years, 59.6% were women, and 48.6% were black. Lower 25(OH)D levels were not significantly associated with WMH score of severity, prevalent high-grade WMH score (≥3), or prevalent infarcts in cross-sectional, multivariable-adjusted models (all P > .05). Similarly, no significant prospective associations were found for lower 25(OH)D levels with change in WMH volume, incident high WMH score (≥3), or incident infarcts on the follow-up MRI, which occurred approximately 10 years later. A single measure of 25(OH)D was not cross-sectionally associated with WMH grade or prevalent subclinical infarcts and was not prospectively associated with WMH progression or subclinical brain infarcts seen on serial cerebral MRIs obtained approximately 10 years apart. These findings do not support optimizing vitamin D levels for brain health.	\N	\N
24871260	A major symptom of hand-arm vibration syndrome is a secondary Raynaud's phenomenon-vibration white finger (VWF)-which results from a vasospasm of the digital arteries caused by work with vibration devices leading to occupational disease. Pharmacotherapy of VWF is often ineffective or has adverse effects. The aim of this work was to verify the influence of inhalation of partially ionized oxygen (O2•-) on peripheral blood vessels in the hands of patients with VWF. Ninety one (91)patients with VWF underwent four-finger adsorption plethysmography, and the pulse wave amplitude was recorded expressed in numeric parameters-called the native record. Next, a cold water test was conducted following with second plethysmography. The patients were divided in to the three groups. First and second inhaled 20-min of ionized oxygen O2•- or oxygen O2 respectively. Thirth group was control without treatment. All three groups a follow-up third plethysmography-the post-therapy record. Changes in the pulse wave amplitudes were evaluated. Inpatients group inhaling O2•- a modest increase of pulse wave amplitude was observed compared to the native record; patients inhaling medical oxygen O2 and the control showed a undesirable decline of pulse wave amplitude in VWF fingers. Strong vasodilatation were more frequent in the group inhaling O2•- compare to O2 (p < 0.05). Peripheral vasodilatation achieved by inhalation of O2•- could be used for VWF treatment without undesirable side effect in hospital as well as at home environment.	\N	\N
24872268	Excessive postoperative hemorrhage in cardiac surgery is a serious complication associated with adverse postoperative events. Also, its associated risk of re-exploration, places a high demand on hospital resources in terms of transfusion needs, ventilatory support requirements, intensive care support, and manpower requirements. To determine predictors of 24-hour drain volume (pleural and mediastinal) after coronary artery bypass graft (CABG), in order to focus on preventive measures for patients with identified risk factors. Fifty-four consecutive adult patients who had CABG at the Madras Medical Mission, Chennai, India in July 2008 were retrospectively studied. In order to determine risk factors for excessive post-operative bleeding, 11 pre-operative, and 13 operative and 2 post-operative variables were analyzed using univariate analysis and multiple linear regression. Cardiopulmonary bypass was used for all the patients and anti-fibrinolytic in 13 (22.8%). No mortality was recorded. Mean 24-hour post-operative drain volume was 458 ± 270 ml (range 90-1230). Re-exploration for bleeding was required in 2 (3.5%) patients. Predictors of 24-hour drain volume were heparin therapy before commencement of CPB (p=0.024), intra-operative transfusion of fresh frozen plasma (p=0.010), and pre-operative serum ALT value (p=0.047). The strongest predictor was intra-operative transfusion of platelets (p=0.005). To guard against excessive post-operative haemorrhage after CABG, pre-operative stabilisation and correction of coagulation should be achieved. Also the administration of heparin intra-operatively should be individualized and not only based on dose per body weight.	\N	\N
24875660	Peritoneal dialysis (PD) continues to be underutilized in the United States, even though it is less expensive, provides better quality of life and has better outcomes compared with hemodialysis. The reasons for low utilization of PD are influenced by complex psychosocial and economic factors, lack of physician training, physician bias and inadequate pre-end-stage renal disease care and education to the patients. Providing quality pre-end-stage renal disease education to patients and families and improving education and training of physician in PD, so that they become comfortable with the therapy, are of paramount importance to increase PD growth. Minimizing episodes of PD-related infections and noninfectious complications, preserving peritoneal membrane using more biocompatible solutions and drugs, such as angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, and careful management of volume status can reduce the loss of PD patients to hemodialysis. Timely surgical interventions can prevent the malfunction and loss of PD catheters. Consolidating smaller PD facilities in a given geographical area into a single large PD center can further improve PD outcomes and PD growth. Finally, with the introduction of bundled payment for dialysis services, PD may emerge as a cost-effective therapy and rekindle interest in the dialysis community to consider PD as a better renal replacement therapy option.	\N	\N
24877851	This was a systematic review of the literature to determine which compression method is superior in promoting ulcer healing and reducing recurrence in patients with lower extremity venous ulcer disease. We conducted a comprehensive search of multiple databases for randomized and nonrandomized comparative studies from 1990 to December 2013. We identified 36 studies and two Cochrane systematic reviews. Many studies had moderate risk of bias. We found no overall difference between compression stockings vs compression bandages with respect to ulcer healing, time to ulcer healing, or ulcer recurrence outcomes. When we compared stockings vs short stretch bandages, stockings were superior with respect to ulcer healing. However, stockings compared with four-layer systems showed no difference in ulcer healing outcomes. When four-layer systems were compared with compression with less than four layers, there was also no significant difference in ulcer healing outcomes. Similarly, short stretch bandages were not superior to long stretch bandages with respect to ulcer healing, time to ulcer healing, or ulcer recurrence. One Cochrane review presented many additional comparisons and reported increased wound healing with compression compared with no compression, with multicomponent systems over single component systems, and compression systems with an elastic component over no elastic component. Another Cochrane review demonstrated a reduction in recurrence with compression in patients with healed ulcers. At least moderate-quality evidence supports compression over no compression, multicomponent systems over single component systems, and systems with an elastic component over those without. We did not find significant differences with respect to ulcer healing outcomes for other comparisons. Low-quality evidence supports the effect of compression on ulcer recurrence.	\N	\N
24878150	To explore barriers and facilitators to implementing and sustaining Healthy Choices, a 3-year multicomponent obesity prevention intervention implemented in middle schools in Massachusetts. Using purposive sampling, 56 in-depth interviews were conducted with middle school employees representing different positions (administrators, teachers, food service personnel, and employees serving as intervention coordinators). Interviews were recorded and transcribed. Emergent themes were identified using thematic analyses. State-mandated testing, budget limitations, and time constraints were viewed as implementation barriers, whereas staff buy-in, external support, and technical assistance were seen as facilitating implementation. Respondents thought that intervention sustainability depended on external funding and expert assistance. Results confirm the importance of gaining faculty and staff support. Schools implementing large-scale interventions should consider developing sustainable partnerships with organizations that can provide resources and ongoing training. Sustainability of complex interventions may depend on state-level strategies that provide resources for implementation and technical assistance.	\N	\N
24882305	Loeys-Dietz syndrome (LDS) is a recently recognized connective tissue disorder caused by mutations of the transforming growth factor (TGF)-β receptors. It is an autosomal dominant syndrome characterized by the triad of arterial tortuosity and aneurysms, hypertelorism, and bifid uvula or cleft palate. We treated an 18-year-old woman with a 100-mm-diameter aortic root aneurysm and severe aortic valve regurgitation. She underwent urgent aortic root replacement and bioprosthetic valve implantation. LDS was diagnosed by postoperative genetic screening results. Histopathologic examination of the aortic wall showed diffuse degeneration and elastin fragmentation in the media.	\N	\N
24895051	Haploidentical stem cell transplantation (haploSCT) offers an alternative treatment option for advanced leukemia patients lacking a HLA-compatible donor. Transfer of NK cells represents a promising therapeutic option in combination with SCT, as NK cells can promote graft versus leukemia with low risk of GVH disease. In this study, we show results from a phase I/II trial in which 24 acute myeloid leukemia patients underwent haploSCT in combination with early transfer of unmodified NK cells and observed a promising 2-year overall survival rate of 37%. By performing immunomonitoring and subsequent principal component analysis, we tracked donor NK-cell dynamics in the patients and distinguished between NK cells reconstituting from CD34(+) precursors, giving rise over time to a continuum of multiple differentiation stages, and adoptively transferred NK cells. Transferred NK cells displayed a mature phenotype and proliferated in vivo during the early days after haploSCT even in the absence of exogenous IL-2 administration. Moreover, we identified the NK-cell phenotype associated with in vivo expansion. Thus, our study indicates a promising path for adoptive transfer of unmodified NK cells in the treatment of high-risk acute myeloid leukemia.	\N	\N
24896322	The design of antioxidant pharmaceuticals is a major challenge for the treatment of many clinical conditions and in aging. Free radical damage (FRD) is primarily catalysed by iron catalytic centers. Most of the natural and synthetic antioxidants are ineffective in inhibiting FRD because of the achievement of low concentrations at the affected tissues. Despite that many chelators inhibit FRD in vitro and in vivo, only Deferiprone (L1) has been shown to be effective and safe in the reversal of oxidative stress related tissue damage in iron overload and other conditions such as cardiomyopathy, acute kidney disease, Friedreich ataxia etc. Deferiprone, other chelators and their combinations could be used as main, adjuvant and alternative therapies in untreated conditions eg forms of cancer, Alzheimer's and Parkinson's diseases. Therapeutic targeting in each case requires specific chelator selection based on structure/activity correlation and consideration of other parameters eg ADMET. The ability of L1 to reach extracellular and intracellular compartments of almost all tissues including the brain is a major advantage for further development and use in many clinical conditions.	\N	\N
24896980	Abnormally aggregated tau is the hallmark pathology of tauopathy neurodegenerative disorders and is a target for development of both diagnostic tools and therapeutic strategies across the tauopathy disease spectrum. Development of carbon-11- or fluorine-18-labeled radiotracers with appropriate affinity and specificity for tau would allow noninvasive quantification of tau burden using positron emission tomography (PET) imaging. We have synthesized [(18)F]lansoprazole, [(11)C]N-methyl lansoprazole, and [(18)F]N-methyl lansoprazole and identified them as high affinity radiotracers for tau with low to subnanomolar binding affinities. Herein, we report radiosyntheses and extensive preclinical evaluation with the aim of selecting a lead radiotracer for translation into human PET imaging trials. We demonstrate that [(18)F]N-methyl lansoprazole, on account of the favorable half-life of fluorine-18 and its rapid brain entry in nonhuman primates, favorable kinetics, low white matter binding, and selectivity for binding to tau over amyloid, is the lead compound for progression into clinical trials.	\N	\N
24902046	Infection, graft-versus-host disease (GVHD), and to a lesser extent sinusoidal obstructive syndrome (SOS) represent the major causes of morbidity and mortality in patients undergoing allogeneic hematopoietic stem cell transplantation (AHSCT). During the last decade, progress in prevention and treatment of these complications led to improvement in the outcome of these patients. Despite the fact that nonmyeloablative regimens have been increasingly used in elderly patients and in patients with co-morbidities, the nonrelapse related mortality remains a challenge and long-term follow-up is required. The objective of this manuscript is to provide an updated concise review of the complications of AHSCT and of the available treatment interventions.	\N	\N
24910429	Acute myeloid leukemia (AML) therapy involves compounds that are cytotoxic to both normal and cancer cells, and relapsed AML is resistant to subsequent chemotherapy. Thus, agents are needed that selectively kill AML cells with minimal toxicity. Here, we report that AML is dependent on DDX5 and that inhibiting DDX5 expression slows AML cell proliferation in vitro and AML progression in vivo but is not toxic to cells from normal bone marrow. Inhibition of DDX5 expression in AML cells induces apoptosis via induction of reactive oxygen species (ROS). This apoptotic response can be blocked either by BCL2 overexpression or treatment with the ROS scavenger N-acetyl-L-cysteine. Combining DDX5 knockdown with a BCL2 family inhibitor cooperates to induce cell death in AML cells. By inhibiting DDX5 expression in vivo, we show that DDX5 is dispensable for normal hematopoiesis and tissue homeostasis. These results validate DDX5 as a potential target for blocking AML.	\N	\N
24924164	Drug resistance mutations (DRMs) can serve as distinct, nonpolymorphic markers for evaluating diversity of expressed HIV-1. We screened for DRMs during early-acute viremia and examined the diversity in reverse transcriptase (RT) relative to envelope (env) in cases of transmitted drug resistance. We evaluated 111 longitudinal plasma samples collected every 2-7 days from 15 individuals who seroconverted for HIV-1 infection in 1994-2000. The samples were screened with sensitive polymerase chain reaction assays for the commonly transmitted M41L and K70R mutations and for K65R, which was undetected by bulk sequencing. Mutation-positive samples were further characterized by clonal sequencing of RT and env V1-V3. Drug resistance mutations were detected in 4 of 15 seroconverters at 5-50 days of viral nucleic acid expression; most mutations disappeared about the time of seroconversion. Clonal sequencing verified low-level K65R at frequencies of 0.4%-4.9%. In each case, K65R coexisted unlinked with variants carrying 2-5 thymidine analog mutations at frequencies of 1.6%-23.0%. In one seroconverter, variants with M184V and nonnucleoside RT inhibitor mutations were also identified at first RNA expression. Each seroconverter displayed a homogeneous V1-V3 env population. Reverse-transcriptase DRMs demonstrate that the breadth of variants in transmission may be greater than what is reflected in envelope sequences.	\N	\N
24935472	In the context of cancer, transforming growth factor β (TGF-β) is a cell growth suppressor; however, it is also a critical inducer of invasion and metastasis. SMAD is the important mediator of TGF-β signaling pathway, which includes receptor-regulated SMADs (R-SMADs), common-mediator SMADs (co-SMADs), and inhibitory SMADs (I-SMADs). I-SMADs block the activation of R-SMADs and co-SMADs and thus play important roles especially in the SMAD-dependent signaling. SMAD7 belongs to the I-SMADs. As an inhibitor of TGF-β signaling, SMAD7 is overexpressed in numerous cancer types and its abundance is positively correlated to the malignancy. Emerging evidence has revealed the switch-in-role of SMAD7 in cancer, from a TGF-β inhibiting protein at the early stages that facilitates proliferation to an enhancer of invasion at the late stages. This role change may be accompanied or elicited by the tumor microenvironment and/or somatic mutation. Hence, current knowledge suggests a tumor-favorable timer nature of SMAD7 in cancer progression. In this review, we summarized the advances and recent findings of SMAD7 and TGF-β signaling in cancer, followed by specific discussion on the possible factors that account for the functional changes of SMAD7.	\N	\N
24940479	Although the pathophysiology of facioscapulohumeral dystrophy (FSHD) has been controversial over the last decades, progress in recent years has led to a model that incorporates these decades of findings and is gaining general acceptance in the FSHD research community. Here we review how the contributions from many labs over many years led to an understanding of a fundamentally new mechanism of human disease. FSHD is caused by inefficient repeat-mediated epigenetic repression of the D4Z4 macrosatellite repeat array on chromosome 4, resulting in the variegated expression of the DUX4 retrogene, encoding a double-homeobox transcription factor, in skeletal muscle. Normally expressed in the testis and epigenetically repressed in somatic tissues, DUX4 expression in skeletal muscle induces expression of many germline, stem cell, and other genes that might account for the pathophysiology of FSHD. Although some disagreements regarding the details of mechanisms remain in the field, the coalescing agreement on a central model of pathophysiology represents a pivot-point in FSHD research, transitioning the field from discovery-oriented studies to translational studies aimed at developing therapies based on a sound model of disease pathophysiology.	\N	\N
24944260	To determine whether droxidopa, an oral norepinephrine precursor, improves symptomatic neurogenic orthostatic hypotension (nOH). Patients with symptomatic nOH due to Parkinson disease, multiple system atrophy, pure autonomic failure, or nondiabetic autonomic neuropathy underwent open-label droxidopa dose optimization (100-600 mg 3 times daily), followed, in responders, by 7-day washout and then a 7-day double-blind trial of droxidopa vs placebo. Outcome measures included patient self-ratings on the Orthostatic Hypotension Questionnaire (OHQ), a validated, nOH-specific tool that assesses symptom severity and symptom impact on daily activities. From randomization to endpoint (n = 162), improvement in mean OHQ composite score favored droxidopa over placebo by 0.90 units (p = 0.003). Improvement in OHQ symptom subscore favored droxidopa by 0.73 units (p = 0.010), with maximum change in "dizziness/lightheadedness." Improvement in symptom-impact subscore favored droxidopa by 1.06 units (p = 0.003), with maximum change for "standing a long time." Mean standing systolic blood pressure (BP) increased by 11.2 vs 3.9 mm Hg (p < 0.001), and mean supine systolic BP by 7.6 vs 0.8 mm Hg (p < 0.001). At endpoint, supine systolic BP >180 mm Hg was observed in 4.9% of droxidopa and 2.5% of placebo recipients. Adverse events reported in ≥ 3% of double-blind droxidopa recipients were headache (7.4%) and dizziness (3.7%). No patients discontinued double-blind treatment because of adverse events. In patients with symptomatic nOH, droxidopa improved symptoms and symptom impact on daily activities, with an associated increase in standing systolic BP, and was generally well tolerated. This study provides Class I evidence that in patients with symptomatic nOH who respond to open-label droxidopa, droxidopa improves subjective and objective manifestation of nOH at 7 days.	\N	\N
24948193	Acute inflammation is the result of a complex signal transduction pathway that protects and heals our body and is necessary for our good health and normal wellbeing. Whereas, chronic inflammation can be correlated well with the onset of a plethora of autoimmune disorders; rheumatoid arthritis, systemic lupus and polymyalgia, rheumatic and other diseases like asthma, inflammatory bowel diseases, cardiovascular disorders, ulcerative colitis and Crohn's disease. Also, it has been reported to be associated with the onset of various cancers. An effective anti-inflammatory drug should be able to inhibit the development of chronic inflammation without interfering in normal homeostasis. A number of herbal drugs have been identified in the past that can target inflammatory cytokines. Among these, Ganoderma lucidum: a powerful medicinal mushroom has been found to possess immune-modulating and immune-potentiating capabilities and has been characterized as a wonder herb. This review mainly focuses on the molecular mechanism of anti-inflammatory and antiallergic action of this mushroom and also sheds light on various patent studies related to its pharmacological action.	\N	\N
24952923	Extraosseous Gaucher cell deposits are a rare complication of Gaucher disease that can mimic malignancy. We describe a case of Gaucher cell deposition in the subcutaneous soft tissues overlying the lower thoracic spine in an 18-year-old woman with known type III Gaucher disease. This case is unique in the literature because this subcutaneous Gaucher mass was not associated with extension from underlying bone involvement or clear lymph node origin. It demonstrated no discernible continuity with the adjacent thoracic spinous processes, the cortices of which appeared intact. Although patients with Gaucher disease are at increased risk of malignancy, Gaucher cell deposition should remain a differential consideration for soft tissue masses with or without adjacent bone involvement in patients with known Gaucher disease.	\N	\N
24953225	The association between the C3435T polymorphism in the MDR1 gene and refractory epilepsy remains controversial. The association appears to be influenced by ethnicity and region. We have performed a systematic review and meta-analysis to assess the link between the MDR1 C3435T polymorphism and refractory epilepsy in the Chinese population. We searched the Cochrane Library, MIDLINE, EMBASE, CBM disc, CNKI, VIP, and WANFANG databases for literature published through August 2013 for case-control studies that evaluated the association between the MDR1 C3435T polymorphism and refractory epilepsy. Twenty-one case-control studies involving 4269 patients (1863 cases in the group with drug-resistant epilepsy and 2406 in the group with drug-responsive epilepsy) were included in the systematic review and meta-analysis. The analysis showed that there were significantly more cases with the MDR1 3435 CC genotype in the group with drug-resistant epilepsy than in the group with drug-responsive epilepsy [odds ratio (OR)=1.50, 95% confidence interval (CI)=1.09-2.06, P=0.01]. In a subanalysis of patients from the southern regions of China, the correlation was not significant [odds ratio (OR)=1.2, 95% confidence interval (CI)=0.89-1.64, P=0.24]. The relationship established in a subset of the Chinese population between the MDR1 C3435T polymorphism and refractory epilepsy will guide epilepsy treatment and development of new AEDs.	\N	\N
24955837	Pulmonary arterial hypertension (PAH) is a life-threatening disorder that is associated with elevated pulmonary pressures and right heart failure resulting from progressive loss and thickening of small pulmonary arteries. Despite their ability to improve symptoms, current therapies fail to prevent disease progression, leaving lung transplantation as the only therapy in end-stage PAH. To overcome the limitations of current therapies, there is an active search for disease-modifying agents capable of altering the natural history of, and improving clinical outcomes in, PAH. The Wnt signaling pathways have emerged as attractive treatment targets in PAH given their role in the preservation of pulmonary vascular homeostasis and the recent development of Wnt-specific compounds and biological therapies capable of modulating pathway activity. In this review, we summarize the literature describing the role of Wnt signaling in the pulmonary circulation and discuss promising advances in the field of Wnt therapeutics that could lead to novel clinical therapies capable of preventing and/or reversing pulmonary vascular pathology in patients with this devastating disease.	\N	\N
24962034	The HIV Modes of Transmission (MOT) model estimates the annual fraction of new HIV infections (FNI) acquired by different risk groups. It was designed to guide country-specific HIV prevention policies. To determine if the MOT produced context-specific recommendations, we analyzed MOT results by region and epidemic type, and explored the factors (e.g. data used to estimate parameter inputs, adherence to guidelines) influencing the differences. We systematically searched MEDLINE, EMBASE and UNAIDS reports, and contacted UNAIDS country directors for published MOT results from MOT inception (2003) to 25 September 2012. We retrieved four journal articles and 20 UNAIDS reports covering 29 countries. In 13 countries, the largest FNI (range 26 to 63%) was acquired by the low-risk group and increased with low-risk population size. The FNI among female sex workers (FSWs) remained low (median 1.3%, range 0.04 to 14.4%), with little variability by region and epidemic type despite variability in sexual behaviour. In India and Thailand, where FSWs play an important role in transmission, the FNI among FSWs was 2 and 4%, respectively. In contrast, the FNI among men who have sex with men (MSM) varied across regions (range 0.1 to 89%) and increased with MSM population size. The FNI among people who inject drugs (PWID, range 0 to 82%) was largest in early-phase epidemics with low overall HIV prevalence. Most MOT studies were conducted and reported as per guidelines but data quality remains an issue. Although countries are generally performing the MOT as per guidelines, there is little variation in the FNI (except among MSM and PWID) by region and epidemic type. Homogeneity in MOT FNI for FSWs, clients and low-risk groups may limit the utility of MOT for guiding country-specific interventions in heterosexual HIV epidemics.	\N	\N
24965397	Several studies indicated that the expression level of MLL3 gene in gastric cancer tissue was associated with prognosis, and previous studies also suggested that genetic polymorphisms of MLL3 were related to the risk for gastric cancer. The present study aimed to investigate the association of a missense mutation (S3660L) in the MLL3 gene with gastric cancer risk in a Chinese population. In the present study, we identified a novel missense mutation in MLL3 gene (S3660L) by directly sequencing method in 48 gastric cancer patients. To further explore the relation between gastric cancer and this mutation, we selected 354 gastric cancer patients and 377 healthy control subjects and designed a case-control study. We found that the AG genotype (14.9 vs 6.40%, odds ratio/OR=2.58, 95% CI: 1.33-4.54, p<0.001) and A allele (7.5 vs 3.2%, OR=2.46, 95% CI: 1.55~5.34, p<0.001) were common in the gastric cancer patients than in the control subjects. We concluded that this novel missense (S3660L) mutation in MLL3 gene is likely to increase the gastric cancer risk.	\N	\N
24970372	During the 2009 A(H1N1) influenza pandemic, a suite of studies conducted in Canada showed an unexpected finding, that patients with medically attended laboratory-confirmed pandemic influenza were more likely to have received seasonal influenza vaccination than test-negative control patients. Different bodies, including scientific journals and government scientific advisory committees, reviewed the evidence simultaneously to determine its scientific validity and implications. Decision-making was complicated when the findings made their way into the media. The normal trajectory of non-urgent research includes peer-review publication after which decision-makers can process the information taking into account other evidence and logistic considerations. In the situation that arose, however, the congruence of an unexpected finding and the simultaneous review of the evidence both within and outside the traditional peer-review sphere raised several interesting issues about how to deal with emerging evidence during a public health emergency. These events are used in this article to aid discussion of the complex interrelationship between researchers, public health decision-makers and scientific journals, the trade-offs between sharing information early and maintaining the peer-review quality assurance process, and to emphasise the need for critical reflection on the practical and ethical norms that govern the way in which research is evaluated, published and communicated in public health emergencies.	\N	\N
24973485	This study explored the care challenges experienced by older patients with multimorbidity, their informal caregivers and family physicians. Semi-structured interviews were conducted with 27 patients, their informal caregivers and family physicians. Qualitative description was used to identify key themes in the interview transcripts. Participants experienced many common challenges when managing multimorbidity, including a lack of decision-making support, poor communication and uncoordinated health services. Within these themes, unique perspectives specific to the role of being a patient, caregiver or family physician emerged. The study adds to a limited evidence base on the experience of patients with multimorbidity. By including the perspectives of their family caregivers and physicians, we provide important insight into the management of multimorbidity and recommend the uptake of specific strategies to address them.	\N	\N
24986275	Cyclical outbreaks of mumps have been noticed across Chandigarh city during winter months. Chandigarh does not provide measles, mumps and rubella (MMR) vaccination in the State immunization schedule. Epidemiological shift in age at diagnosis of mumps was noticed with higher incidence in older children and adults. Increased occurrence of complications can be predicted with this age shift. Silent burden of rubella with serious outcomes in newborns further strengthen the case for MMR vaccine inclusion in routine immunization program of Chandigarh.	\N	\N
24988612	Autophagy, the process of degradation of unwanted or damaged cell elements, is extremely important for a variety of human diseases, especially cancers. This process influences various stages of initiation and progression of cancer, which is caused by overlapping signaling pathways of autophagy and carcinogenesis. However, due to the complexity of cancer as a systemic disease, the fate of tumor cells is not determined by one signal pathway. Chronic autophagy inhibition leads to tumor promotion, due to instability of the genome, defective cell growth, also as a result of cellular stress. However, increased induction of autophagy may be a mechanism for tumor cell survival in the state of hypoxia, acidosis, as well as under the influence of chemotherapy. Therefore, in the context of cancer development, the process of autophagy should be considered in two directions. Determination of the molecular mechanisms underlying the process of autophagy and its role in the carcinogenesis is a key element of the anticancer strategy. The main objective of modern oncology, which should eventually lead to personalized therapy, is the possibility to predict the response of a particular type of cancer to the used drug. Results of in vitro and in vivo studies show the magnitude of the relationship between changes in the genome, and response to the therapy. This information indicates the mechanism and thereby the target point of the drugs. In this review we focus on the mechanism of autophagy and its role in cancer therapy, which can help to understand the autophagy-cancer relationship and indicate the direction for the design of new drugs with anticancer activity.	\N	\N
24989056	Flow volume loops (FVLs) are considered part of the workup of patients with thyroid enlargement presenting to the endocrinology clinic. They are used to detect upper airway obstruction (UAO) secondary to tracheal compression (TC) from a goitre. Surgical assessment in contrast tends to focus on clinical evaluation supplemented when required by imaging. The aim of this study was to investigate whether FVLs influence the decision to operate in patients with a goitre. We identified patients with a goitre referred by the department of endocrinology for FVLs between 2006 and 2011. The results of the FVL were collated, and their impact on patient management was assessed. Ninety-six patients were referred for FVL. In 38 patients, the indication was specifically to evaluate the effects of a goitre. Of these, 33 were reported as normal. Five FVLs were reported as abnormal (3 suggesting lung pathology and 2 TC). Both patients with TC on FVL presented no CT evidence of TC and underwent surgery due to abnormal cytology. Of the 33 normal FVLs, 7 underwent surgery: 2 for local compression, 4 for abnormal cytology and 1 for Graves' disease. None of the FVLs influenced the decision to operate. FVLs may detect subradiological TC, but rarely influence management in patients with a goitre. In view of this and the cost of £235 per investigation, FVL should be reserved for goitre patients with suspected primary lung pathology, where the distinction between large and small airway compression is likely to influence management.	\N	\N
24994677	Uveal melanoma (UM) is the most common primary tumor of the eye in adults. There is no standard adjuvant treatment to prevent metastasis and no effective therapy in the metastatic setting. We have established a unique panel of 7 UM cell lines from either patient's tumors or patient-derived tumor xenografts (PDXs). This panel recapitulates the molecular landscape of the disease in terms of genetic alterations and mutations. All the cell lines display GNAQ or GNA11 activating mutations, and importantly four of them display BAP1 (BRCA1 associated protein-1) deficiency, a hallmark of aggressive disease. The mTOR pathway was shown to be activated in most of the cell lines independent of AKT signaling. mTOR inhibitor Everolimus reduced the viability of UM cell lines and significantly delayed tumor growth in 4 PDXs. Our data suggest that mTOR inhibition with Everolimus, possibly in combination with other agents, may be considered as a therapeutic option for the management of uveal melanoma.	\N	\N
25003989	Understanding how the immune system facilitates or controls HIV-1 disease progression has important implications for the design of effective interventions. We report that although B-cell dysregulations associated with HIV-1 disease progression are accompanied by an overall decrease in the percentage of total blood B-cells, we observe an increase in relative frequencies of cells presenting characteristics of both transitional immature and first-line marginal zone (MZ) B-cell populations, we designated as precursor MZ-like B-cells. B-cells with similar attributes have been associated with IL-10 expression and "regulatory" potential. As such, the relative frequencies of precursor MZ-like B-cells expressing IL-10 are increased in the blood of viremic HIV-1-infected individuals when compared to HIV-negative subjects. Importantly, in aviremic HIV-1 Elite-Controllers (EC), we found unaltered relative percentages of precursor MZ-like B-cells which presented normal IL-10 expression patterns. Furthermore, EC had increased relative frequencies of blood MZ-like B-cells expressing LT-α. Thus in contrast to viremic HIV-1-infected individuals, EC present MZ-like B-cell populations which IL-10 and LT-α expression profiles may favour homeostasis of immune responses and lymphoid microenvironments.	\N	\N
25011952	We recently demonstrated a beneficial effect of metformin compared with glipizide in type 2 diabetic patients regarding cardiovascular outcomes for 3-year treatment in the SPREAD-DIMCAD study. However, the potential mechanism for the clinical effects remains unclear. Here, we performed a comprehensive lipidomics study to evaluate the different lipid metabolites in serum samples obtained from participants in this study. Liquid chromatography-quadrupole time of flight-mass spectrometry was used to evaluate the different lipid metabolites in serum samples obtained from the participants (21 patients in glipizide group and 23 patients in metformin group) before and after each year of treatment (at 0 [baseline], 1, 2, and 3 years of study drug administration). A total of 118 serum lipid molecular species was identified and quantified. During treatment, metformin induced a substantially greater change in serum lipid species compared with glipizide, especially at the 2- and 3-year time points (with 2, 11, and 12 lipid species being significantly different between the groups after each year of treatment [1, 2, or 3 years], P < 0.05). Among the significantly changed lipid species, three lipid metabolites were linked to long-term composite cardiovascular events (adjusted P < 0.05). After treatment, triacylglycerols (TAGs) of a relatively higher carbon number showed a clearly increased trend in metformin group compared with the glipizide group, whereas the changes in TAGs with different double bonds were minimal. Our findings revealed the differential therapeutic effects of metformin and glipizide on comprehensive lipidomics, which were comparable with their different long-term effects on cardiovascular outcomes.	\N	\N
25014130	To conduct the first population size estimation and biological and behavioral surveillance survey among men who have sex with men (MSM) in Angola. Population size estimation with multiplier method and a cross-sectional study using respondent-driven sampling. Luanda Province, Angola. Study was conducted in a large hospital. Seven hundred ninety-two self-identified MSM accepted a unique object for population size estimation. Three hundred fifty-one MSM were recruited with respondent-driven sampling for biological and behavioral surveillance survey. Interviews and testing for HIV and syphilis were conducted on-site. Analysis used Respondent-Driven Sampling Analysis Tool and STATA 11.0. Univariate, bivariate, and multivariate analyses examined factors associated with HIV and unprotected sex. Six imputation strategies were used for missing data for those refusing to test for HIV. A population size of 6236 MSM was estimated. Twenty-seven of 351 individuals were tested positive. Adjusted HIV prevalence was 3.7% (8.7% crude). With imputation, HIV seroprevalence was estimated between 3.8% [95% confidence interval (CI): 1.6 to 6.5] and 10.5% (95% CI: 5.6 to 15.3). Being older than 25 (odds ratio = 10.8, 95% CI: 3.5 to 32.8) and having suffered episodes of homophobia (odds ratio = 12.7, 95% CI: 3.2 to 49.6) significantly increased the chance of HIV seropositivity. Risk behaviors are widely reported, but HIV seroprevalence is lower than expected. The difference between crude and adjusted values was mostly due to treatment of missing values in Respondent-Driven Sampling Analysis Tool. Solutions are proposed in this article. Although concerns were raised about feasibility and adverse outcomes for MSM, the study was successfully and rapidly completed with no adverse effects.	\N	\N
25015744	Endoscopic ultrasound (EUS)-guided drainage is an effective treatment for many abscesses in the abdomen. We review our experience with EUS-guided drainage of pelvic abscesses. Thirty consecutive patients who underwent EUS-guided pelvic abscess drainage were evaluated after excluding three patients with distance to transducer >2 cm or organized abscess. Thirty patients (25 male) aged 60 ± 4.5 years (mean ± SD) had 4 prostatic abscesses, 7 perisigmoid abscesses, and 19 perirectal abscesses with mean ± SD sizes of 2.5 ± 0.3, 4.7 ± 0.6, and 5.4 ± 0.4 cm, respectively. Surgery was the most common predisposing factor (n = 14, 46.6 %) followed by diverticulitis (n = 5, 16.6 %). Interventions included aspiration only (2 prostatic and 3 perisigmoid), aspiration and dilatation (2 patients in each group), and dilatation and stenting (2 perisigmoid and 17 perirectal). Five (16.6 %) patients needed re-intervention, and two (6.6 %) needed surgery. There were no recurrences. Technical success of EUS-guided pelvic abscess drainage overall was 90.9 % (30/33) and was 93.3 % (27/30) in patients in whom EUS-guided drainage was attempted, with 16.5 % (n = 5) re-intervention rate. EUS-guided drainage has an excellent success rate in drainage of pelvic abscesses.	\N	\N
25022060	The measurement of antinuclear antibodies (ANA) is used for screening of connective tissue diseases (CTD) in the laboratory. ANA detection is performed by indirect immunofluorescence (IF) assay on HEp-2 cells from human larynx carcinoma. However, it lacks specificity for the identification of specific diseases and antigen reactivity. The aim of the present study was to evaluate the EliA CTD Screen (EliA), a new enzyme fluoroimmunoassay (Phadia AB, Uppsala, Sweden) for detection of ANA in human serum. The study involved a total of 732 serum samples, 200 from healthy donors, 297 from patients with CTD and 235 from patients with rheumatoid arthritis, vasculitis syndrome and relative disease of CTD. For all sera, ANA was measured by IF, commercial assay (MESACUP) and EliA. The sensitivity and specificity of EliA were 73.7% and 78.7%, respectively, whereas those of MESACUP were 80.8% and 64.7%, respectively. Area under the receiver operating curves for EliA, MESACUP and IF were 0.821, 0.786 and 0.730, respectively. The concordance rate between EliA and MESACUP was 84.2%. These discrepancies between those 2 assays were found in 84 sera. Further investigation were done by each ANA antigen tests for the discrepant results of EliA in 83 sera. The discrepancies might be occurred by antigen difference or non-specific response. AUC results showed that the diagnostic performance of EliA was superior to MESACUP and IF. EliA had a good performance as method for screening of CTD.	\N	\N
25027632	This longitudinal, exploratory study was designed to better understand the lived experience of spousal caregivers age 60 and older providing care to partners with Alzheimer's disease and related dementias resident in a care facility. Twenty eight spousal caregivers were interviewed up to three times over a period of 2 years, and long-term care facility staff from four locations across British Columbia (BC), Canada participated in four focus groups. Thematic analysis of interview and focus group transcripts revealed a central, unifying theme 'together but apart'. The results identify key targets for policy makers and service providers to support positive health and well-being outcomes for spousal caregivers providing care to their partners diagnosed with Alzheimer's disease and related dementia and living in care facilities.	\N	\N
25034390	Patients with multiple myeloma (MM) manifesting acute kidney injury (AKI) and who later recover renal function and independence from renal replacement therapy (RRT) are considered to have a better outcome. The aim of this work was to study the factors associated with renal function recovery (independence of hemodialysis) and longer survival in these patients. A retrospective single center study including patients with a diagnosis of MM and severe AKI, defined as stage 3 of the Kidney Disease: Improving Global Outcomes (KDIGO) criteria: 3.0 times baseline increase in serum creatinine (sCr) or increase in sCr to ≥4.0mg/dL or initiation of RRT, was conducted. Data was registry-based and collected between January 2000 and December 2011. We examined demographic and laboratorial data, presenting clinical features, precipitating factors, need for RRT and chemotherapy. Death was considered the primary endpoint. Lower serum β2-microglobulin was the only independent factor associated with recovery of renal function and independence of RRT (OR 0.95, 95% CI: 0.91-0.99, P=0.02). The median survival after AKI was 10.7±12.1months. The factors associated with longer survival were independence of RRT (HR 2.21; 95% CI: 1.08-4.49; P=0.02), lower CRP (HR 1.07; 95% CI: 1.03-1.12; P=0.001) and younger age (HR 1.03; 95% CI: 1.01-1.06; P=0.005). Our study suggests that MM patients with lower serum β2-microglobulin have a higher likelihood of recovering renal function after severe AKI. Independence of RRT, lower CRP and younger age are associated with longer survival.	\N	\N
25038555	The rapidly increasing availability of electronic health records (EHRs) from multiple heterogeneous sources has spearheaded the adoption of data-driven approaches for improved clinical research, decision making, prognosis, and patient management. Unfortunately, EHR data do not always directly and reliably map to medical concepts that clinical researchers need or use. Some recent studies have focused on EHR-derived phenotyping, which aims at mapping the EHR data to specific medical concepts; however, most of these approaches require labor intensive supervision from experienced clinical professionals. Furthermore, existing approaches are often disease-centric and specialized to the idiosyncrasies of the information technology and/or business practices of a single healthcare organization. In this paper, we propose Limestone, a nonnegative tensor factorization method to derive phenotype candidates with virtually no human supervision. Limestone represents the data source interactions naturally using tensors (a generalization of matrices). In particular, we investigate the interaction of diagnoses and medications among patients. The resulting tensor factors are reported as phenotype candidates that automatically reveal patient clusters on specific diagnoses and medications. Using the proposed method, multiple phenotypes can be identified simultaneously from data. We demonstrate the capability of Limestone on a cohort of 31,815 patient records from the Geisinger Health System. The dataset spans 7years of longitudinal patient records and was initially constructed for a heart failure onset prediction study. Our experiments demonstrate the robustness, stability, and the conciseness of Limestone-derived phenotypes. Our results show that using only 40 phenotypes, we can outperform the original 640 features (169 diagnosis categories and 471 medication types) to achieve an area under the receiver operator characteristic curve (AUC) of 0.720 (95% CI 0.715 to 0.725). Moreover, in consultation with a medical expert, we confirmed 82% of the top 50 candidates automatically extracted by Limestone are clinically meaningful.	\N	\N
25044634	The potential benefit of vitamin K as a therapeutic in osteoporosis is controversial and the vitamin K regimen being used clinically (45 mg/day) employs doses that are many times higher than required to ensure maximal gamma-carboxylation of the vitamin K-dependent bone proteins. We therefore tested the hypothesis that vitamin K catabolites, 5-carbon (CAN5C) and 7-carbon carboxylic acid (CAN7C) aliphatic side-chain derivatives of the naphthoquinone moiety exert an osteotrophic role consistent with the treatment of osteoporosis. Osteoblast-like MG63 cell cultures were challenged with lipopolysaccharide and the levels of interleukin-6, an osteoclastogenic cytokine, measured with and without catabolites; low concentrations of CAN7C significantly inhibited interleukin-6 release, but CAN5C did not. In models of bone loss induced by ovariectomy or sciatic neurectomy in C57BL/6 mice, we found that the rarer CAN7C catabolite markedly restricted ovariectomy-induced bone loss and possibly limited sciatic neurectomy-induced bone loss. CAN7C activity depends on a free carboxylic acid and its particular side-chain structure. These in vivo data indicate for the first time that the clinical utility of vitamin K for osteoporosis may reside in an unusual catabolite.	\N	\N
25046696	Cystic and alveolar hydatid disease of humans caused by infection with Echinococcus granulosus or Echinococcus multilocularis are significant zoonoses in developing countries. For human infections, the main definitive host is the dog, and reduction in the population of unwanted dogs, together with anthelmintic treatment of wanted dogs, are recommended control procedures for these zoonoses. Both owned and unowned dogs have been shown to be a major source of Echinococcus spp. infection in developing countries. Unowned dogs are the most challenging category in dog population management for the control of major zoonotic diseases. Unowned dogs are those dogs that do not have an owner, and those dogs whose owner cannot readily be identified. Control of numbers of unowned dogs can be done in various ways if funds are available. Fertility control and humane euthanasia are likely to be the most effective procedures in developing countries. Fertility control requires significant funding, and where resources are scarce humane euthanasia may be the most effective option. Both procedures are ongoing events, with no predictable end point. This paper examines the sociology and technology for the population management of owned and unowned dogs, specifically for the reduction of human hydatid disease. Examples are given for developing and developed countries. Although a "One Health" approach is desirable, the technology for hydatid control is different from that for rabies, and FAO Animal Welfare recommendations for dog population management should be adjusted accordingly.	\N	\N
25051669	The paper presents data on the frequency of polymorphisms of candidate genes involved in the formation of endothelial dysfunction--endothelin-1 (EDN1 Lys198Asn) and endothelial nitric oxide synthase (NOS3 T786C) together with the concentrations of their active products (nitric oxide, endothelin-1) in individuals with chronic mercury intoxication. The concentration change of nitric oxide and endothelin-1 indicates the presence of endothelial dysfunction in the individuals examined. The studied polymorphisms appeared to play a minor role in the pathogenesis of endothelial dysfunction in patients with chronic mercury intoxication.	\N	\N
25055486	Postoperative intracranial infectious complications are one of the most topical problems of neurosurgical intensive care due to theirs significant capability to impair outcomes of the main disease. To define the risk factors of postoperative meningitis in patients with chiasm-sellar tumors. 1. to define the effect of somatic and intracranial risk factors on occurrence of postoperative meningitis in patients after transsphenoidal and transcranial approaches to the tumor. 2. To define the effect of postoperative meningitis on outcomes of treatment in patients after transsphenoidal and transcranial approaches to the tumor. Somatic and intracranial risk factors of occurrence of postoperative meningitis (pneumonia, urinary tract infection, sepsis, intra-abdominal hypertension, the presence of external ventricular and lumbar drainage, monitoring of intracranial pressure, cerebrospinal fluid, and reoperation) were fixed every day. The study was conducted in the ICU of the Burdenko from October, 2010 to July, 2012. The 34 patients (19 males, 15 females) were included in the study (average age 47.5 years). The patients were divided into two groups; 17 patients each group. The group-1 included patients after transcranial approach to the tumor and the group-2 included patients after transsphenoidal approach. In the group-1 a meningitis occurred in 3 patients (17.6% +/- 9.2%, DI [-0.4 - 35.6]). In the group-2 a meningitis occurred in 7 patients (41.2% +/- 11.9) DI 95% [17.8 - 64.4]. Accumulation of cerebrospinal fluid under the skin flap authentically increased a risk of a meningitis occurrence in patients after transcranial approach to the tumor (p = 0.031). There was no defined statistical significance of other risk factors. But there was defined a trend of the increasing of meningitis occurrence in patients after transsphenoidal approach in case of lumbar drainage or reoperation. Duration of mechanical ventilation and ICU stay in patients with meningitis was authentically longer than in patients without meningitis in both groups. In the group-2 the duration of mechanical ventilation and ICU stay was significantly shorter than in the group-1. Meningitis is not a typical complication of postoperative period in patients with transcranial approach to the tumor. After transsphenoidal approach a meningitis occurrence is likely in case of postoperative liquorrhea, lumbar drainage or reoperation. Subcutaneous accumulation of cerebrospinal fluid is a single defined statistically significant risk factor of meningitis. Postoperative meningitis impairs a condition of patients with chiasm-sellar tumors, increases the duration of mechanical ventilation and impairs treatment outcomes.	\N	\N
25056937	Cancer is responsible for many deaths and is a major source of healthcare expenditures. The identification of new, non-invasive biomarkers might allow improvement of the direct diagnostic or prognostic ability of already available tools. Here, we took the innovative approach of interrogating the activity of exopeptidases in the serum of cancer patients with the aim of establishing a distinction based on enzymatic function, instead of simple protein levels, as a means to biomarker discovery. We first analyzed two well-characterized mouse models of prostate cancer, each with a distinct genetic lesion, and established that broad exopeptidase and targeted aminopeptidase activity tests reveal proteolytic changes associated with tumor development. We also describe new peptide-based freeze-frame reagents uniquely suited to probe the altered balance of selected aminopeptidases, as opposed to the full array of exopeptidases, and/or their modulators in patient serum or plasma. One particular proteolytic activity was impaired in animals with aggressive disease relative to cancer-free littermates. We identified the protease in question as dipeptidyl peptidase 4 (DPP4) by analyzing selected knockout mice and evaluating the effect of specific inhibitors. DPP4 activity was also reduced in the sera of patients with metastatic prostate cancer relative to patients with localized disease or healthy controls. However, no significant differences in DPP4 serum levels were observed, which established the loss of activity as the result of impaired enzymatic function. Biochemical analysis indicated that reduced activity was the result not of post-translational modifications or allosteric changes, but instead of a low-molecular-weight inhibitor. After we adjusted for age and total prostate-specific antigen, reduced DPP4 activity remained a significant predictor of cancer status. The results of this proof-of-principle study suggest that DPP4 activity might be a potential blood-based indicator of the presence of metastatic cancer of prostatic origin, either by itself or, more likely, as a means to improve the sensitivity and specificity of existing markers.	\N	\N
25063009	When microinvasion cannot be ruled out on core needle biopsy (CNB) in the setting of ductal carcinoma in situ (DCIS), the surgeon must decide whether to perform a sentinel lymph node biopsy (SLNB) at the time of surgery. Up to 10 % of patients with T1mi have nodal disease, but the utility of SLNB in DCIS suspicious for microinvasion (Smic) is unclear. The University of Chicago pathology database was queried for a diagnosis of Smic or definite microinvasion (Mic) on CNB from 2000 to 2014. We analyzed histology, imaging, core needle size, and the use of myoepithelial immunohistochemistry (IHC) markers. We identified 103 women, 72 with Smic and 31 with Mic on CNB. After surgery, 32 % of Smic patients had infiltrating ductal carcinoma (IDC). Seventy-two percent of Smic patients underwent SLNB, with 67 % performed at the initial surgery. SLNB was positive in 6 % and 10 % of Smic and Mic patients, respectively (p = 0.66). Excluding N1mic, the incidence of macrometastatic nodal disease was 1.9 % for Smic patients and 3.3 % for Mic patients (p = 1.00). For Smic patients, IDC was associated with a larger lesion size and smaller CNB needle. In the setting of Smic, grade, necrosis, or presence of a mass did not increase the risk of IDC. In patients with Smic on CNB, the incidence of macrometastatic nodal disease after SLNB is rare. Surgeons may consider omitting SLNB until IDC is definitively confirmed, especially in patients with Smic apart from other high-risk features.	\N	\N
25065742	Mitochondrial DNA (mtDNA) is a genome possessed by mitochondria. Since reactive oxygen species (ROS) are generated during aerobic respiration in mitochondria, mtDNA is commonly exposed to the risk of DNA damage. Mitochondrial disease is caused by mitochondrial dysfunction, and mutations or deletions on mitochondrial tRNA (mt tRNA) genes are often observed in mtDNA of patients with the disease. Hence, the correlation between mt tRNA activity and mitochondrial dysfunction has been assessed. Then, cybrid cells, which are constructed by the fusion of an enucleated cell harboring altered mtDNA with a ρ(0) cell, have long been used for the analysis due to difficulty in mtDNA manipulation. Here, we propose a new method that involves mt tRNA cleavage by a bacterial tRNA-specific ribonuclease. The ribonuclease tagged with a mitochondrial-targeting sequence (MTS) was successfully translocated to the mitochondrial matrix. Additionally, mt tRNA cleavage, which resulted in the decrease of cytochrome c oxidase (COX) activity, was observed.	\N	\N
25076776	Schizophrenia and bipolar disorder are severe neuropsychiatric disorders, affecting about 1% of the population. Identifying endophenotypes in the brains of neuropsychiatric patients is now considered the way to understand the underlying mechanisms and to improve therapeutic outcomes. However, the endophenotypes and brain mechanisms of the disorders remain unknown. We have previously reported that alpha-CaMKII heterozygous knockout mice show abnormal behaviors related to neuropsychiatric disorders. In these mutant mice, almost all neurons in the hippocampal dentate gyrus stay at a pseudo-immature state, which we refer to as "immature dentate gyrus (iDG)." So far, the iDG phenotype and similar behavioral abnormalities have been found in Schnurri-2 knockout, SNAP-25 mutant, and forebrain-specific calcineurin knockout mice. In addition, we found that both chronic fluoxetine treatment and pilocarpine-induced seizures can reverse the maturation state of the mature neurons, resulting in the iDG phenotype in wild-type mice. Such an iDG-like phenomenon was observed in the post-mortem brains from patients with schizophrenia/bipolar disorder. Recent studies suggest that cortex and amygdala of schizophrenia patients are also at a pseudo-immature state. Based on the findings, we proposed that immaturity of certain types of cells in the brain is a potential endophenotype of neuropsychiatric disorders.	\N	\N
25081727	To retrospectively review the safety and clinical efficacy of bevacizumab concomitant with chemotherapy in Chinese patients with advanced non-squamous non-small cell lung cancer (NSNSCLC). Clinical data for 79 patients with NSNSCLC who received bevacizumab concomitant with chemotherapy in Chinese PLA General Hospital from April 28th 2009 to May 5th 2013 were retrospectively reviewed to analyze the clinical efficacy including disease control rate (DCR), overall response rate (ORR), progression-free survival (PFS), overall survival (OS), the Eastern Cooperative Oncology Group (ECOG) score and the safety. The Eastern Cooperative Oncology Group (ECOG) score was 0-2. By the final cutoff date (June 9, 2013), 54 (68.4%) patients had disease progression and 37 (46.8%) died. The ORR was 32.9% and the DCR was 83.5%. The ORR of the first-, second-, and third- or later-line treatments were 51.4%, 25.0% and 12.5%, while the DCR were 94.3%, 80.0% and 70.8%, respectively. The median OS (mOS) and PFS (mPFS) were 13.5 and 5.83 months, respectively. The mOS of patients with the first-, second-, and third- or later-line treatments were 16.2, 10.9 and 8.30 months, while the mPFS were 7.27, 5.90 and 5.17 months, respectively. Chemotherapy-related adverse events included myelosuppression, vomiting, hepatic dysfunction and renal dysfunction, while the common serious bevacizumab-related adverse events were thromboembolic problems, gastrointestinal perforation and reversible posterior leukoencephalopathy syndrome, which could be well managed. Bevacizumab concomitant with chemotherapy is effective and the related toxicity can be well tolerated in Chinese patients with NSNSCLC.	\N	\N
25083284	Diagnosing coeliac disease (CD) can be challenging, despite highly specific autoantibodies and typical mucosal changes in the small intestine. The T-cell response to gluten is a hallmark of the disease that has been hitherto unexploited in clinical work-up. We aimed to develop a new method that directly visualizes and characterizes gluten-reactive CD4+ T cells in blood, independently of gluten challenge, and to explore its diagnostic potential. We performed bead-enrichment of DQ2.5-glia-α1a and DQ2.5-glia-α2 tetramer+ cells in the blood of control individuals, treated (TCD) and untreated patients (UCD). We visualized these cells by flow cytometry, sorted them and cloned them. We assessed their specificity by antigen stimulation and re-staining with tetramers. We detected significantly more gliadin-tetramer+ CD4+ effector memory T cells (TEM) in UCD and TCD patients, compared to controls. Significantly more gliadin-tetramer+ TEM in the CD patients than in controls expressed the gut-homing marker integrin-β7. Quantification of gut-homing, gluten-specific TEM in peripheral blood, visualized with human leukocyte antigen (HLA) -tetramers, may be used to distinguish CD patients from healthy individuals. Easy access to gluten-reactive blood T cells from diseased and healthy individuals may lead to new insights on the disease-driving CD4+ T cells in CD.	\N	\N
25095816	Falls in people with Parkinson's disease (PD) are frequent and recurrent events with devastating and widespread consequences. Despite this, understanding of the predictive and explanatory value of fall risk factors, as well as the development and testing of interventions aimed at reducing falls, are in their infancy. This review focuses on fall prediction and risk factors that are potentially remediable with physical interventions. We show that falls can be predicted with high accuracy using a simple three-step clinical tool. Evidence from recently published randomized controlled trials supports the implementation of balance-challenging exercises in reducing falls. Larger scale trials utilizing technologically advanced monitoring methods will further elucidate those interventions most likely to be cost effective according to individual risk factor profiles.	\N	\N
25097994	Results of surgical treatment of 1220 patients, suffering inguinal hernia, were analyzed. Among the patients there were 810 ageing more than 60 yrs old (main group), from 40 to 59 yrs--410 (control group). There was established, that in patients older than 60 yrs, due to presence of age-related atrophic-dystrophic changes in the inguinal channel muscles, the disease recurrence rate is more than in younger patients. That is why in the inguinal channel hernioplasty the priority must be on the side of alloplastic methods with application of miniinvasive and endoscopic procedures. There was not trustworthy difference between the groups of patients for the rate of intraoperative and early postoperative complications.	\N	\N
25115192	Good prognostic tools for predicting disease progression in early stage prostate cancer (PCa) are still missing. Detection of molecular subtypes, for instance by using microarray gene technology, can give new prognostic information which can assist personalized treatment planning. The detection of new subtypes with validation across additional and larger patient cohorts is important for bringing a potential prognostic tool into the clinic. We used fresh frozen prostatectomy tissue of high molecular quality to further explore four molecular subtype signatures of PCa based on Gene Set Enrichment Analysis (GSEA) of 15 selected gene sets published in a previous study. For this analysis we used a statistical test of dependent correlations to compare reference signatures to signatures in new normal and PCa samples, and also explore signatures within and between sample subgroups in the new samples. An important finding was the consistent signatures observed for samples from the same patient independent of Gleason score. This proves that the signatures are robust and can surpass a normally high tumor heterogeneity within each patient. Our data did not distinguish between four different subtypes of PCa as previously published, but rather highlighted two groups of samples which could be related to good and poor prognosis based on survival data from the previous study.The poor prognosis group highlighted a set of samples characterized by enrichment of ESC, ERG-fusion and MYC + rich signatures in patients diagnosed with low Gleason score,. The other group consisted of PCa samples showing good prognosis as well as normal samples. Accounting for sample composition (the amount of benign structures such as stroma and epithelial cells in addition to the cancer component) was important to improve subtype assignments and should also be considered in future studies. Our study validates a previous molecular subtyping of PCa in a new patient cohort, and identifies a subgroup of PCa samples highly interesting for detecting high risk PCa at an early stage. The importance of taking sample tissue composition into account when assigning subtype is emphasized.	\N	\N
25120773	Hirschsprung's disease (HSCR) is characterized by the absence of enteric ganglion cells along variable regions of the colon. Established theory demonstrates that HSCR is the consequence caused by the abnormal arrest of the migration and differentiation of neural crest-derived stem cells (NCSCs). And retinoid signaling was considered to be involved. We speculated that, HA117, a retinoid-related transcript of a long noncoding RNA (LncRNA), may be involved in the genesis of HSCR. In current research, colon specimens were collected from 25 HSCR patients and grouped into 3 segments: proximal anastomosis, dilated segment and stenotic segment. Real-Time PCR was used to analyze the expression profiles of HA117 and its neighboring gene DPF3 in different colon segments. Fluorescence in situ hybridization (FISH) was employed to detect the distribution of HA117 in the gut wall. Immunohistochemistry was performed to analyze the protein expression of DPF3 in different colon segments. HA117 expression in stenotic segment was higher compared to proximal anastomosis and dilated segment (p < 0.05). Whereas DPF3b mRNA was lower in stenotic segment than that in two other segments (p < 0.05). FISH detected HA117 was distributed in mucosa and muscle layer, mainly present in stenotic segment. Immunohistochemical staining showed that intensive DPF3 staining occurred in proximal anastomosis and the positive staining was hardly observed in stenotic segment. The results suggested that HA117 may be a factor exerting an anti-differentiation or or anti-maturation role in the genesis of HSCR. This gave us a novel cue for better understanding the etiology of HSCR.	\N	\N
25132753	More than 50% of the world population is infected with Helicobacter pylori (H. pylori). The bacterium highly links to peptic ulcer diseases and duodenal ulcer, which was classified as a group I carcinogen in 1994 by the WHO. The pathogenesis of H. pylori is contributed by its virulence factors including urease, flagella, vacuolating cytotoxin A (VacA), cytotoxin-associated gene antigen (Cag A), and others. Of those virulence factors, VacA and CagA play the key roles. Infection with H. pylori vacA-positive strains can lead to vacuolation and apoptosis, whereas infection with cagA-positive strains might result in severe gastric inflammation and gastric cancer. Numerous medicinal plants have been reported for their anti-H. pylori activity, and the relevant active compounds including polyphenols, flavonoids, quinones, coumarins, terpenoids, and alkaloids have been studied. The anti-H. pylori action mechanisms, including inhibition of enzymatic (urease, DNA gyrase, dihydrofolate reductase, N-acetyltransferase, and myeloperoxidase) and adhesive activities, high redox potential, and hydrophilic/hydrophobic natures of compounds, have also been discussed in detail. H. pylori-induced gastric inflammation may progress to superficial gastritis, atrophic gastritis, and finally gastric cancer. Many natural products have anti-H. pylori-induced inflammation activity and the relevant mechanisms include suppression of nuclear factor-κB and mitogen-activated protein kinase pathway activation and inhibition of oxidative stress. Anti-H. pylori induced gastric inflammatory effects of plant products, including quercetin, apigenin, carotenoids-rich algae, tea product, garlic extract, apple peel polyphenol, and finger-root extract, have been documented. In conclusion, many medicinal plant products possess anti-H. pylori activity as well as an anti-H. pylori-induced gastric inflammatory effect. Those plant products have showed great potential as pharmaceutical candidates for H. pylori eradication and H. pylori induced related gastric disease prevention.	\N	\N
25142630	To describe metastatic pattern of uterine leiomyosarcomas (ULMS) and correlate it with clinical and histopathologic parameters. We included 113 women (mean age, 53 years; range, 29 to 72 years) with histopathology-confirmed ULMS from 2000 to 2012. Distribution of metastases was noted from imaging by two radiologists in consensus. Predictors of development of metastases were analyzed with univariate and multivariate analysis. Impact of various clinical and histopathologic parameters on survival was compared using Log-rank test and Cox proportional hazard regression model. Distant metastases were seen in 81.4% (92/113) of the patients after median interval of 7 months (interquartile range, 1 to 21). Lung was most common site of metastases (74%) followed by peritoneum (41%), bones (33%), and liver (27%). Local tumor recurrence was noted in 57 patients (50%), 51 of whom had distant metastases. Statistically significant correlation was noted between local recurrence and peritoneal metastases (p<0.001) and between lung and other common sites of hematogeneous metastases (p<0.05). Age, serosal involvement, local recurrence, and the International Federation of Gynecology and Obstetrics (FIGO) stage were predictive factors for metastases. At the time of reporting, 65% (74/113) of the patients have died; median survival was 45 months. Stage, local recurrence, and age were poor prognostic factors. ULMS metastasizes most frequently to lung, peritoneum, bone, and liver. Local recurrence was associated with peritoneal spread and lung metastases with other sites of hematogeneous metastases. Age, FIGO stage and local recurrence predicted metastatic disease and advanced stage, older age and local recurrence predicted poor outcome.	\N	\N
25148165	The purpose of this study is to compare CT urography (CTU) with unenhanced CT in the evaluation of upper urinary tracts in adults younger than 50 years with asymptomatic microscopic hematuria. In this study, 1516 CTU examinations were reviewed in adults younger than 50 years. Inclusion criteria were no significant prior urologic disease and asymptomatic microscopic hematuria with at least one urinalysis with greater than or equal to 3 RBCs/high-power field and less than or equal to 50 RBCs/high-power field. Upper urinary tract findings on CTU were classified as malignancy-related or non-malignancy-related hematuria and incidental non-hematuria-related findings. A blinded radiologist reviewed the unenhanced images, recording upper urinary tract findings and recommendations for further contrast-enhanced imaging. The modified Wald equation at a 95% CI, the "Rule of Threes" equation, and binomial distribution were used for malignancy-related findings. Four hundred forty-five examinations in 442 patients met inclusion criteria. CTU reports showed zero malignancy-related hematuria findings, 64 non-malignancy-related hematuria findings (62 renal calculi and two others), and 138 incidental non-hematuria-related findings. Unenhanced CT interpretation had a sensitivity of 100% (64/64) and a specificity of 89.2% (337/378). The theoretic risk of an upper urinary tract malignancy is 0-1.1%. CTU added no additional diagnostic benefit versus unenhanced CT in evaluating the upper urinary tracts of adults younger than 50 years with asymptomatic microscopic hematuria. Using only unenhanced CT can reduce radiation and minimize contrast agent-associated risk, with a less than 1.0% risk of missing upper urinary tract hematuria-related malignancy.	\N	\N
25151899	To assess the effects of neoadjuvant chemoradiotherapy on survival outcomes of low rectal cancer after sphincter-preserving or removing surgery. A total of 135 patients with rectal cancer within 10 cm from anal verge after neoadjuvant chemoradiotherapy were enrolled into this retrospective study from 2005 to 2012 at a single institute. There were 79 males and 56 females with a mean age of (58 ± 12) years and an average distance of (5.2 ± 2.1) cm from anal verge. The effects of gender, age, distance of tumor from anal verge, surgical procedure, T-stage downstaging, lateral resection margin and post-treatment lymphatic node status on 3-year disease-free survival (DFS) were examined. The overall 3-year DFS was 85.2% (115/135). Among 95 sphincter-preserving operations, there were anterior resection (n = 79), anterior perineal plane for ultra low anterior resection (APPEAR) technique (n = 12), Hartmann procedure (n = 3) and Parks procedure (n = 1). Among 40 sphincter-removing operations, there were abdominoperineal resection (APR) procedure (n = 39) and intersphincteric resection(ISR) (n = 1). The survival of patients undergoing sphincter-preserving or removing procedures did not differ in 3-year DFS (85.3% (81/95) vs 85.0% (34/40) , χ(2) = 0.000, P = 0.985) . Lateral resection margin and post-treatment lymphatic node status significantly affected DFS. The differential level from anal verge showed a trend of close relationship to 3-year DFS (81.5% (22/27) for 2-3 cm, 82.5% (47/57) for 4-5 cm vs 95.1% (39/41) for 6-7 cm), but without statistic significance (χ(2) = 3.111, 3.522; P = 0.078, 0.061). The survival rate for patients with sphincter-preserving at 6-7 cm from anal verge was significantly higher than that at 4-5 cm (95.0% (38/40) vs 79.5% (31/39) ,χ(2) = 4.227, P = 0.039) , but showed no differences to that with sphincter-removing at 2-3 cm from anal verge (81.0% (17/21),χ(2) = 2.864, P = 0.091) . The multivariate analysis showed that post-treatment lymphatic node status was the only prognostic factor to 3-year DFS (Wald = 4.454, P = 0.035) . Lateral resection margin and post-treatment lymphatic node status play an important role on DFS for patients with low rectal cancer after neoadjuvant chemoradiotherapy. The distance from anal verge is correlated with 3-year disease-free survival. Patients with tumor at 4-5 cm from annal verge can not benefit for survival when they get sphincter-preserving operations.	\N	\N
25155018	Frontotemporal dementia (FTD) is the most common cause of dementia in people under 60 yr of age and is pathologically associated with mislocalization of TAR DNA/RNA binding protein 43 (TDP-43) in approximately half of cases (FLTD-TDP). Mutations in the gene encoding progranulin (GRN), which lead to reduced progranulin levels, are a significant cause of familial FTLD-TDP. Grn-KO mice were developed as an FTLD model, but lack cortical TDP-43 mislocalization and neurodegeneration. Here, we report retinal thinning as an early disease phenotype in humans with GRN mutations that precedes dementia onset and an age-dependent retinal neurodegenerative phenotype in Grn-KO mice. Retinal neuron loss in Grn-KO mice is preceded by nuclear depletion of TDP-43 and accompanied by reduced expression of the small GTPase Ran, which is a master regulator of nuclear import required for nuclear localization of TDP-43. In addition, TDP-43 regulates Ran expression, likely via binding to its 3'-UTR. Augmented expression of Ran in progranulin-deficient neurons restores nuclear TDP-43 levels and improves their survival. Our findings establish retinal neurodegeneration as a new phenotype in progranulin-deficient FTLD, and suggest a pathological loop involving reciprocal loss of Ran and nuclear TDP-43 as an underlying mechanism.	\N	\N
25159901	Previous studies have suggested that long-chain n-3 fatty acids derived from seafood are associated with a lower risk of mortality, CHD and stroke. Whether α-linolenic acid (ALA, 18 : 3n-3), a plant-derived long-chain essential n-3 fatty acid, is associated with a lower risk of these outcomes is unclear. The aim of the present study was to examine the associations of plasma phospholipid and dietary ALA with the risk of mortality, CHD and stroke among older adults who participated in the Cardiovascular Health Study, a cohort study of adults aged ≥ 65 years. A total of 2709 participants were included in the plasma phospholipid ALA analysis and 2583 participants were included in the dietary ALA analysis. Cox regression was used to assess the associations of plasma phospholipid and dietary ALA with the risk of mortality, incident CHD and stroke. In minimally and multivariable-adjusted models, plasma phospholipid ALA was found to be not associated with the risk of mortality, incident CHD or stroke. After adjustment for age, sex, race, enrolment site, education, smoking status, diabetes, BMI, alcohol consumption, treated hypertension and total energy intake, higher dietary ALA intake was found to be associated with a lower risk of total and non-cardiovascular mortality; on comparing the highest quintiles of dietary ALA with the lowest quintiles, the HR for total mortality and non-cardiovascular mortality were found to be 0·73 (95 % CI 0·61, 0·88) and 0·64 (95 % CI 0·52, 0·80), respectively. Dietary ALA was found to be not associated with the risk of cardiovascular mortality, incident CHD or stroke. In conclusion, the results of the present suggest study that dietary ALA, but not plasma phospholipid ALA, is associated with a lower risk of total and non-cardiovascular mortality in older adults.	\N	\N
25176287	Oxygen-enhanced MRI (OE-MRI) biomarkers have potential value in assessment of COPD, but need further evaluation before treatment-induced changes can be interpreted. The objective was to evaluate how OE-MRI parameters of regional ventilation and oxygen uptake respond to standard pharmacological interventions in COPD, and how the response compares to that of gold standard pulmonary function tests. COPD patients (n=40), mean FEV1 58% predicted normal, received single-dose inhaled formoterol 9μg, or placebo, followed by 8 weeks treatment bid with a combination of budesonide and formoterol Turbuhaler(®) 320/9μg or formoterol Turbuhaler(®). OE-MRI biomarkers were obtained, as well as X-ray computed tomography (CT) biomarkers and pulmonary function tests, in a two-center study. An ANCOVA statistical model was used to assess effect size of intervention measurable in OE-MRI parameters of lung function. OE-MRI data were successfully acquired at both study sites. 8-week treatment with budesonide/formoterol significantly decreased lung wash-out time by 31% (p<0.01), decreased the change in lung oxygen level upon breathing pure oxygen by 13% (p<0.05) and increased oxygen extraction from the lung by 58% (p<0.01). Single-dose formoterol increased both lung wash-out time (+47%, p<0.05) and lung oxygenation time (+47%, p<0.05). FEV1 was improved by single-dose formoterol (+12%, p<0.001) and 8 weeks of budesonide/formoterol (+ 18%, p<0.001), consistent with published studies. In COPD, OE-MRI parameters showed response to both single-dose bronchodilatory effects of a β2-agonist, formoterol, and 8-week treatment with an inhaled corticosteroid, budesonide, and the measurements are feasible in a small-scale multi-center trial setting.	\N	\N
25178342	In the last decade, the clinical picture of primary hyperparathyroidism has changed, with the majority of patients being diagnosed while asymptomatic and the "classical" clinical pattern characterized by bone disease, recurrent nephrolithiasis, peptic ulcer disease, neurological or psychiatric disorders being rarely encountered. In this context, most patients have minimal hypercalcemia and small parathyroid adenomas. Not surprisingly, giant parathyroid adenomas have seldom been described in the literature. We herein report three cases of giant parathyroid adenomas weighing more than 30 g and discuss their clinicopathological and therapeutic particularities. We also review the relevant literature, with the principal aim of outlining the rarity of these giant parathyroid adenomas and the issues concerning their diagnosis and treatment.	\N	\N
25179307	To explore if inhibition of vitronectin can be used for the treatment of hepatocellular carcinoma. RNAi technology was used to silence the expression of VTN in HepG2 and SMMC 7721 cells. Change of growth characteristics in these cells was evaluated. VTN silencing does not affect growth characteristics of cancer cells in monolayer cell culture, but could suppress the colonized growth of cells in soft agar. VTN-siRNA suppresses colony formation more than 80% compared with that of control in SMMC7721cells and leads to the inhibition of colony formation of over 70% in HepG2 cells. In addition, VTN silencing decreases the size of tumor xenografts in nude mice, particularly in male mice, with an inhibition rate of 46.6%. VTN plays a significant role in the malignant growth of tumor. Inhibition of VTN could potentially be applied for the treatment of hepatocellular carcinoma.	\N	\N
25182131	The difficulties arising from association analysis with rare variants underline the importance of suitable reference population cohorts, which integrate detailed spatial information. We analyzed a sample of 1684 individuals from Western France, who were genotyped at genome-wide level, from two cohorts D.E.S.I.R and CavsGen. We found that fine-scale population structure occurs at the scale of Western France, with distinct admixture proportions for individuals originating from the Brittany Region and the Vendée Department. Genetic differentiation increases with distance at a high rate in these two parts of Northwestern France and linkage disequilibrium is higher in Brittany suggesting a lower effective population size. When looking for genomic regions informative about Breton origin, we found two prominent associated regions that include the lactase region and the HLA complex. For both the lactase and the HLA regions, there is a low differentiation between Bretons and Irish, and this is also found at the genome-wide level. At a more refined scale, and within the Pays de la Loire Region, we also found evidence of fine-scale population structure, although principal component analysis showed that individuals from different departments cannot be confidently discriminated. Because of the evidence for fine-scale genetic structure in Western France, we anticipate that rare and geographically localized variants will be identified in future full-sequence analyses.	\N	\N
25185440	To estimate the prevalence and risk factors of dry eye disease (DED) in a female cohort in the UK. Population-based cross-sectional association study of 3824 women from the TwinsUK cohort aged 20-87 years. A questionnaire was used to evaluate DED and several risk factors. Binary logistic regression, corrected for age, was used to examine the association between DED and risk factors. 9.6% of women had a DED diagnosis and concomitant use of artificial tears, and 20.8% experienced DED symptoms in the past 3 months. Risk factors that were significantly associated with DED were age, asthma, eczema, the presence of any allergy, cataract surgery, rheumatoid arthritis, osteoarthritis, migraine and stroke. The highest effect sizes were found with depression, pelvic pain, irritable bowel syndrome and chronic widespread pain syndrome (all p<0.0005). Subjects with DED symptoms scored significantly lower on self-perceived health, compared with controls (p=0.001). DED is common and increases with age within this cohort of female twins. We confirmed established risk factors for the first time in a British population, and found important risk factors that might relate to an underlying aetiology involving chronic pain predisposition or somatisation.	\N	\N
25187623	The phenomenon that adverse environmental exposures in early life are associated with increased susceptibilities for many adult, particularly metabolic diseases, is now referred to as 'developmental origins of health and disease (DOHAD)' or 'Barker' hypothesis. Fetal overnutrition and undernutrition have similar long-lasting effects on the setting of the neuroendocrine control systems, energy homeostasis, and metabolism, leading to life-long increased morbidity. There are sensitive time windows during early development, where environmental cues can program persistent epigenetic modifications which are generally assumed to mediate these gene-environment interactions. Most of our current knowledge on fetal programing comes from animal models and epidemiological studies in humans, in particular the Dutch famine birth cohort. In industrialized countries, there is more concern about adverse long-term consequences of fetal overnutrition, i.e. by exposure to gestational diabetes mellitus and/or maternal obesity which affect 10-20% of pregnancies. Epigenetic changes due to maternal diabetes/obesity may predispose the offspring to develop metabolic disease later in life and, thus, transmit the adverse environmental exposure to the next generation. This vicious cycle could contribute significantly to the worldwide metabolic disease epidemics. In this review article, we focus on the epigenetics of an adverse intrauterine environment, in particular gestational diabetes, and its implications for the prevention of complex disease.	\N	\N
25197402	After 3 months of combination treatment using interferon α-2a and Ribavirin, a case of 59-year-old female patient with chronic viral hepatitis C demonstrated symptoms such as headache, dizziness accompanied by nausea, vomiting, dry cough, breathing difficulty, and shortness of breath. Dynamic electrocardiogram showed occasional atrial premature beats, paroxysmal tachycardia, and abnormal ST-T (T wave inversion and prolongation of the QT interval). Ambulatory blood pressure indicated that mean blood pressure was elevated than before. Myocardial radionuclide scan showed focal myocardial ischemia in left ventricular inferior wall. Pulmonary function tests showed that pulmonary diffusion function was decreased, indicating the possibility of interstitial pneumonia. The patient had no history of coronary heart disease or chest X-ray abnormalities before medication, but had hypertensive medical history for 8 years with good blood pressure control. After withdrawal of antiviral drugs, symptoms such as dry cough, breathing difficulty and T wave inversion were gradually relieved. This case indicated that myocardial ischemia and pulmonary lesions were associated with the application of pegylated interferon α-2a.	\N	\N
25204216	Acquired immunodeficiency syndrome (AIDS) is a major health problem worldwide. The number of infected people is increasing daily. Knowledge and awareness toward prevention and control of the disease is necessary among both educated and illiterate people. This study is aimed at assessing the knowledge and awareness about human immunodeficiency virus (HIV)/AIDS among undergraduate students studying in a technical institute in Gorakhpur, Uttar Pradesh, India. A community-based cross-sectional study was conducted among youths aged 15-30 years studying in a technical institution in Gorakhpur. Data were collected using a semistructured questionnaire developed with the help of existing literature, from 250 participants (students). The main source of information was the television; knowledge about the difference between HIV/AIDS was satisfactory. The findings showed that the knowledge about modes of prevention (blood checkup, needle/syringe sterilization) was satisfactory. There were several misconceptions about the modes of transmission of the disease, such as through mosquito bites, eating/drinking, and kissing. The knowledge of the study population was satisfactory, and there is a need for innovation and comprehensive education to impart better knowledge and understanding about HIV/AIDS.	\N	\N
25204587	Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disorder involving both upper and lower motor neurons in the cerebral cortex, brainstem and spinal cord. Vascular endothelial growth factor (VEGF) was originally described as a factor with a regulatory role in vascular growth and development, and now it also functions as a neurotrophic factor protecting motoneurons from insults such as oxidative stress, hypoxia and glutamate-excitotoxicity, but the role of VEGF in ALS is still unclear. The aim of this study is to measure cerebrospinal fluid (CSF) and serum VEGF levels in patients with ALS, and to investigate whether there are correlations between CSF and serum VEGF levels and clinical parameters of the disease and whether VEGF has a prognostic and evaluating potential for ALS. Results showed that VEGF levels were found to increase significantly in CSF and serum in ALS patients studied; they were positively and significantly correlated with the disease duration in ALS patients and inversely and significantly correlated with disease progression rate (DPR) of ALS patients. Moreover, CSF and serum from ALS patients with long duration and slow disease progression rate revealed higher VEGF levels as compared to ALS patients with short duration and rapid disease progression rate. In conclusion, VEGF upregulation may indicate an activation of compensatory responses in ALS which may reflect or in fact account for increased duration and slow disease progression rate. We propose that VEGF may be a useful biomarker having the prognostic and evaluating potential for ALS.	\N	\N
25216396	Whether carotid artery stenosis predicts stroke after noncardiac surgery remains unknown. We therefore tested the primary hypothesis that degree of carotid artery stenosis is associated with in-hospital stroke or 30-day all-cause mortality after noncardiac surgery. As carotid artery stenosis is also a marker for cardiovascular disease, our secondary hypothesis was that degree of carotid artery stenosis is associated with postoperative myocardial injury. We included adults who had noncardiac, noncarotid surgery at Cleveland Clinic from 2007 to 2011 and had carotid duplex ultrasound performed either within 6 months before or 1 month after surgery. Internal carotid artery peak systolic velocity (ICA PSV) was used as a measure of carotid artery stenosis severity. A multivariate (i.e., multiple outcomes per patient) generalized estimating equation model was used to assess the association between highest ICA PSV and the composite of stroke and 30-day mortality after adjusting for predefined potentially confounding variables. Of 2,110 patients included, 112 (5.3%) died within 30 days and 54 (2.6%) suffered postoperative in-hospital stroke. ICA PSV was not associated with this composite outcome (odds ratio of 1.0 [95% confidence interval: 0.99, 1.02] for a 10-unit increase, P = 0.55). ICA PSV was also not associated with postoperative myocardial injury (odds ratio 1.00 [0.99, 1.02], P = 0.49). This cohort represents a high-risk population, as carotid duplex examinations were likely prompted by neurological symptoms. There was nonetheless no association between carotid artery stenosis and perioperative stroke or 30-day mortality after noncardiac surgery.	\N	\N
25222481	Thrombocytopenia (defined as a platelet count <150×10(9)) is a well-known complication in patients with liver cirrhosis and has been observed in 76% to 85% of patients. Significant thrombocytopenia (platelet count <50×10(9) to 75×10(9)) occurs in approximately 13% of patients with cirrhosis. Thrombocytopenia can negatively impact the care of patients with severe liver disease by potentially interfering with diagnostic and therapeutic procedures. Multiple factors can contribute to the development of thrombocytopenia including splenic platelet sequestration, immunological processes, bone marrow suppression by chronic viral infection, and reduced levels or activity of the hematopoietic growth factor thrombopoietin. The present review focuses on the etiologies and management options for severe thrombocytopenia in the setting of advanced liver disease.	\N	\N
25225437	Cabozantinib (XL184), an oral inhibitor of multiple receptor tyrosine kinases such as MET and VEGFR2, was evaluated in a phase II nonrandomized expansion study in castration-resistant prostate cancer (CRPC). Patients received open-label cabozantinib at daily starting doses of 100 mg or 40 mg until disease progression or unacceptable toxicity. The primary end point was bone scan response, defined as ≥ 30% reduction in bone scan lesion area. Other efficacy end points included overall survival, pain, analgesic use, and biomarkers. One hundred forty-four patients sequentially enrolled in either a 100-mg (n = 93) or 40-mg (n = 51) study cohort. Ninety-one patients (63%) had a bone scan response, often by week 6. Treatment resulted in clinically meaningful pain relief (57% of patients) and reduction or discontinuation of narcotic analgesics (55% of patients), as well as improvements in measurable soft tissue disease, circulating tumor cells, and bone biomarkers. Improvements in each of these outcomes were observed in both cohorts: bone scan response in 73% and 45%, respectively; reductions in measurable soft tissue disease in 80% and 79%, respectively. Median overall survival was 10.8 months for the entire population. Most common grade 3 or 4 adverse events were fatigue (22%) and hypertension (14%). Fewer dose reductions because of toxicity were required in the 40-mg group. The evidence suggests that cabozantinib has clinically meaningful activity in CRPC. Cabozantinib resulted in improvements in bone scans, pain, analgesic use, measurable soft tissue disease, circulating tumor cells, and bone biomarkers. Taken together, these phase II observations warrant further development of cabozantinib in prostate cancer.	\N	\N
25230241	Chagas disease (CD) has been associated with an elevated risk of stroke, but current data are conflicting and prospective controlled studies are lacking. We performed a systematic review and meta-analysis examining the association between stroke and CD. Pubmed, Embase, Cochrane Central, Latin American database, and unpublished data were searched with the use of the following terms: ("Chagas" OR "American trypanosomiasis") AND ("dilated" OR "ischemic" OR "idiopathic" OR "nonChagasic" OR "stroke" OR "cerebrovascular"). We included studies that reported prevalence or incidence of stroke in a CD group compared with a non-CD control group. Odds ratios (ORs) and their 95% confidence intervals (CIs) were computed with the use of a random-effects model. A total of 8 studies and 4,158 patients were included, of whom 1,528 (36.7%) had CD. Risk of stroke was elevated in the group of patients with CD (OR 2.10, 95% CI 1.17-3.78). Similar results were observed in a subanalysis of cardiomyopathy patients (OR 1.74, 95% CI 1.02-3.00) and in sensitivity analysis with removal of each individual study. Furthermore, exclusion of studies at higher risk for bias also yielded consistent results (OR 1.70, 95% CI 1.06-2.71). Subanalysis restricted to studies that included patients with the indeterminate form found no significant difference in the stroke prevalence between CD and non-CD patients (OR 3.10, 95% CI 0.89-10.77). CD is significantly associated with cerebrovascular events, particularly among patients with cardiomyopathy. These findings underline the need for prospective controlled studies in patients with Chagas cardiomyopathy to ascertain the prognostic significance of cerebrovascular events and to evaluate the role of therapeutic anticoagulation in primary prevention.	\N	\N
25231249	Drug-induced liver injury (DILI) is a major safety concern during drug development and remains one of the main reasons for withdrawal of drugs from the market. Although it is crucial to develop methods that will detect potential hepatotoxicity of drug candidates as early and as quickly as possible, there is still a lack of sensitive and specific biomarkers for DILI that consequently leads to a scarcity of reliable hepatotoxic data. Hence, in this study, we assessed characteristic molecular signatures in rat liver treated with drugs (pyrazinamide, ranitidine, enalapril, carbamazepine and chlorpromazine) that are known to cause DILI in humans. Unsupervised hierarchical clustering analysis of transcriptome changes induced by DILI-causing drugs resulted in three different subclusters on dendrogram, i.e., hepatocellular, cholestatic and mixed type of DILI at early time points (2 days), and multiclassification analysis suggested 31 genes as discernible markers for each DILI pattern. Further analysis for characteristic molecular signature of each DILI pattern provided a molecular basis for different modes of DILI action. A proteomics study of the same rat livers was used to confirm the results, and the two sets of data showed 60 matching classifiers. In conclusion, the data of different DILI-causing drug treatments from genomic analysis in a rat model suggest that DILI-specific molecular signatures can discriminate different patterns of DILI at an early exposure time point, and that they provide useful information for mechanistic studies that may lead to a better understanding of the molecular basis of DILI.	\N	\N
25297522	Ebola viruses and Marburg viruses include some of the most virulent and fatal pathogens known to humans. These viruses cause severe haemorrhagic fevers, with case fatality rates in the range 25-90%. The diagnosis of filovirus using formalin-fixed tissues from fatal cases poses a significant challenge. The most characteristic histopathological findings are seen in the liver; however, the findings overlap with many other viral and non-viral haemorrhagic diseases. The need to distinguish filovirus infections from other haemorrhagic fevers, particularly in areas with multiple endemic viral haemorrhagic agents, is of paramount importance. In this review we discuss the current state of knowledge of filovirus infections and their pathogenesis, including histopathological findings, epidemiology, modes of transmission and filovirus entry and spread within host organisms. The pathogenesis of filovirus infections is complex and involves activation of the mononuclear phagocytic system, with release of pro-inflammatory cytokines, chemokines and growth factors, endothelial dysfunction, alterations of the innate and adaptive immune systems, direct organ and endothelial damage from unrestricted viral replication late in infection, and coagulopathy. Although our understanding of the pathogenesis of filovirus infections has rapidly increased in the past few years, many questions remain unanswered.	\N	\N
25302175	Cervical cancer is a worldwide disease that constitutes a significant public health problem, especially in developing countries, not only due to its high incidence but also because the most affected population comprises women who belong to marginalized socio-economic classes. Clinical and molecular research has identified immunological impairment in squamous intraepithelial cervical lesions and cervical cancer patients. Human Papillomavirus (HPV) has several mechanisms for avoiding the immune system: it down-regulates the expression of interferon and upregulates interleukin (IL)-10 and transforming growth factor (TGF)-β1 to produce a local immunosuppressive environment, which, along with altered tumor surface antigens, forms an immunosuppressive network that inhibits the antitumor immune response. In this review we analyzed the available data on several deregulated cellular immune functions in patients with NIC I, NIC II and NIC III and cervical cancer. The effects of immunosuppressive cytokines on innate immune response, T-cell activation and cellular factors that promote tumor cell proliferation in cervical cancer patients are summarized. We discuss the functional consequences of HPV E2, E6, and E7 protein interactions with IL-10 and TGF-β1 promoters in the induction of these cytokines and postulate its effect on the cellular immune response in squamous intraepithelial cervical lesions and cervical cancer patients. This review provides a comprehensive picture of the immunological functions of IL-10 and TGF-β1 in response to HPV in humans.	\N	\N
25305425	Vascular blowout syndrome is a well-known, life-threatening condition complicating advanced-stage head and neck malignancies but has rarely been reported in the gynecologic oncology realm in association with the femoral circulation. A 50-year-old woman with metastatic vulvar squamous cell carcinoma presented with left threatened femoral arterial blowout, secondary to an exophytic neoplastic mass originating from the left inguinal lymph nodes. Bland embolization of the tumor as well as 3 vessel covered stent revascularization was successfully performed with excellent tumor devascularization and reinstitution of arterial integrity. Successful devascularization of the tumor, with no non-target embolization was achieved, with excellent apposition and deployment of 3 covered stents in the femoral artery bifurcation. We present a unique case of threatened femoral artery blowout syndrome in the setting of metastatic vulvar carcinoma requiring various endovascular techniques for palliation. These endovascular techniques can be invaluable in minimally invasive palliation of advanced stage neoplasms abutting the iliofemoral circulation.	\N	\N
25312087	Despite the pressing need for novel cancer treatments, our improved understanding of tumor biology is not being successfully translated into better therapies. Here we present a lentiviral vector that enables in vivo validation of cancer therapeutic targets when combined with existing cancer animal models that faithfully reproduce the natural history of human disease. Unlike the conventional genetic approaches with targeted alleles, the outlined experimental strategy could be used to assess the preclinical efficacy of a growing number of putative therapeutic hits in a rapid and cost-effective manner.	\N	\N
25313751	There is a rising trend in the incidence of (colorectal carcinoma) colorectal cancer (CRC) in India. Nuclear factor kappa B (NFkB) is a transcription factor which belongs to the Rel family. It has an impact on phenomena such as apoptosis, tumor progression and differentiation. (1) To evaluate the grade and stage in 50 cases of colorectal carcinoma. (2) To evaluate the NFkB translocation into the nucleus of the cells. (3) To compare the benign and malignant areas with the degree of NFkB translocation and compare the translocation with the grade and pathological stage. The grade and stage of the tumors was evaluated. NFkB staining was performed on the tissues. The results of the immunostaining were analyzed semi quantitatively as a percentage of positive cells. Statistical Package for Social Sciences 13.0 statistical package program (SPSS, Lead Technologies Inc, USA) for windows was used. Correlation was carried out using the Pearson's correlation co-efficient and the Chi-square test. There were 29 males (58%) and 21 females (42%). Most of the cases were well-differentiated adenocarcinomas (58%). There was a significant difference between NFkB translocation in the epithelial cells and lymphocytes in the benign and malignant areas (P - 0.04 and P - 0.001 respectively). There was a significant correlation between the grade of NFkB staining in the malignant epithelial cells with the tumor and nodal status (P - 0.001 and P - 0.001). It is likely that NFkB is an important factor in the pathogenesis of CRC. Further studies including therapeutic intervention using strategies which prevent activation of NFkB in colorectal carcinoma patients will tell if we could alter the course of the disease favorably.	\N	\N
25320726	Methimazole and propylthiouracil have been used in the management of hyperthyroidism for more than half a century. However, hepatotoxicity is one of the most deleterious side effects associated with these medications. The mechanism(s) of hepatic injury induced by antithyroid agents is not fully recognized yet. Furthermore, there are no specific tools for predicting the occurrence of hepatotoxicity induced by these drugs. The purpose of this article is to give an overview on possible susceptibility factors in liver injury induced by antithyroid agents. Age, gender, metabolism characteristics, alcohol consumption, underlying diseases, immunologic mechanisms, and drug interactions are involved in enhancing antithyroid drugs-induced hepatic damage. An outline on the clinically used treatments for antithyroid drugs-induced hepatotoxicity and the potential therapeutic strategies found to be effective against this complication are also discussed.	\N	\N
25323223	Pneumococcal conjugated vaccines (PCVs) have shown protection against invasive pneumococcal disease by vaccine serotypes, but an increase in non-vaccine serotype disease has been observed. Type-specific effects on clinical manifestation need to be explored. Clinical data from 2096 adults and 192 children with invasive pneumococcal disease were correlated to pneumococcal molecular serotypes. Invasive disease potential for pneumococcal serotypes were calculated using 165 invasive and 550 carriage isolates from children. The invasive disease potential was lower for non-PCV13 compared to vaccine-type strains. Patients infected with non-PCV13 strains had more underlying diseases, were less likely to have pneumonia and, in adults, tended to have a higher mortality. Furthermore, patients infected with pneumococci belonging to clonal serotypes only expressing non-PCV13 capsules had a higher risk for septicaemia and mortality. PCV vaccination will probably lead to a decrease in invasive pneumococcal disease but an alteration in the clinical manifestation of invasive pneumococcal disease. Genetic lineages causing invasive pneumococcal disease in adults often express non-vaccine serotypes, which can expand after vaccination with an increased risk of infection in patients with underlying diseases.	\N	\N
25326379	Ubiquitin C-terminal hydrolase L1 (UCH-L1) is a deubiquitinating enzyme that is highly expressed in neurons. A possible role for UCH-L1 in neurodegeneration has been highlighted because of its presence in Lewy bodies associated with Parkinson disease and neurofibrillary tangles observed in Alzheimer disease. UCH-L1 exists in two forms in neurons, a soluble cytoplasmic form (UCH-L1(C)) and a membrane-associated form (UCH-L1(M)). Alzheimer brains show reduced levels of soluble UCH-L1(C) correlating with the formation of UCH-L1-immunoreactive tau tangles, whereas UCH-L1(M) has been implicated in α-synuclein dysfunction. Given these reports of divergent roles, we investigated the properties of UCH-L1 membrane association. Surprisingly, our results indicate that UCH-L1 does not partition to the membrane in the cultured cell lines we tested. Furthermore, in primary cultured neurons, a proportion of UCH-L1(M) does partition to the membrane, but, contrary to a previous report, this does not require farnesylation. Deletion of the four C-terminal residues caused the loss of protein solubility, abrogation of substrate binding, increased cell death, and an abnormal intracellular distribution, consistent with protein dysfunction and aggregation. These data indicate that UCH-L1 is differently processed in neurons compared with clonal cell lines and that farnesylation does not account for the membrane association in neurons.	\N	\N
25332150	We conducted this pilot randomized clinical trial to determine the feasibility of a large clinical trial aimed at testing whether early use of catheter ablation of ventricular tachycardia (VT) is superior to antiarrhythmic medications at reducing mortality. Patients were enrolled at 4 sites if they had ischemic heart disease, an implantable cardioverter defibrillator (ICD), and received ≥1 ICD shock or ≥3 antitachycardia pacing therapies for VT. Patients were randomized to 2 arms: (1) antiarrhythmic medication (n = 14) and (2) catheter ablation (n = 13); patients were followed at 3 and 6 months. Endpoints included recurrent VT, time to first ICD therapy for VT, and death. Of 243 screened patients, 27 were enrolled. Main reasons for screen failures were: (1) patient was already on an antiarrhythmic medication (88 [41%]), (2) VT due to a reversible cause (23 [11%]), and (3) incessant VT (20 [9%]). Fourteen patients had recurrent VT, 8 (62%) in the ablation arm and 6 (43%) in the antiarrhythmic medication arm. Median time to recurrent VT was 75 days (25th, 75th: 51, 89) in the ablation arm and 57 days (30, 145) in the antiarrhythmic arm. Four patients died, 2 in each arm. This clinical trial shows that most patients in clinical practice have already failed antiarrhythmic drug therapy before catheter ablation is considered, and the VT recurrence rates and death in these patients are high. For a large clinical trial to be feasible, factors limiting early consideration of catheter ablation need to be identified and addressed.	\N	\N
25336691	To evaluate the relevance between lumican expression patterns and the clinical course of patients with pancreatic ductal adenocarcinoma (PDAC), and to investigate the role of lumican in PDAC progression. One hundred thirty-one patient tumors were chosen for tissue microarray staining, and Cox regression analysis was used to test the associations between lumican expression and clinical, pathologic, and oncologic outcomes in all patients. Primary PDAC cells and recombinant human lumican protein were used to establish a working model to mimic the in vivo interactions between stromal lumican and PDAC cells. Using this model, we tested the effects of lumican on EGFR signaling via Akt and hypoxia-inducible factor-1α (HIF1α) and its subsequent influence on glucose consumption, lactate production, intracellular ATP, and apoptotic cell death. Lumican was present in the stroma surrounding PDAC cells in roughly one-half of primary tumors and the direct xenografts. Patients with stromal lumican were associated with a profound reduction in metastatic recurrence after surgery and 3-fold longer survival than patients without stromal lumican. In PDAC cells, extracellular lumican reduced EGFR expression and phosphorylation through enhanced dimerization and internalization of EGFR and the resultant inhibition of Akt kinase activity. Lumican also reduced HIF1α expression and activity via Akt. PDAC cells with enhanced HIF1α activity were resistant to lumican-induced inhibition of glucose consumption, lactate production, intracellular ATP, and apoptosis. There is a positive association between stromal lumican in primary PDAC tumors and prolonged survival after tumor resection. Lumican plays a restrictive role in EGFR-expressing pancreatic cancer progression.	\N	\N
25348595	Bioorthogonal cleavable linkers are attractive building blocks for compounds that can be manipulated to study biological and cellular processes. Sodium dithionite sensitive azobenzene-containing (Abc) peptides were applied for the temporary stabilization of recombinant MHC complexes, which can then be employed to generate libraries of MHC tetramers after exchange with a novel epitope. This technology represents an important tool for high-throughput studies of disease-specific T cell responses.	\N	\N
25348708	Papillary squamous cell carcinoma (PSCC) of the uterine cervix is difficult to diagnose due to its rarity and limited data regarding its clinical behavior. We attempted to assess the degree of stromal invasion using magnetic resonance imaging (MRI) and evaluate possible treatments for this lesion in view of its clinical behavior. We analyzed 28 cases of PSCC diagnosed on the colposcopic selective biopsies. We studied the rate of accuracy of diagnoses of the colposcopic selective biopsies compared with the final diagnoses, and compared the rate of stromal invasion between the MRI and pathological findings while focusing on surgical methods and the clinical prognosis. Of the 28 patients, only 12 exhibited true PSCC. The other 16 patients were ultimately diagnosed with SCC or adenosquamous carcinoma based on the finding of the surgical specimens and exhibited relatively poor prognoses. Among the 12 true PSCC cases, the rate of diagnostic accuracy of stromal invasion (with or without) was only 58% (7/12) on the colposcopic selective biopsies. However, we were able to predict the presence of stromal invasion (microscopic borderline: approximately 3 mm) before surgery using MRI. None of the 10 patients treated with radical surgery displayed lymph node metastases. In addition, all 12 study patients exhibited no recurrence (mean: 49 months) and survived. MRI can be used to detect preinvasive and microinvasive disease before surgery. It is possible to select a less invasive surgical method than radical surgery in cases of preinvasive and microinvasive PSCC in view of the indolent clinical behavior of this disease.	\N	\N
25348855	This perspective discusses the report by Pinsky and colleagues, which addresses whether noncalcified pulmonary nodules identified on CT screening carry short- and long-term risk for lung cancer. We are facing challenges related to distinguishing a large majority of benign nodules from malignant ones and among those a majority of aggressive from indolent cancers. Key questions in determining individual probabilities of disease, given their history, findings on CT, and upcoming biomarkers of risk, remain most challenging. Reducing the false positives associated with current low-dose computed tomography practices and identification of individuals who need therapy and at what time during tumor surveillance could reduce costs and morbidities associated with unnecessary interventions.	\N	\N
25359996	To determine whether the prescription of co-trimoxazole with an angiotensin converting enzyme inhibitor or angiotensin receptor blocker is associated with sudden death. Population based nested case-control study. Ontario, Canada, from 1 April 1994 to 1 January 2012. Ontario residents aged 66 years or older treated with an angiotensin converting enzyme inhibitor or angiotensin receptor blocker. Cases were those who died suddenly shortly after receiving an outpatient prescription for one of co-trimoxazole, amoxicillin, ciprofloxacin, norfloxacin, or nitrofurantoin. Each case was matched with up to four controls on age, sex, chronic kidney disease, and diabetes. Odds ratio for the association between sudden death and exposure to each antibiotic relative to amoxicillin, after adjustment for predictors of sudden death according to a disease risk index. Of 39,879 sudden deaths, 1027 occurred within seven days of exposure to an antibiotic and were matched to 3733 controls. Relative to amoxicillin, co-trimoxazole was associated with an increased risk of sudden death (adjusted odds ratio 1.38, 95% confidence interval 1.09 to 1.76). The risk was marginally higher at 14 days (adjusted odds ratio 1.54, 1.29 to 1.84). This corresponds to approximately three sudden deaths within 14 days per 1000 co-trimoxazole prescriptions. Ciprofloxacin (a known cause of QT interval prolongation) was also associated with an increased risk of sudden death (adjusted odds ratio 1.29, 1.03 to 1.62), but no such risk was observed with nitrofurantoin or norfloxacin. In older patients receiving angiotensin converting enzyme inhibitors or angiotensin receptor blockers, co-trimoxazole is associated with an increased risk of sudden death. Unrecognized severe hyperkalemia may underlie this finding. When appropriate, alternative antibiotics should be considered in such patients.	\N	\N
25372658	In March 2014, the World Health Organization was notified of an outbreak of Zaire ebolavirus in a remote area of Guinea. The outbreak then spread to the capital, Conakry, and to neighboring countries and has subsequently become the largest epidemic of Ebola virus disease (EVD) to date. From March 25 to April 26, 2014, we performed a study of all patients with laboratory-confirmed EVD in Conakry. Mortality was the primary outcome. Secondary outcomes included patient characteristics, complications, treatments, and comparisons between survivors and nonsurvivors. Of 80 patients who presented with symptoms, 37 had laboratory-confirmed EVD. Among confirmed cases, the median age was 38 years (interquartile range, 28 to 46), 24 patients (65%) were men, and 14 (38%) were health care workers; among the health care workers, nosocomial transmission was implicated in 12 patients (32%). Patients with confirmed EVD presented to the hospital a median of 5 days (interquartile range, 3 to 7) after the onset of symptoms, most commonly with fever (in 84% of the patients; mean temperature, 38.6°C), fatigue (in 65%), diarrhea (in 62%), and tachycardia (mean heart rate, >93 beats per minute). Of these patients, 28 (76%) were treated with intravenous fluids and 37 (100%) with antibiotics. Sixteen patients (43%) died, with a median time from symptom onset to death of 8 days (interquartile range, 7 to 11). Patients who were 40 years of age or older, as compared with those under the age of 40 years, had a relative risk of death of 3.49 (95% confidence interval, 1.42 to 8.59; P=0.007). Patients with EVD presented with evidence of dehydration associated with vomiting and severe diarrhea. Despite attempts at volume repletion, antimicrobial therapy, and limited laboratory services, the rate of death was 43%.	\N	\N
25375073	As of October 29, 2014, a total of 6,454 Ebola virus disease (Ebola) cases had been reported in Liberia by the Liberian Ministry of Health and Social Welfare, with 2,609 deaths. Although the national strategy for combating the ongoing Ebola epidemic calls for construction of Ebola treatment units (ETUs) in all 15 counties of Liberia, only a limited number are operational, and most of these are within Montserrado County. ETUs are intended to improve medical care delivery to persons whose illnesses meet Ebola case definitions, while also allowing for the safe isolation of patients to break chains of transmission in the community. Until additional ETUs are constructed, the Ministry of Health and Social Welfare is supporting development of community care centers (CCCs) for isolation of patients who are awaiting Ebola diagnostic test results and for provision of basic care (e.g., oral rehydration salts solutions) to patients confirmed to have Ebola who are awaiting transfer to ETUs. CCCs often have less bed capacity than ETUs and are frequently placed in areas not served by ETUs; if built rapidly enough and in sufficient quantity, CCCs will allow Ebola-related health measures to reach a larger proportion of the population. Staffing requirements for CCCs are frequently lower than for ETUs because CCCs are often designed such that basic patient needs such as food are provided for by friends and family of patients rather than by CCC staff. (It is customary in Liberia for friends and family to provide food for hospitalized patients.) Creation of CCCs in Liberia has been led by county health officials and nongovernmental organizations, and this local, community-based approach is intended to destigmatize Ebola, to encourage persons with illness to seek care rather than remain at home, and to facilitate contact tracing of exposed family members. This report describes one Liberian county's approach to establishing a CCC.	\N	\N
25378846	The world-wide use of fireworks with their consequent detrimental effect on the air quality is widely recognized with elevated ambient air levels of particulate matter and its several metallic components and gases identified in several studies carried out during such events. Exposed individuals may be at risk following inhalation of such produced pollutants. This review focuses on the impact of fireworks on air quality and the potential effect of fireworks on the respiratory system of healthy individuals as well as those suffering from underlying respiratory diseases, particularly asthma and chronic obstructive pulmonary disease (COPD). This applies not only to spectators including children but also to pyrotechnicians themselves. An extensive Medline search revealed that a strong evidence of the impact of fireworks on respiratory health is lacking in susceptible as well as healthy individuals with no formal studies on COPD or asthma, other than a few case reports in the latter. The implementation of global strategies to control the use of fireworks and hence improve air quality could possibly reduce their likely detrimental effect on human respiratory health in exposed individuals, but clearly a more targeted research is needed.	\N	\N
25380207	In this paper a review of the researches on the role of Escherichia coli strain Nissle 1917 (EcN) in gastrointestinal diseases was presented. EcN is a non-pathogenic strain of the Enterobacteriaceae family, which has probiotic properties. In a number of studies conducted among humans and  experimental animals the application of EcN in treatment of gastrointestinal diseases was observed. Most studies about EcN has been devoted to this organism efficacy in ulcerative colitis treatment. Comparable results were obtained, by citied authors, in the treatment (sustaining remission) of EcN and mesalazine in ulcerative colitis. Moreover, this probiotic therapy, compared to placebo, contributes to obtaining a faster remission and improvement of intestinal histopathology. The use of EcN in Crohn's disease has not been the subject of as many studies as in the case of ulcerative colitis. Assessing the importance of EcN in treatment of other gastrointestinal disorders, authors of the studies observed, that in patients with irritable bowel syndrome, who receiving this probiotic there was a pain, nausea and bloating reduction. In studies conducted among children a positive impact of EcN in prevention and treatment of diarrhea was demonstrated. Similar results were obtained in studies conducted in experimental animals. Based on the presented review it can be concluded that the strain of Escherichia coli Nissle 1917 is useful in treatment of gastrointestinal diseases, especially in treatment of ulcerative colitis. This probiotic may constitute a part of treatment of irritable bowel syndrome and diarrhea. The effectiveness of this strain in treatment of Crohn's disease is not clearly established and further research are require.	\N	\N
25385258	The objective of this meta-analysis was to determine the association of the apolipoprotein E (ApoE) gene with exceptional longevity (EL) (i.e., reaching 100+ years) by identifying possible unequal distribution of alleles/genotypes in the common variants ε2, ε3, and ε4 among centenarians and younger population. The association of ApoE with EL was analyzed in a total of 2776 centenarians (cases) and 11,941 younger controls (from 13 case-control studies) using the chi-squared test with the Yates correction. We conducted combined and separate analyses for all ethnic groups studied in the literature (Caucasian and Asian). The main result for all ethnic groups combined was that the likelihood of reaching EL was negatively associated with ε4 allele carriage [pooled odds ratio (OR)=0.43; 95% confidence interval (CI) 0.36, 0.50; p<0.001] and with ε4/ε4 (OR=0.18; 95% CI 0.08, 0.39; p<0.001), ε3/ε4 (OR=0.44; 95% CI 0.37, 0.53; p<0.001) and ε2/ε4 genotypes (OR=0.48; 95% CI 0.31, 0.74; p<0.001). In contrast, the ε2/ε3 genotype was positively associated with EL (OR=1.35; 95% CI 1.06, 1.72; p=0.017). When compared with the ε3 allele, the ε2 allele was not associated with increased odds of EL (OR=1.08; 95% CI 0.77, 1.50, p=0.660). The present meta-analysis confirms that, besides its previously documented influence on Alzheimer's and cardiovascular disease risk, the ApoE gene is associated with the likelihood of reaching EL.	\N	\N
25386825	Hypertension is the most common cardiovascular disease and remains the most prevalent risk factor for cardiovascular diseases and a major cause of death worldwide. Despite the large number of antihypertensive drugs available, in the majority of patients blood pressure still remains not optimally controlled and persists at high risk of cardiovascular complications. The limitations of current therapies have stimulated the research and development of new classes of antihypertensive agents, with different mechanisms of action, that provide a better blood pressure control, greater protection against organ damage, better tolerability and more effective prevention of cardiovascular diseases. However, essential hypertension is a multifactorial and multigenic disorder, which means that various mechanisms contribute to a greater or lesser extent to increase BP. Recent advances in the understanding of the multiple and complex cellular signalling pathways that modulate vascular smooth muscle cell contraction and growth involved in the regulation of vascular tone and in hypertension-induced end-organ damage have provided valuable insight in identifying new therapeutic targets. This article reviews new antihypertensive drugs under development, focusing on their mechanisms of action and possible advantages compared with traditional drugs.	\N	\N
25391248	We demonstrate histological evidence for hyperparathyroidism in patients with gastrectomy. This is, at least in part, explained by impaired calcium absorption, resulting in mineralization defects and secondary hyperparathyroidism. Additionally, we demonstrate improved bone mineralization in patients with gastrectomy after gluconate therapy and showed the effectiveness of calcium gluconate over carbonate to balance impaired calcium hemostasis in mice. Gastrectomy and hypochlorhydria due to long-term proton pump inhibitor therapy are associated with increased fracture risk because of intestinal calcium malabsorption. Hence, our objectives were to histologically investigate bone metabolism in patients with gastrectomy and to analyze the impact of calcium gluconate supplementation on skeletal integrity in the setting of impaired gastric acidification. Undecalcified bone biopsies of 26 gastrectomized individuals were histologically analyzed. In the clinical setting, we retrospectively identified 5 gastrectomized patients with sufficient vitamin D level, who were additionally supplemented with calcium gluconate and had a real bone mineral density (aBMD) follow-up assessments. A mouse model of achlorhydria (ATP4b-/-) was used to compare the effect of calcium gluconate and calcium carbonate supplementation on bone metabolism. Biopsies from gastrectomized individuals showed significantly increased osteoid, osteoclast, and osteoblast indices and fibroosteoclasia (p < 0.05) as well as impaired calcium distribution in mineralized bone matrix compared to healthy controls. Five gastrectomized patients with sufficient vitamin D level demonstrated a significant increase in aBMD after a treatment with calcium gluconate alone for at least 6 months (p < 0.05). Calcium gluconate was superior to calcium carbonate in maintaining calcium metabolism in a mouse model of achlorhydria. Gastrectomy is associated with severe osteomalacia, marrow fibrosis, and impaired calcium distribution within the mineralized matrix. We show that calcium gluconate supplementation can increase bone mineral density in gastrectomized individuals and performs superior to calcium carbonate in restoring calcium/skeletal homoeostasis in a mouse model of achlorhydria.	\N	\N
25391854	Genetic polymorphisms in Solute carrier family 1 (glial high affinity glutamate transporter), member 2 (SLC1A2) have been linked with essential tremor. SLC1A2 encodes excitatory amino acid transporter type 2 (EAAT2), which clears glutamate from the synaptic cleft. One postulated mechanism for essential tremor is the over-excitation of glutamatergic olivo-cerebellar climbing fibers, leading to excitotoxic death of Purkinje cells. Other glutamatergic excitatory signals are transmitted to Purkinje cells via parallel fibers of cerebellar granule neurons. Therefore, the expression level of glutamate transporters could be important in essential tremor pathogenesis. Using Western blotting, we compared the expression levels of the two main glutamate transporters in the cerebellar cortex, EAAT1 and EAAT2, in postmortem tissue from 16 essential tremor cases and 13 age-matched controls. We also studied the localization of EAAT1 and EAAT2 using immunohistochemistry in 10 essential tremor cases and 12 controls. EAAT1 protein levels were similar in cases and controls (1.12 ± 0.83 vs. 1.01 ± 0.69, p =0.71) whereas EAAT2 protein levels in essential tremor cases were only 1/3 of that in controls (0.35 ± 0.23 vs. 1.00 ± 0.62, p < 0.01). Interestingly, EAAT2, but not EAAT1, was expressed in astrocytic processes surrounding the Purkinje cell axon initial segment, a region of previously observed pathological changes in essential tremor. Our main finding, a significant reduction in cerebellar cortical EAAT2 protein levels in essential tremor, suggests that Purkinje cells in essential tremor might be more vulnerable to excitotoxic damage than those of controls.	\N	\N
25400038	Schistosomiasis, one of the most important neglected tropical diseases worldwide, is caused by flatworms (blood flukes or schistosomes) that live in the bloodstream of humans. The hepatointestinal form of this debilitating disease results from a chronic infection with Schistosoma mansoni or Schistosoma japonicum. No vaccine is available to prevent schistosomiasis, and treatment relies predominantly on the use of a single drug, praziquantel. In spite of considerable research effort over the years, very little is known about the complex in vivo events that lead to granuloma formation and other pathological changes during infection. Here we use, for the first time, a lentivirus-based transduction system to deliver microRNA-adapted short hairpin RNAs (shRNAmirs) into the parasite to silence and explore selected protein-encoding genes of S. mansoni implicated in the disease process. This gene-silencing system has potential to be used for functional genomic-phenomic studies of a range of socioeconomically important pathogens.	\N	\N
25400122	We report a 10-year-old male with relapsing Ph-like acute lymphoblastic leukemia (ALL) bearing ATF7IP/PDGFRB translocation. He was refractory to conventional therapy, and was finally treated with single-agent second-generation TKI dasatinib. The therapeutic response was prompt, with the disappearance of minimum residual disease (MRD) based on genomic PCR analysis within 3 months, and he has maintained complete molecular remission for 12 months. This case report describes an early-phase response to TKI monotherapy on Ph-like ALL, and technical tips for MRD monitoring on long-term follow-up.	\N	\N
25404522	Untreated human immunodeficiency virus type 1 (HIV) infection is associated with persistent immune activation, which is an independent driver of disease progression in European and United States cohorts. In Uganda, HIV-1 subtypes A and D and recombinant AD viruses predominate and exhibit differential rates of disease progression. HIV-1 seroconverters (n = 156) from rural Uganda were evaluated to assess the effects of T-cell activation, viral load, and viral subtype on disease progression during clinical follow-up. The frequency of activated T cells was increased in HIV-1-infected Ugandans, compared with community matched uninfected individuals, but did not differ significantly between viral subtypes. Higher HIV-1 load, subtype D, older age, and high T-cell activation levels were associated with faster disease progression to AIDS or death. In a multivariate Cox regression analysis, HIV-1 load was the strongest predictor of progression, with subtype also contributing. T-cell activation did not emerge an independent predictor of disease progression from this particular cohort. These findings suggest that the independent contribution of T-cell activation on morbidity and mortality observed in European and North American cohorts may not be directly translated to the HIV epidemic in East Africa. In this setting, HIV-1 load appears to be the primary determinant of disease progression.	\N	\N
25406883	Periorbital burns are an infrequent but potentially devastating injury. This study aimed to elucidate the spectrum of such injuries presenting to a UK burns centre and the outcome achieved in the cases requiring periorbital reconstruction for the restoration of function and form. Patients admitted to a UK regional burns centre between January 2005 and January 2011 with periorbital burns were identified from the Patient Administration System (PAS), theatre logs and the International Burns Injury database (IBID). Multiple parameters were assessed using patient notes, ITU and hospital image databases. Over 6 years, 167 patients with facial burns requiring surgery were treated, including 103 patients with eyelid burns. The mean burn size was 33% total body surface area. The eyelid burn depth varied; 67% superficial partial thickness, 17% deep dermal and 16% full thickness. Two patients lost complete vision in one eye, one patient underwent amniotic membrane grafting. In total 16 patients required periorbital reconstruction to maintain eye closure, with 1.8 operations on average per patient. Acute surgery was required in 11 patients, whilst late intervention (>3 months) was needed in 5, 2 patients had both acute and delayed surgery. Of the 5 late intervention patients 4 were treated with full thickness skin grafts and 1 with a Z plasty. Average time for final reconstruction with delayed surgery was 4.5 months. The goal in management of periorbital burns is preservation of vision, prevention of future complications and restoration of an acceptable aesthetic outcome. Total visual loss is thankfully rare, but early ophthalmology intervention is vital given the evidence of corneal damage as a brief therapeutic window exists.	\N	\N
25410176	The goal of this cross-sectional observational study was to quantify the pattern-shift visual evoked potentials (VEP) and the thickness as well as the volume of retinal layers using optical coherence tomography (OCT) across a cohort of Parkinson's disease (PD) patients and age-matched controls. Forty-three PD patients and 38 controls were enrolled. All participants underwent a detailed neurological and ophthalmologic evaluation. Idiopathic PD cases were included. Cases with glaucoma or increased intra-ocular pressure were excluded. Patients were assessed by VEP and high-resolution Fourier-domain OCT, which quantified the inner and outer thicknesses of the retinal layers. VEP latencies and the thicknesses of the retinal layers were the main outcome measures. The mean age, with standard deviation (SD), of the PD patients and controls were 63.1 (7.5) and 62.4 (7.2) years, respectively. The patients were predominantly in the initial Hoehn-Yahr (HY) disease stages (34.8% in stage 1 or 1.5, and 55.8 % in stage 2). The VEP latencies and the thicknesses as well as the volumes of the retinal inner and outer layers of the groups were similar. A negative correlation between the retinal thickness and the age was noted in both groups. The thickness of the retinal nerve fibre layer (RNFL) was 102.7 μm in PD patients vs. 104.2 μm in controls. The thicknesses of retinal layers, VEP, and RNFL of PD patients were similar to those of the controls. Despite the use of a representative cohort of PD patients and high-resolution OCT in this study, further studies are required to establish the validity of using OCT and VEP measurements as the anatomic and functional biomarkers for the evaluation of retinal and visual pathways in PD patients.	\N	\N
25412555	Ovary cancer is a disease charged of paradigms and a serious health problem. It's important to know its natural history, because has a multifactor origins, and understanding its behavior since risk factors until patient's death because metastatic disease is a challenger for oncology group. In this work we made a bibliographic, analytic review that brings up concepts related to its origin, evolution, risk factors, preclinical horizon, and clinical symptoms until the death of patient.	\N	\N
25424781	While a PhD candidate, doing my thesis at the Oak Ridge National Laboratory, Biology Division under Dr. Charles Congdon, my introduction to the immune response was studying graft vs. host (GVH) disease as a consequence of bone marrow transplantation in mice. The sequalae of GVH was impressive, and demonstrated the potential of negative clinical consequences of the immune system. The idea of harnessing this immunological phenomena in cancer therapy was appealing even in the late 1960s. The problem was that at the time T-cells as a component of the immune system were identified but not defined. We moved to soluble antigen stimulation in mice and recognized and described the post antigen stimulation changes in lymphatic tissue germinal centers during the first 48 h after the induction of the humoral immune response. We described the extracellular localization of soluble antigens on the surface of dendritic reticular cells of the stroma, directing a response of B-cells to produce antibody against non-self. The ensuing reaction was the rapid proliferation of B-cells toward antibody secreting plasma cells.	\N	\N
25428209	The Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST) is a multicenter randomized trial of stenting versus endarterectomy in patients with symptomatic and asymptomatic carotid disease. This study assesses management of vascular risk factors. Management was provided by the patient's physician, with biannual monitoring results collected by the local site. Therapeutic targets were low-density lipoprotein, cholesterol <100 mg/dL, systolic blood pressure <140 mm Hg, fasting blood glucose <126 mg/dL, and nonsmoking status. Optimal control was defined as achieving all 4 goals concurrently. Generalized estimating equations were used to compare risk factors at baseline with those observed in scheduled follow-up visits for up to 48 months. In the analysis cohort of 2210, significant improvements in risk-factor control were observed across risk factors for all follow-up visits compared with baseline. At 48 months, achievement of the low-density lipoprotein cholesterol goal improved from 59.1% to 73.6% (P<0.001), achievement of the systolic blood pressure goal improved from 51.6% to 65.1% (P<0.001), achievement of the glucose goal improved from 74.9% to 80.7% (P=0.0101), and nonsmoking improved from 74.4% to 80.9% (P<0.0001). The percentage with optimal risk-factor control also improved significantly, from 16.7% to 36.2% (P<0.001), but nearly 2 of 3 study participants did not achieve optimal control during the study. Site-based risk-factor control improved significantly in the first 6 months and over the long term in CREST but was often suboptimal. Intensive medical management should be considered for future trials of carotid revascularization. ClinicalTrials.gov. Unique identifier: NCT00004732.	\N	\N
25439075	Gastric cancer is the third cause of cancer death worldwide, and Helicobacter pylori infection causes almost 90% of non-cardia cancers, the predominant type. H. pylori infection is treatable, and in clinical trials there is evidence of a 30-40% reduction in incidence of gastric cancer among treated subjects. However, with a few exceptions, there are no public health programmes for gastric cancer prevention. In December 2013, the International Agency for Research on Cancer (IARC), organized a Working Group of international experts to discuss and make recommendations for gastric cancer control. The Working Group considered that the enormous burden of disease, which is not expected to decline in the coming decades, requires decisive public health action to include gastric cancer in cancer control programmes. Interventions should be tailored to the local conditions and consider population-based screening and eradication of H. pylori, in the context of evaluation of feasibility, efficacy and adverse consequences.	\N	\N
25439990	We report a case of KSHV/EBV associated germinotropic lymphoproliferative disorder (LPG) in a 49-year-old African patient, without immunosuppression. LPG is a rare entity arising in immunocompetent patients in opposition to other lymphoproliferative disorders associated to Kaposi sarcoma-associated herpes virus (KSHV). The disease presents itself as localized lymphadenopathy with an infiltration of germinal centers by plasmablastic cells coinfected by KSHV and EBV (Epstein-Barr Virus). After treatment, the outcome is favorable. Differential diagnosis in our case, due to the presence of clusters of Hodgkin-like cells in the mantle zone, included lymphocyte rich classic Hodgkin lymphoma (LHCRL) and nodular lymphocyte predominant Hodgkin lymphoma (LHNPL). Finally, we highlight the differential diagnostic criteria of KSHV lymphoproliferative diseases.	\N	\N
25440885	While important efforts were made in the development of positron emission tomography (PET) tracers for the in vivo molecular diagnosis of Alzheimer's disease, very few investigations to develop magnetic resonance imaging (MRI) probes were performed. Here, a new generation of Gd(III)-based contrast agents (CAs) is proposed to detect the amyloid β-protein (Aβ) aggregates by MRI, one of the earliest biological hallmarks of the pathology. A building block strategy was used to synthesize a library of 16 CAs to investigate structure-activity relationships (SARs) on physicochemical properties and binding affinity for the Aβ aggregates. Three types of blocks were used to modulate the CA structures: (i) the Gd(III) chelates (Gd(III)-DOTA and Gd(III)-PCTA), (ii) the biovectors (2-arylbenzothiazole, 2-arylbenzoxazole and stilbene derivatives) and (iii) the linkers (neutrals, positives and negatives with several lengths). These investigations revealed unexpected SARs and a difficulty of these probes to cross the blood-brain barrier (BBB). General insights for the development of Gd(III)-based CAs to detect the Aβ aggregates are described.	\N	\N
25445322	Aleutian disease virus (ADV, Amdovirus, Parvoviridae) primarily infects farmed mustelids (mink and ferrets) but also other fur-bearing animals and humans. Three Aleutian disease (AD) cases have been described in captive striped skunks; however, little is known about the relevance of AD in free-ranging carnivores. This work describes the pathological findings and temporospatial distribution in 7 cases of AD in free-ranging striped skunks. All cases showed neurologic disease and were found in a 46-month period (2010-2013) within a localized geographical region in California. Lesions included multisystemic plasmacytic and lymphocytic inflammation (ie, interstitial nephritis, myocarditis, hepatitis, meningoencephalitis, pneumonia, and splenitis), glomerulonephritis, arteritis with or without fibrinoid necrosis in several organs (ie, kidney, heart, brain, and spleen), splenomegaly, ascites/hydrothorax, and/or encephalomalacia with cerebral microangiopathy. ADV infection was confirmed in all cases by specific polymerase chain reaction and/or in situ hybridization. The results suggest that AD is an emerging disease in free-ranging striped skunks in California.	\N	\N
25445432	The relationship between pre-hospital care and the prognosis of out-of-hospital cardiac arrest (OHCA) caused by respiratory disease is unclear. This study aimed to assess the impact of pre-hospital care on the prognosis of OHCA caused by respiratory disease. In a nationwide, population-based, observational study, we enrolled 121,081 adults aged ≥18 years who experienced OHCA from January 1, 2010, to December 31, 2010. The primary endpoint was favourable neurological outcomes. Of the 120,256 eligible adult OHCA patients, 7,071 (5.9%) experienced OHCA caused by respiratory disease. Of these 7,071 patients, 3,911 (55.3%) received no cardiopulmonary resuscitation (CPR), 2,403 (34.0%) received chest-compression-only CPR, and 757 (10.7%) received conventional CPR by a bystander. There was no significant difference between the three types of bystander CPR with regard to the neurological outcome (no CPR: OR 0.68, 95%CI 0.39-1.24, p=0.1951; chest-compression-only CPR: OR 0.68, 95%CI 0.37-1.29, p=0.2295; and conventional CPR: as a reference). Pre-hospital administration of epinephrine (OR 0.37, 95%CI 0.13-0.85, p=0.0170) and the implementation of advanced airway management (OR 0.32, 95%CI 0.19-0.52, p<0.0001) were associated with poor neurological outcomes. Even in OHCA caused by respiratory disease, not only pre-hospital epinephrine administration but also pre-hospital advanced airway management and rescue breathing in bystander CPR may not be critical.	\N	\N
25456683	Group A streptococcal (GAS) infections are frequent in developing countries but the epidemiology is incompletely known. In 2005, 90 % of symptomatic pharyngitis, 96 % of invasive diseases and 97 % of deaths due to GAS were observed in these countries. Clinical features of GAS invasive infections are identical to those reported in developed countries, but frequency and mortality are higher, as is the number of the different emm types involved. In the world, from 15.6 to 19.6 millions of persons are affected by rheumatic heart disease (282,000 new cases and 233,000-468,000 deaths per year). Incidence of acute post-streptococcal glomerulonephritis varies with time and location: in 2005, 472,000 new cases have been reported in the world (83 % in a developing country). World Heart Federation recently aimed at reducing the burden of rheumatic heart diseases by 25 % among < 25 years persons in 2025.	\N	\N
25467562	Patients are increasingly being admitted with chronic atrial fibrillation, and disease-specific management might reduce recurrent admissions and prolong survival. However, evidence is scant to support the application of this therapeutic approach. We aimed to assess SAFETY--a management strategy that is specific to atrial fibrillation. We did a pragmatic, multicentre, randomised controlled trial in patients admitted with chronic, non-valvular atrial fibrillation (but not heart failure). Patients were recruited from three tertiary referral hospitals in Australia. 335 participants were randomly assigned by computer-generated schedule (stratified for rhythm or rate control) to either standard management (n=167) or the SAFETY intervention (n=168). Standard management consisted of routine primary care and hospital outpatient follow-up. The SAFETY intervention comprised a home visit and Holter monitoring 7-14 days after discharge by a cardiac nurse with prolonged follow-up and multidisciplinary support as needed. Clinical reviews were undertaken at 12 and 24 months (minimum follow-up). Coprimary outcomes were death or unplanned readmission (both all-cause), measured as event-free survival and the proportion of actual versus maximum days alive and out of hospital. Analyses were done on an intention-to-treat basis. The trial is registered with the Australian New Zealand Clinical Trials Registry (ANZCTRN 12610000221055). During median follow-up of 905 days (IQR 773-1050), 49 people died and 987 unplanned admissions were recorded (totalling 5530 days in hospital). 127 (76%) patients assigned to the SAFETY intervention died or had an unplanned readmission (median event-free survival 183 days [IQR 116-409]) and 137 (82%) people allocated standard management achieved a coprimary outcome (199 days [116-249]; hazard ratio 0·97, 95% CI 0·76-1·23; p=0·851). Patients assigned to the SAFETY intervention had 99·5% maximum event-free days (95% CI 99·3-99·7), equating to a median of 900 (IQR 767-1025) of 937 maximum days alive and out of hospital. By comparison, those allocated to standard management had 99·2% (95% CI 98·8-99·4) maximum event-free days, equating to a median of 860 (IQR 752-1047) of 937 maximum days alive and out of hospital (effect size 0·22, 95% CI 0·21-0·23; p=0·039). A post-discharge management programme specific to atrial fibrillation was associated with proportionately more days alive and out of hospital (but not prolonged event-free survival) relative to standard management. Disease-specific management is a possible strategy to improve poor health outcomes in patients admitted with chronic atrial fibrillation. National Health and Medical Research Council of Australia.	\N	\N
25470167	This article provides a practical clinical approach for the role of exercise in the treatment and management of neurologic disorders. A number of clinical studies have reported positive benefits from exercise in various neurologic disease states, suggesting that this mode of intervention should be considered as another option in clinical management. Significant evidence-based data exists confirming the positive effects of exercise in otherwise healthy populations. Good evidence also exists that physical activity may benefit people with long-term neurologic conditions. Despite this evidence, exercise is often neglected in patients with normal aging or neurologic disease progression. Neurologists should counsel patients on this therapeutic adjunct and provide specific recommendations when possible.	\N	\N
25476560	Cardiovascular risk remains uncertain in patients with cardiovascular disease despite achieving target lipid levels. Serum levels of lipoprotein(a) [Lp(a)] can be risk factors for adverse events. The aim of this study was to determine the role of Lp(a) as a residual risk factor in patients who achieve target lipid levels by the time of treatment by percutaneous coronary intervention (PCI). A total of 3,508 patients were treated by PCI from 1997 to 2011 at our institution. Among them, we analyzed consecutive 569 patients who achieved target lipid levels of low-density lipoprotein cholesterol <100 mg/dl, high-density lipoprotein cholesterol ≥40 mg/dl, and triglycerides <150 mg/dl at PCI. A total of 411 eligible patients were assigned to groups according to Lp(a) levels of ≥30 mg/dl (high Lp(a); n = 119) or <30 mg/dl (low Lp(a); n = 292). The primary outcome was a composite of all-cause death and acute coronary syndrome. The median follow-up period was 4.7 years. Cumulative event-free survival was significantly worse for the group with high Lp(a) than with low Lp(a) group (p = 0.04). Multivariate analysis selected a high Lp(a) level as an independent predictor of primary outcomes (hazard ratio 1.68, 95% confidence interval 1.03 to 2.70, p = 0.04). In conclusion, a high Lp(a) value (≥30 mg/dl) could be associated with a poor prognosis after PCI even for patients who achieved target lipid levels.	\N	\N
25481243	The presence of somatic mutations in splicing factor 3b subunit 1 (SF3B1) in patients with Myelodysplastic syndromes with ring sideroblasts (MDS-RS) highlights the importance of the RNA-splicing machinery in MDS. We previously reported the presence of bone marrow (BM) RS in Sf3b1 heterozygous (Sf3b1 (+/-)) mice which are rarely found in mouse models of MDS. Sf3b1 (+/-) mice were originally engineered to study the interaction between polycomb genes and other proteins. We used routine blood tests and histopathologic analysis of BM, spleen, and liver to evaluate the hematologic and morphologic characteristics of Sf3b1 (+/-) mice in the context of MDS by comparing the long term follow-up (15 months) of Sf3b1 (+/-) and Sf3b1 (+/+) mice. We then performed a comprehensive RNA-sequencing analysis to evaluate the transcriptome of BM cells from Sf3b1 (+/-) and Sf3b1 (+/+) mice. Sf3b1 (+/-) exhibited macrocytic anemia (MCV: 49.5 ± 1.6 vs 47.2 ± 1.4; Hgb: 5.5 ± 1.7 vs 7.2 ± 1.0) and thrombocytosis (PLTs: 911.4 ± 212.1 vs 878.4 ± 240.9) compared to Sf3b1 (+/+) mice. BM analysis showed dyserythropoiesis and occasional RS in Sf3b1 (+/-) mice. The splenic architecture showed increased megakaryocytes with hyperchromatic nuclei, and evidence of extramedullary hematopoiesis. RNA-sequencing showed higher expression of a gene set containing Jak2 in Sf3b1 (+/-) compared to Sf3b1 (+/+). Our study indicates that Sf3b1 (+/-) mice manifest features of low risk MDS-RS and may be relevant for preclinical therapeutic studies.	\N	\N
25482988	Cancer cell metabolism is deregulated, and signalling pathways can be involved. For instance, PI3K/Akt/mTOR is associated with normal proliferation and differentiation, and its alteration is detectable in cancer cells, that exploit the normal mechanisms to overcome apoptosis. On the other hand, also the family of Phospholipase C (PLC) enzymes play a critical role in cell growth, and any change concerning these enzymes or their downstream targets can be associated with neoplastic transformation. Here, we review the role of PLC and PI3K/Akt/mTOR signal transduction pathways in pathophysiology.	\N	\N
25486686	The current economic difficulties and the changed epidemiological picture, characterized by an increase in life expectancy, which shows in the elderly, chronically ill and disabled the main, both health and social, care needs,r equires a remark on the hospital network and organization. Today, most of the application assistance is usually at low intensity of care, whereas the acute event is shrinking. The prevalence of hospital admissions concern the elderly, who get into acute events but on a substrate of chronicity and co-morbidity conditions. There must be a new model of hospital network, with the possibility of converting some hospital centres for medium intensity care and selecting few centres for high intensity care, where concentrating the more expensive technology and the skill and expertise of the professional. The -suggestion is a renewed health planning that detects:- hospitals for widespread disease, equipped with emergency war for minor codes-hospital at high intensity of care for emergency-urgency- hospital for particular fields of medical speciality and research.	\N	\N
25497401	We present a Dutch family with a novel disease-causing mutation in the mitochondrial tRNA(Ser(UCN)) gene, m.7507A>G. The index patient died during the neonatal period due to cardio-respiratory failure and fatal lactic acidosis. A second patient, his cousin, has severe hearing loss necessitating cochlear implants and progressive exercise intolerance. Laboratory investigations of both patients revealed combined deficiencies of the enzyme complexes of the mitochondrial respiratory chain in several tissues. Reduced levels of fully assembled complexes I and IV in fibroblasts by BN-PAGE associated with (near) homoplasmic levels of the m.7507A>G mutation in several tissues and a severe reduction in the steady-state level of mt-tRNA(Ser(UCN)) in fibroblasts were observed. The novel mitochondrial DNA mutation was shown to segregate with disease; several healthy maternal family members showed high heteroplasmy levels (up to 76 ± 4% in blood and 68 ± 4% in fibroblasts) which did not lead to any alterations in the activities of the enzyme complexes of the respiratory chain in fibroblasts or clinical signs and symptoms. We hereby conclude that the m.7507A>G mutation causes a heterogeneous clinical phenotype and is only pathogenic at very high levels of mtDNA heteroplasmy.	\N	\N
25500436	The abnormal formation and insufficient clearance of neutrophil extracellular traps (NETs) has been reported to be involved in the pathogenesis of lupus nephritis (LN). The abnormal regulation of NETs may contribute to increases in the levels of circulating cell-free DNA (cfDNA). The present study tested the hypothesis that elevated plasma cfDNA levels are related to LN. Fifty-four systemic lupus erythematosus (SLE) patients and 43 control subjects were included in this study. The cfDNA concentrations were measured using the Picogreen Kit, the low-density granulocyte (LDG) percentage in peripheral blood mononuclear cells (PBMCs) was tested using a flow cytometer and the DNase I activity was measured according to the radial enzyme-diffusion method. The mean cfDNA concentration in the SLE group was 236.66±40.09 ng/mL, which was significantly higher than that observed in the healthy control group (187.96±40.55 ng/mL, p<0.0001). Meanwhile, the mean cfDNA concentration in the patients with LN was significantly higher than that observed in the patients without LN (247.27±46.79 ng/mL vs. 213.56±31.34 ng/mL, p=0.0094), and the mean cfDNA concentration in the patients with active LN was significantly higher than that observed in the patients with inactive LN (254.22±50.16 ng/mL vs. 215.93±29.10 ng/mL, p=0.0349). In the SLE group, the cfDNA concentration was to positively correlate with the quantitative 24-hour urinary protein (r=0.350, p=0.013), LDG (r=0.6361, p=0.0019) and neutrophil (r=0.5990, p<0.0001) levels and inversely correlate with the albumin level (r=-0.500, p<0.0001) and endogenous creatinine clearance rate (r=-0.354, p=0.044). Compared to that observed in the control group, the SLE group exhibited a significantly increased percentage of LDGs in PBMCs and a significantly decreased DNase I activity. Our data indicate that elevated plasma cfDNA concentrations may be associated with active LN and partially attributed to the abnormal regulation of NETs in SLE patients, thus suggesting that NETs constitute an intrinsic link between cfDNA and active LN.	\N	\N
25524212	The cause of type 1 diabetes remains unknown. To dissect the link between hyperexpression of human leukocyte antigen (HLA) class I on the islet cells, we examined its expression in subjects with recent-onset type 1 diabetes. IHC showed seemingly pronounced hyperexpression in subjects with recent-onset type 1 diabetes, as well as in some nondiabetic subjects. In all subjects, HLA class I expression on exocrine tissue was low. However, no difference in the level of HLA class I expression was found between islet and exocrine tissue using Western blot, flow cytometry, real-time quantitative PCR, or RNA sequencing analyses. Also, the level of HLA class I expression on the messenger level was not increased in islets from subjects with recent-onset type 1 diabetes compared with that in nondiabetic subjects. Consistently, the HLA class I specific enhanceosome (NLRC5) and related transcription factors, as well as interferons, were not enhanced in islets from recent-onset type 1 diabetic subjects. In conclusion, a discrepancy in HLA class I expression in islets assessed by IHC was observed compared with that using quantitative techniques showing similar expression of HLA class I in islets and exocrine tissue in subjects with recent-onset type 1 diabetes, nor could any differences be found between type 1 diabetic and nondiabetic subjects. Results presented provide important clues for a better understanding on how this complex disease develops.	\N	\N
25536728	Brucellosis is an important disease in developing countries. We aimed to determine the epidemiologic, clinical, and laboratory characteristics of brucellosis, which still has a high morbidity in Turkey. Seventy-two patients with brucellosis, monitored at our clinic from January 2004 to July 2010, were reviewed retrospectively. The average age was determined to be 44.8 ± 18 years, and 40 of the patients were female (55.6%). The most frequent transmission route was the use of raw milk and dairy products, in 45 of the patients (62.5%). The most frequent complaints were joint pain, high fever, weakness, low back pain, and gastrointestinal symptoms, whereas the most frequent physical examination findings were fever, osteoarticular involvement, splenomegaly, hepatomegaly, and lymphadenopathy. All of the patients were positive for Rose Bengal testing. The standard tube agglutination titer was 1/160 or higher in 64 (88.9%) patients. Brucella melitensis was isolated from blood cultures of 13 (18.1%) patients and bone marrow cultures of 7 (9.7%) patients. Complications of sacroiliitis in 6 (8.3%), spondylodiscitis in 4 (5.6%), endocarditis in 2 (2.8%), neurobrucellosis in 1 (1.4%), and epididymo-orchitis in 1 (1.4%) of the patients were observed. Brucellosis has various clinical presentations. It should be included in the differential diagnosis of high fever and joint pains in endemic countries.	\N	\N
25539271	Pancreatic adenocarcinoma is a rapidly progressive malignancy characterized by its tendency for early metastatic spread. MDCT is the primary diagnostic modality for the preoperative staging of patients with pancreatic cancer, with an accuracy established in multiple studies. However, for a variety of reasons, there is often a prolonged interval between staging MDCT and the surgical intervention. This study examines the relationship between the interval between imaging and surgery and the accuracy of MDCT in determining the presence or absence of metastatic disease at surgery in patients with pancreatic cancer. Patients were identified who had undergone surgery for pancreatic cancer at our institution with a dedicated preoperative pancreas-protocol MDCT performed in our department. Findings from the preoperative MDCT report were correlated with the operative findings, as well as the time between imaging and surgery. Two hundred ninety-two MDCT scans were performed on 256 patients who underwent exploration for pancreatic adenocarcinoma. The patients had a median age of 67 years (range, 30-95 years), and 51.6% (132/256) were male. The median time between MDCT and surgical exploration was 15.5 days (range, 1-198 days). MDCT correctly predicted the absence of metastatic disease at surgery in 233 of 274 (85.0%) studies. MDCT was more accurate in predicting the absence of metastatic disease if the study was performed within 25 days of surgery than it was if the study was performed within more than 25 days of surgery (89.3% vs 77.0%; p = 0.0097). Furthermore, regression models showed that the negative predictive value of a given MDCT significantly decreased after approximately 4 weeks. MDCT is an accurate method to stage patients with pancreatic cancer, but its accuracy in excluding distant metastatic disease depreciates over time. Patients should undergo a repeat MDCT within 25 days of any planned definitive operative intervention for pancreatic cancer to avoid unexpectedly finding metastatic disease at surgery.	\N	\N
25545990	Dependence on invasive procedures for classification of patients with Sjögren's syndrome (SS) hampers timely diagnosis and suitable patient followup. The aim of this study was to recapitulate the diagnosis of SS through noninvasive means and to define the biologic state of SS patients' salivary glands. Using a 187-plex capture antibody-based assay, salivary proteomic biomarker profiles were generated from patients with primary SS, patients with rheumatoid arthritis, and asymptomatic controls. Discriminant function analyses and Gene Ontology-based network analyses allowed data analyses with a reductionist approach and with a focus on systems biology. Characterized by significant changes in 61 and 55 proteins, respectively, the salivary proteome of SS patients appeared profoundly altered compared to that of individuals without SS. On this basis, 4-plex and 6-plex biomarker signatures, both including interleukin-4 (IL-4), IL-5, and clusterin, achieved accurate prediction of an individual's group membership for at least 94% of cases. Of note, all misclassified SS patients presented with ectopic germinal center-like structures. Systematic inference of biologic meaning identified SS-related protein patterns delineating B cell-dominated immune responses, macrophage differentiation, and signs of T cell chemotaxis. In addition, proteomic Multi-Analyte Profiles provided insight about proteins related to collagen, cytokine, and growth factor synthesis as well as lipid transport. The SS-related molecular landscape conveyed by saliva showed great congruence with histopathologic features found in SS and advances understanding of this disease at a molecular level. Such salivary biomarker signatures harbor great potential for improving timeliness of SS diagnosis and enabling suitable patient followup.	\N	\N
25546563	Sjögren's Syndrome (SS) is an autoimmune disease that causes sicca (dryness) symptoms by affecting secretions most notably of the lacrimal and salivary glands. Voice disorders have been documented in patients with SS, but the true prevalence and relationships among possible contributing factors remain unknown. This preliminary epidemiological investigation examined prevalence and risk factors for voice disorders in SS. Self-report epidemiological questionnaire. One hundred and one (101) patients with SS (94 females, 7 males; M age = 59.4 years; standard deviation [SD] = 14.1 years) completed an extensive interview using a previously validated questionnaire involving the patient's medical, family, occupational, psychosocial, social/lifestyle, voice use, and general health histories. Summary statistics, chi-squares, risk ratios, and multiple logistic regression were used to determine the frequency and severity of voice disorders in individuals with SS, as well as associations with demographic, lifestyle, health, disease severity, and voice use factors. The prevalence of a current voice disorder in individuals with SS was 59.4%. In general, voice disorders began gradually; were chronic; and correlated with SS disease severity independent of age, sex, duration of the disease, comorbid autoimmune conditions, and use of SS-related medication. Specific voice symptoms including chronic throat dryness and soreness were significantly associated with SS disease severity. Voice disorders are relatively common in SS and are more frequent as disease severity worsens. These findings have important implications for evaluation and treatment of patients with SS. 4.	\N	\N
25549186	After injection into muscle and peripheral nerves, a variety of viral vectors undergo retrograde transport to lower motor neurons. However, because of its attractive safety profile and durable gene expression, adeno-associated virus (AAV) remains the only vector to have been applied to the human nervous system for the treatment of neurodegenerative disease. Nonetheless, only a very small fraction of intramuscularly injected AAV vector arrives at the spinal cord. To engineer a novel AAV vector by inserting a neuronal targeting peptide (Tet1), with binding properties similar to those of tetanus toxin, into the AAV1 capsid. Integral to this approach was the use of structure-based design to increase the effectiveness of functional capsid engineering. This approach allowed the optimization of scaffolding regions for effective display of the foreign epitope while minimizing disruption of the native capsid structure. We also validated an approach by which low-titer tropism-modified AAV vectors can be rescued by particle mosaicism with unmodified capsid proteins. Importantly, our rationally engineered AAV1-based vectors exhibited markedly enhanced transduction of cultured motor neurons, diminished transduction of nontarget cells, and markedly superior retrograde delivery compared with unmodified AAV1 vector. This approach promises a significant advancement in the rational engineering of AAV vectors for diseases of the nervous system and other organs.	\N	\N
25549677	To explore the clinical features of neuromyelitis optica (NMO) spectrum disease (NMOSD) with connective tissue disease (CTD). The clinical features of 184 NMO/NMOSD patients (NMO/NMOSD: 119/184, 64.7%; NMO/NMOSD-CTD: 65/184, 35.3%) from May 2013 to May 2014 were analyzed retrospectively. And the effectiveness of long-term treatment of immunosuppressive drugs in NMOSD was evaluated. NMO/NMOSD-CTD patients had significantly higher female percentage (93.8% vs 83.2%, P < 0.05) and significantly higher percentage of patients with cerebral spinal fluid (CSF)-restricted oligoclonal band (OB)(41.5% vs 21.9%, P < 0.05). As compared with NMO/NMOSD-CTD counterparts, NMO/NMOSD patients had significantly higher percentage of non-specific lesions on brain MRI (62.5% vs 35.9%, P < 0.01). After >6 months consecutive long-term treatment of immunosuppressive drugs, the relapse rate post-treatment (0.36 ± 0.85) was significantly lower than that pre-treatment (2.91 ± 4.10, P < 0.01). And no significant difference existed in expanded disability status scale (EDSS) score between pre-and post-treatment. When using azathioprine (AZA), the percentage of relapse was significantly higher in NMO/NMOSD-CTD patients (50.0%) versus NMO/NMOSD ones (18.5%, P = 0.064); When using cyclophosphamide (CTX), there was no such significant difference. Female patients are more susceptible to have NMO/NMOSD with CTD. NMO/NMOSD-CTD patients tend to have higher percentage of CSF-restricted OB and fewer non-specific lesions on brain MRI. AZA and CTX may effectively reduce relapses in both NMO/NMOSD and NMO/NMOSD-CTD patients. However CTX is superior to AZA for reducing relapses in NMO/NMOSD-CTD patients.	\N	\N
25551964	The aim of this study was to investigate if vaginal preparation procedure affects the occurrence of oocyte pickup-associated pelvic inflammation (OPU-PI) and the reproductive outcome in an in vitro fertilization (IVF) program. The occurrence of OPU-PI and the reproductive outcome were compared between 956 infertile patients undergoing vaginal preparation with saline douching alone versus 1,216 infertile patients undergoing a combination ofpovidone iodine disinfection and subsequent saline douching in an IVF program. OPU-PI occurred in four patients (0.042%) in the saline douching alone group, whereas there were no cases in the combination group (p = 0.016). There were no significant differences in the rate of fertilization, morphologically good embryo acquisition, clinical and ongoing pregnancy between the two groups (p > 0.23). This large cohort study demonstrated that a combination of vaginal povidone iodine disinfection and subsequent saline douching is more effective procedure than saline douching alone to prevent OPU-PI, without spoiling the oocyte quality.	\N	\N
25553466	Hemophilia is an X-linked inherited bleeding disorder consisting of two classifications, hemophilia A and hemophilia B, depending on the underlying mutation. Although the disease is currently treatable with intravenous delivery of replacement recombinant clotting factor, this approach represents a significant cost both monetarily and in terms of quality of life. Gene therapy is an attractive alternative approach to the treatment of hemophilia that would ideally provide life-long correction of clotting activity with a single injection. In this review, we will discuss the multitude of approaches that have been explored for the treatment of both hemophilia A and B, including both in vivo and ex vivo approaches with viral and nonviral delivery vectors.	\N	\N
25553772	Farnesoid x receptor (FXR) belongs to the group of nuclear receptors (NRs), which regulate the expression of various genes by binding to DNA either as a monomer or a heterodimer with retinoid x receptor. FXR affects several metabolic pathways through its specific target genes, regulating bile acid (BA) synthesis and homeostasis, glucose and lipid metabolism, also exhibiting a crucial role in intestinal bacterial growth and liver regeneration. Additionally, FXR is involved in the pathogenesis of different cholestatic diseases, as well as non-alcoholic fatty liver disease, inflammatory bowel disease (IBD) and primary idiopathic BA malabsorption. Analyses of certain FXR polymorphisms revealed associations with clinical phenotypes and susceptibility to various human diseases. FXR single-nucleotide polymorphisms seem to be correlated with differences in glucose homeostasis, gallstone formation, intrahepatic cholestasis of pregnancy, IBD and therapeutic response to hypolipidemic therapy, among studied populations. Unfortunately, little data are still available and more studies remain to be done to determine the contribution of FXR polymorphisms in estimating risk factors and clinical outcomes for several diseases.	\N	\N
25575898	The Hundred Person Wellness Project is an ambitious pilot undertaking, which aims to intensely monitor 100 individuals over 10 months. Patients with abnormal findings will be treated, in hopes that this early intervention will avoid, or delay, symptomatic disease. Google's "Baseline Study" is of similar scope and will enroll 10,000 people over 2 to 3 years. I here speculate that these approaches will likely not be effective in preventing disease, but instead, lead to unnecessary and potentially harmful interventions. Examples from the cancer screening experience over the last 30 years are provided, which show that intensive testing may uncover indolent disease or incidental findings which, when treated, may cause more harm than good. Additional examples show that aggressive treatments for cancer and other diseases do not always lead to better patient outcomes. I conclude that the recent advances in omics provide us with unprecedented opportunities for high content clinical testing, but such testing should be used with caution to avoid the harmful consequences of over-diagnosis and over-treatment. Despite the detailed rebuttals by Hood and colleagues in another commentary in BMC Medicine, time will show the actual benefits and harms of these ambitious initiatives.	\N	\N
25585384	In 2014, a major epidemic of human Ebola virus disease emerged in West Africa, where human-to-human transmission has now been sustained for greater than 12 months. In the summer of 2014, there was great uncertainty about the answers to several key policy questions concerning the path to containment. What is the relative importance of nosocomial transmission compared with community-acquired infection? How much must hospital capacity increase to provide care for the anticipated patient burden? To which interventions will Ebola transmission be most responsive? What must be done to achieve containment? In recent years, epidemic models have been used to guide public health interventions. But, model-based policy relies on high quality causal understanding of transmission, including the availability of appropriate dynamic transmission models and reliable reporting about the sequence of case incidence for model fitting, which were lacking for this epidemic. To investigate the range of potential transmission scenarios, we developed a multi-type branching process model that incorporates key heterogeneities and time-varying parameters to reflect changing human behavior and deliberate interventions in Liberia. Ensembles of this model were evaluated at a set of parameters that were both epidemiologically plausible and capable of reproducing the observed trajectory. Results of this model suggested that epidemic outcome would depend on both hospital capacity and individual behavior. Simulations suggested that if hospital capacity was not increased, then transmission might outpace the rate of isolation and the ability to provide care for the ill, infectious, and dying. Similarly, the model suggested that containment would require individuals to adopt behaviors that increase the rates of case identification and isolation and secure burial of the deceased. As of mid-October, it was unclear that this epidemic would be contained even by 99% hospitalization at the planned hospital capacity. A new version of the model, updated to reflect information collected during October and November 2014, predicts a significantly more constrained set of possible futures. This model suggests that epidemic outcome still depends very heavily on individual behavior. Particularly, if future patient hospitalization rates return to background levels (estimated to be around 70%), then transmission is predicted to remain just below the critical point around Reff = 1. At the higher hospitalization rate of 85%, this model predicts near complete elimination in March to June, 2015.	\N	\N
25590983	Pseudomonas aeruginosa, the predominant cause of chronic airway infections of patients with cystic fibrosis, exhibits extensive phenotypic diversity among isolates within and between sputum samples, but little is known about the underlying genetic diversity. To characterize the population genetic structure of transmissible P. aeruginosa Liverpool Epidemic Strain in chronic infections of nine patients with cystic fibrosis, and infer evolutionary processes associated with adaptation to the cystic fibrosis lung. We performed whole-genome sequencing of P. aeruginosa isolates and pooled populations and used comparative analyses of genome sequences including phylogenetic reconstructions and resolution of population structure from genome-wide allele frequencies. Genome sequences were obtained for 360 isolates from nine patients. Phylogenetic reconstruction of the ancestry of 40 individually sequenced isolates from one patient sputum sample revealed the coexistence of two genetically diverged, recombining lineages exchanging potentially adaptive mutations. Analysis of population samples for eight additional patients indicated coexisting lineages in six cases. Reconstruction of the ancestry of individually sequenced isolates from all patients indicated smaller genetic distances between than within patients in most cases. Our population-level analysis demonstrates that coexistence of distinct lineages of P. aeruginosa Liverpool Epidemic Strain within individuals is common. In several cases, coexisting lineages may have been present in the infecting inoculum or assembled through multiple transmissions. Divergent lineages can share mutations via homologous recombination, potentially aiding adaptation to the airway during chronic infection. The genetic diversity of this transmissible strain within infections, revealed by high-resolution genomics, has implications for patient segregation and therapeutic strategies.	\N	\N
25595571	Noonan Syndrome (NS) is characterized by short stature, typical facial dysmorphology and congenital heart defects. The incidence of NS is estimated to be between 1:1000 and 1:2500 live births. The syndrome is transmitted as an autosomal dominant trait. In approximately 50% of cases, the disease is caused by missense mutations in the PTPN11 gene on chromosome 12, resulting in a gain of function of the non-receptor protein tyrosine phosphatase SHP-2 protein. Autoimmune Hepatitis (AIH) is a cryptogenic, chronic and progressive necroinflammatory liver disease. Common features of AIH are hypergammaglobulinemia (IgG), presence of circulating autoantibodies, histological picture of interface hepatitis and response to immunosuppressant drugs. Conventional treatment with Prednisone and Azathioprine is effective in most patients. We describe the case of a 6 years-old girl with Noonan Syndrome and Autoimmune Hepatitis type 1. Molecular analysis of PTPN11 gene showed heterozygous mutation c.923A>G (Asn308Ser) in exon 8. Though association between NS and autoimmune disorders is known, this is the second case of association between Noonan Syndrome and Autoimmune Hepatitis type 1 described in literature. In the management of NS, an accurate clinical evaluation would be recommended. When there is a clinical suspicion of autoimmune phenomena, appropriate laboratory tests should be performed with the aim of clarifying whether the immune system is involved in NS. We think that autoimmunity represents a characteristic of NS, even if the etiopathogenesis is still unknown.	\N	\N
25600917	Hepatitis B virus surface antigen (HBsAg) levels reflect disease status and can predict the clinical response to antiviral treatment; however, the emergence of HBsAg mutant strains has become a challenge. The Abbott HBsAg quantification assay provides enhanced detection of HBsAg and HBsAg mutants. We aimed to evaluate the performance of the Abbott HBsAg quantification assay with automatic sample dilutions (shortened as automatic Architect assay), compared with the Abbott HBsAg quantification assay with manual sample dilutions (shortened as manual Architect assay) and the Roche HBsAg quantification assay with automatic sample dilutions (shortened as Elecsys). A total of 130 sera samples obtained from 87 hepatitis B virus (HBV)-infected patients were collected to assess the correlation between the automatic and manual Architect assays. Among the 87 patients, 41 provided 42 sera samples to confirm the linearity and reproducibility of the automatic Architect assay, and find out the correlation among the Elecsys and two Architect assays. The coefficients of variation (0.44-9.53%) and R(2) = 0.996-1, which were both determined using values obtained from the automatic Architect assay, showed good reproducibility and linearity. Results of the two Architect assays demonstrated a feasible correlation (n = 130 samples; R = 0.898, p < 0.01). With regard to subgroups, correlations between the two Architect assays were better in the hepatitis B e antigen (HBeAg)-negative group (HBeAg-negative group vs. HBeAg-positive group: R = 0.885 vs. R = 0.865, both p < 0.01) and low HBV DNA group (low DNA group vs. high DNA group: R = 0.886 vs. R = 0.844, both p < 0.01). Significant correlations were also found between the results of the Elecsys and Architect assays (R > 0.93 in all cases). In conclusion, the correlation between the automatic and manual dilution Architect assays was feasible, particularly in the HBeAg-negative and low DNA groups. With lower labor costs and less human error than the manual version, the Abbott automatic dilution Architect assay provided a good clinical performance with regard to the HBsAg levels.	\N	\N
25601965	Many cancer patients receive supplemental ascorbate (vitamin C) in the belief that it synergizes the anticancer effects of chemotherapy and reduces its toxicity. A systematic review was performed to evaluate the antitumor effects and toxicity of ascorbate treatment. Medline (1946 to March 2014), EMBASE (1947 to March 2014), and the Cochrane central register (1993 to March 2014) were searched for randomized and observational studies. Of 696 identified records, 61 full-text articles were screened and 34 were included. In total, 5 randomized controlled trials (RCTs) (n = 322), 12 phase I/II trials (n = 287), 6 observational studies (n = 7,599), and 11 case reports (n = 267) were identified. Because of study heterogeneity, no meta-analyses were performed. No RCTs reported any statistically significant improvements in overall or progression-free survival or reduced toxicity with ascorbate relative to control arm. Evidence for ascorbate's antitumor effects was limited to case reports and observational and uncontrolled studies. There is no high-quality evidence to suggest that ascorbate supplementation in cancer patients either enhances the antitumor effects of chemotherapy or reduces its toxicity. Given the high financial and time costs to patients of this treatment, high-quality placebo-controlled trials are needed.	\N	\N
25602998	No current therapy for relapsing-remitting multiple sclerosis (MS) results in significant reversal of disability. To determine the association of nonmyeloablative hematopoietic stem cell transplantation with neurological disability and other clinical outcomes in patients with MS. Case series of patients with relapsing-remitting MS (n = 123) or secondary-progressive MS (n = 28) (mean age, 36 years; range, 18-60 years; 85 women) treated at a single US institution between 2003 and 2014 and followed up for 5 years. Final follow-up was completed in June 2014. Treatment with cyclophosphamide and alemtuzumab (22 patients) or cyclophosphamide and thymoglobulin (129 patients) followed by infusion of unmanipulated peripheral blood stem cells. Primary end point was reversal or progression of disability measured by change in the Expanded Disability Status Scale (EDSS) score of 1.0 or greater (score range, 0-10). Secondary outcomes included changes in the Neurologic Rating Scale (NRS) score of 10 or greater (score range, 0-100), Multiple Sclerosis Functional Composite (MSFC) score, quality-of-life Short Form 36 questionnaire scores, and T2 lesion volume on brain magnetic resonance imaging scan. Outcome analysis was available for 145 patients with a median follow-up of 2 years and a mean of 2.5 years. Scores from the EDSS improved significantly from a pretransplant median of 4.0 to 3.0 (interquartile range [IQR], 1.5 to 4.0; n = 82) at 2 years and to 2.5 (IQR, 1.9 to 4.5; n = 36) at 4 years (P < .001 at each assessment). There was significant improvement in disability (decrease in EDSS score of ≥1.0) in 41 patients (50%; 95% CI, 39% to 61%) at 2 years and in 23 patients (64%; 95% CI, 46% to 79%) at 4 years. Four-year relapse-free survival was 80% and progression-free survival was 87%. The NRS scores improved significantly from a pretransplant median of 74 to 88.0 (IQR, 77.3 to 93.0; n = 78) at 2 years and to 87.5 (IQR, 75.0 to 93.8; n = 34) at 4 years (P < .001 at each assessment). The median MSFC scores were 0.38 (IQR, -0.01 to 0.64) at 2 years (P < .001) and 0.45 (0.04 to 0.60) at 4 years (P = .02). Total quality-of-life scores improved from a mean of 46 (95% CI, 43 to 49) pretransplant to 64 (95% CI, 61 to 68) at a median follow-up of 2 years posttransplant (n = 132) (P < .001). There was a decrease in T2 lesion volume from a pretransplant median of 8.57 cm3 (IQR, 2.78 to 22.08 cm3) to 5.74 cm3 (IQR, 1.88 to 14.45 cm3) (P < .001) at the last posttransplant assessment (mean follow-up, 27 months; n = 128). Among patients with relapsing-remitting MS, nonmyeloablative hematopoietic stem cell transplantation was associated with improvement in neurological disability and other clinical outcomes. These preliminary findings from this uncontrolled study require confirmation in randomized trials.	\N	\N
25622254	The accumulation and aggregation of misfolded proteins in the brain, such as amyloid-β (Aβ) and hyperphosphorylated tau, is a neuropathological hallmark of Alzheimer's disease (AD). Previously, we developed and validated a novel non-human primate model for sporadic AD (sAD) research using intracerebroventricular administration of streptozotocin (icv STZ). To date, no characterization of AD-related genes in different brain regions has been performed. Therefore, in the current study, the expression of seven amyloid precursor protein (APP) pathway-related and five tau phosphorylation-related genes was investigated by quantitative real-time PCR experiments, using two matched-pair brain samples from control and icv STZ-treated cynomolgus monkeys. The genes showed similar expression patterns within the control and icv STZ-treated groups; however, marked differences in gene expression patterns were observed between the control and icv STZ-treated groups. Remarkably, other than β-secretase (BACE1) and cyclin-dependent kinase 5 (CDK5), all the genes tested showed similar expression patterns in AD models compared to controls, with increased levels in the precuneus and occipital cortex. However, significant changes in gene expression patterns were not detected in the frontal cortex, hippocampus, or posterior cingulate. Based on these results, we conclude that APP may be cleaved via the general metabolic mechanisms of increased α- and γ-secretase levels, and that hyperphosphorylation of tau could be mediated by elevated levels of tau protein kinase, specifically in the precuneus and occipital cortex.	\N	\N
25631478	The dihydropteroate sulfate (DHPS) gene is associated with resistance to sulfa/sulfone drugs in Pneumocystis jirovecii. We investigated the DHPS mutation rate in three groups of Iranian HIV-positive and HIV-negative patients by polymerase chain reaction-restricted fragment length polymorphism analysis. Furthermore, an association between P. jirovecii DHPS mutations and strain typing was investigated based on direct sequencing of internal transcribed spacer region 1 (ITS1) and ITS2. The overall P. jirovecii DHPS mutation rate was (5/34; 14.7%), the lowest rate identified was in HIV-positive patients (1/16; 6.25%) and the highest rate was in malignancies patients (3/11; 27.3%). A moderate rate of mutation was detected in chronic obstructive pulmonary disease (COPD) patients (1/7; 14.3%). Most of the isolates were wild type (29/34; 85.3%). Double mutations in DHPS were detected in patients with malignancies, whereas single mutations at codons 55 and 57 were identified in the HIV-positive and COPD patients, respectively. In this study, two new and rare haplotypes were identified with DHPS mutations. Additionally, a positive relationship between P. jirovecii strain genotypes and DHPS mutations was identified. In contrast, no DHPS mutations were detected in the predominant (Eg) haplotype. This should be regarded as a warning of an increasing incidence of drug-resistant P. jirovecii strains.	\N	\N
25636578	Psoriasis is a T cell-dependent immune-mediated disease of the skin and joints. It is clear that co-stimulatory and co-inhibitory molecules (currently named co-signaling molecules collectively) synergize with TCR signaling to promote or inhibit T cell activation and function. In recent years, enthusiasm in the field of co-signaling research has been fueled by the success of co-stimulatory and co-inhibitory immunotherapy for the treatment of human diseases. This review outlines the involvement of several sets of co-signaling molecules in the immunopathogenesis of psoriasis. We then describe the relevant preclinical studies and summarize recent clinical findings on targeting these molecules for the treatment of psoriasis.	\N	\N
25648029	Western blot is the gold standard method to determine individual protein expression levels. However, western blot is technically difficult to perform in large sample sizes because it is a time consuming and labor intensive process. Dot blot is often used instead when dealing with large sample sizes, but the main disadvantage of the existing dot blot techniques, is the absence of signal normalization to a housekeeping protein. In this study we established a one dot two development signals (ODTDS) dot blot method employing two different signal development systems. The first signal from the protein of interest was detected by horseradish peroxidase (HRP). The second signal, detecting the housekeeping protein, was obtained by using alkaline phosphatase (AP). Inter-assay results variations within ODTDS dot blot and western blot and intra-assay variations between both methods were low (1.04-5.71%) as assessed by coefficient of variation. ODTDS dot blot technique can be used instead of western blot when dealing with large sample sizes without a reduction in results accuracy.	\N	\N
25656590	The purpose of this study was to examine the practice patterns of intraoperative completion imaging (CI) for lower extremity bypass (LEB) in the Vascular Quality Initiative (VQI). A retrospective review of all LEB procedures in the VQI database from January 2003 to October 2013 was performed. Regions with fewer than 200 LEB procedures were excluded from the regional analysis. The modality of CI was defined as duplex ultrasound, angiography, or both. A total of 14,140 LEBs were captured, with the rate of CI being 43%. After exclusion of three regions for insufficient volume (<200 LEBs), 13,945 LEB operations across 13 regions were available for regional analysis. Use of any type of intraoperative CI varied across regions from a low of 8% to a high of 70%, with angiography being performed most frequently. When CI was performed, the type of imaging modality varied between regions from a high of 99% for angiography to a high of 75% for duplex ultrasound. CI was more common in male patients (44% of male patients vs 42% of female patients; P = .032), diabetics (44% of diabetic patients vs 42% of nondiabetic patients; P = .026), and patients with coronary artery disease (45% of patients with coronary artery disease vs 42% of patients with no coronary artery disease; P = .0015). CI was performed less frequently in LEB using single-segment great saphenous vein vs LEB using lesser saphenous, arm, or composite vein (48% vs 57%; P < .0001). CI was used in 51% of LEBs with a tibial or pedal target vessel vs 38% of LEBs with a more proximal target vessel (P < .0001). Patients with an indication of critical limb ischemia underwent CI in 45% of LEBs vs 39% with an indication other than critical limb ischemia (P < .0001). Within the VQI database, considerable practice pattern variation exists in the use of CI. Currently, CI is most commonly employed for patients with critical limb ischemia, infrageniculate target vessel, and disadvantaged venous conduit. Further study is required to standardize and to define the appropriate use of CI for LEBs.	\N	\N
25659158	Dengue virus infection is a leading cause of morbidity among children in the Philippines in recent years. In order to investigate the association of HLA Class I and II alleles and dengue disease severity in a cohort of Filipino children, we performed a case control study in 2 hospitals in Metro Manila from June 2008 to December 2009. A total of 250 laboratory confirmed dengue patients and 300 healthy individuals aged 5 to 15 years old were typed for HLA-A, B and DRB1 alleles. The frequency of HLA-A*33:01 was significantly decreased in severe dengue (DHF/ DSS; Pc = 0.0016)) and DSS (Pc = 0.0032) compared to the background population. These findings support a previous study that this allele may confer protection against the severe form of dengue and provide the first evidence of HLA association with dengue in the Philippines. Future studies should be directed in investigating the possible mechanisms of protection.	\N	\N
25659380	The 18th WHO Global Tuberculosis Annual Report indicates that there were an estimated 8.6 million incident cases of tuberculosis (TB) in 2012, which included 2.9 million women and 530,000 children. TB caused 1.3 million deaths including 320,000 human immunodeficiency virus (HIV)-infected people; three-quarters of deaths occurred in Africa and Southeast Asia. With one-third of the world's population latently infected with Mycobacterium tuberculosis (Mtb), active TB disease is primarily associated with a break down in immune surveillance. This explains the strong link between active TB disease and other communicable diseases (CDs) or noncommunicable diseases (NCDs) that exert a toll on the immune system. Comorbid NCD risk factors include diabetes, smoking, malnutrition, and chronic lung disease, all of which have increased relentlessly over the past decade in developing countries. The huge overlap between killer infections such as TB, HIV, malaria, and severe viral infections with NCDs, results in a "double burden of disease" in developing countries. The current focus on vertical disease programs fails to recognize comorbidities or to encourage joint management approaches. This review highlights major disease overlaps and discusses the rationale for better integration of tuberculosis care with services for NCDs and other infectious diseases to enhance the overall efficiency of the public health responses.	\N	\N
25662376	To determine the number, distribution and cost of hospital admissions for chronic obstructive pulmonary disease (COPD) in New Zealand. National patient-level routine data on admissions with a principal diagnosis of COPD (mostly ICD-10- AN J440 and J441) were obtained for the period July 1st 2008 to June 30th 2013. Admissions with length of stay (LOS) = 90 days were excluded. There were 61,516 admissions in 5 years. Admission rates and budget impact (in 2012/13 dollar values) were stable but the average length of stay (ALOS) declined from 5.09 to 4.37 days. In FY2012/13 the admission rate was 2.82 per 1000 population, with age standardised rate (ASR) 4.4- and 3.6-fold higher for Maori and Pacific peoples respectively than for European/others. For age = 15 years the ASR was 2.55 per 1000. Admission rates were higher for men than women and increased steeply with age and socioeconomic deprivation (NZDep06). The mean age at discharge was lower for Maori and Pacific peoples than for European/Others (63.4, 67.1 and 72.3 years). The mean 30-day readmission rate was 6.7%. The average LOS increased with age and was shorter for Maori (3.6 days) and Pacific peoples (3.5 days) than for European/Others (4.7 days). Admission rates varied widely across District Health Boards, and were higher in rural than urban regions. The estimated cost of admissions in FY2012/13 was $NZ59.6m. Hospital admissions for COPD are costly and are over-represented in high risk groups including rural, elderly, socioeconomically deprived and Maori and Pacific peoples. Effective interventions that are targeted to high risk groups are required to improve equity and reduce the burden of COPD.	\N	\N
25664604	A novel oral octreotide formulation was tested for efficacy and safety in a phase III, multicenter, open-label, dose-titration, baseline-controlled study in patients with acromegaly. We enrolled 155 complete or partially controlled patients (IGF-1 <1.3 × upper limit of normal [ULN], and 2-h integrated GH <2.5 ng/mL) receiving injectable somatostatin receptor ligand (SRL) for ≥ 3 months. Subjects were switched to 40 mg/d oral octreotide capsules (OOCs), and the dose escalated to 60 and then up to 80 mg/d to control IGF-1. Subsequent fixed doses were maintained for a 7-month core treatment, followed by a voluntary 6-month extension. Of 151 evaluable subjects initiating OOCs, 65% maintained response and achieved the primary endpoint of IGF-1 <1.3 × ULN and mean integrated GH <2.5 ng/mL at the end of the core treatment period and 62% at the end of treatment (up to 13 mo). The effect was durable, and 85 % of subjects initially controlled on OOCs maintained this response up to 13 months. When controlled on OOCs, GH levels were reduced compared to baseline, and acromegaly-related symptoms improved. Of 102 subjects completing the core treatment, 86% elected to enroll in the 6-month extension. Twenty-six subjects who were considered treatment failures (IGF-1 ≥ 1.3 × ULN) terminated early, and 23 withdrew for adverse events, consistent with those known for octreotide or disease related. OOC, an oral therapeutic peptide, achieves efficacy in controlling IGF-1 and GH after switching from injectable SRLs for up to 13 months, with a safety profile consistent with approved SRLs. OOC appears to be effective and safe as an acromegaly monotherapy.	\N	\N
25675517	Rheumatoid arthritis (RA) is an inflammatory autoimmune disease characterized by joint destruction and severe morbidity. Methotrexate (MTX) is the standard first-line therapy of RA. However, about 40% of RA patients are unresponsive to MTX treatment. Regulatory T cells (Tregs, CD4(+)CD25(+)FoxP3(+)) are thought to play an important role in attenuating RA. To investigate the role of Tregs in MTX resistance, we recruited 122 RA patients (53 responsive, R-MTX; 69 unresponsive, UR-MTX) and 33 healthy controls. Three months after MTX treatment, R-MTX but not UR-MTX showed higher frequency of peripheral blood CD39(+)CD4(+)CD25(+)FoxP3(+) Tregs than the healthy controls. Tregs produce adenosine (ADO) through ATP degradation by sequential actions of two cell surface ectonucleotidases: CD39 and CD73. Tregs from UR-MTX expressed a lower density of CD39, produced less ADO, and had reduced suppressive activity than Tregs from R-MTX. In a prospective study, before MTX treatment, UR-MTX expressed a lower density of CD39 on Tregs than those of R-MTX or control (P < 0.01). In a murine model of arthritis, CD39 blockade reversed the antiarthritic effects of MTX treatment. Our results demonstrate that MTX unresponsiveness in RA is associated with low expression of CD39 on Tregs and the decreased suppressive activity of these cells through reduced ADO production. Our findings thus provide hitherto unrecognized mechanism of immune regulation in RA and on mode of action of MTX. Furthermore, our data suggest that low expression of CD39 on Tregs could be a noninvasive biomarker for identifying MTX-resistant RA patients.	\N	\N
25675716	Cardiorehabilitation of patients with multivessel coronary lesions is an obligatory component of ambulatory stage of care. With the aim of potentiating cardioprotective and antiischemic impact of rehabilitative preventive measures in 36 patients with ischemic heart disease (IHD) and multivessel coronary artery involvement who had undergone percutaneous coronary intervention we studied cardioprotective and antiischemic effect of long-term (24 weeks) administration of 70 mg/day trimetazidine in combination with moderate intensity physical training with the use of distance surveillance by a physician. The chosen therapeutic approach in patients with residual ischemia after incomplete anatomical revascularization provided early persistent formation of cardioprotective and antiischemic effect proven by increase of tolerance to physical exercise, improvement of diastolic function, and positive dynamics of both ECG parameters and biochemical markers of myocardial ischemia.	\N	\N
25678847	5-Fluorouracil (5Fu) chemotherapy is the first treatment of choice for advanced gastric cancer (GC), but its effectiveness is limited by drug resistance. Emerging evidence suggests that the existence of cancer stem cells (CSCs) contributes to chemoresistance. The aim of the present study was to determine whether 5Fu chemotherapy generates residual cells with CSC-like properties in GC. Human GC cell lines, SGC7901 and AGS, were exposed to increasing 5Fu concentrations. The residual cells were assessed for both chemosensitivity and CSC-like properties. B lymphoma Mo-MLV insertion region 1 (BMI1), a putative CSC protein, was analyzed by immunohistochemical staining and subjected to pairwise comparison in GC tissues treated with or without neoadjuvant 5Fu-based chemotherapy. The correlation between BMI1 expression and recurrence-free survival in GC patients who received 5Fu-based neoadjuvant chemotherapy was then examined. The residual cells exhibited 5Fu chemoresistance. These 5Fu-resistant cells displayed some CSC features, such as a high percentage of quiescent cells, increased self-renewal ability and tumorigenicity. The 5Fu-resistant cells were also enriched with cells expressing cluster of differentiation (CD)133+, CD326+ and CD44+CD24-. Moreover, the BMI1 gene was overexpressed in 5Fu-resistant cells, and BMI1 knockdown effectively reversed chemoresistance. The BMI1 protein was highly expressed consistently in the remaining GC tissues after 5Fu-based neoadjuvant chemotherapy, and BMI1 levels were correlated positively with recurrence-free survival in GC patients who received 5Fu-based neoadjuvant chemotherapy. Our data provided molecular evidence illustrating that 5Fu chemotherapy in GC resulted in acquisition of CSC-like properties. Moreover, enhanced BMI1 expression contributed to 5Fu resistance and may serve as a potential therapeutic target to reverse chemoresistance in GC patients.	\N	\N
25679282	There is inconsistency among the perioperative management strategies currently used for chronic subdural hematoma (cSDH). Moreover, postoperative complications such as acute intracranial bleeding and cSDH recurrence affect clinical outcome of cSDH surgery. This study evaluated the risk factors associated with acute intracranial bleeding and cSDH recurrence and identified an effective perioperative strategy for cSDH patients. A retrospective study of patients who underwent bur hole craniostomy for cSDH between 2008 and 2012 was performed. A consecutive series of 303 cSDH patients (234 males and 69 females; mean age 67.17 years) was analyzed. Postoperative acute intracranial bleeding developed in 14 patients (4.57%) within a mean of 3.07 days and recurrence was observed in 37 patients (12.21%) within a mean of 31.69 days (range 10-104 days) after initial bur hole craniostomy. The comorbidities of hematological disease and prior shunt surgery were clinical factors associated with acute bleeding. There was a significant risk of recurrence in patients with diabetes mellitus, but recurrence did not affect the final neurological outcome (p = 0.776). Surgical details, including the number of operative bur holes, saline irrigation of the hematoma cavity, use of a drain, and type of postoperative ambulation, were not significantly associated with outcome. However, a large amount of drainage was associated with postoperative acute bleeding. Bur hole craniostomy is an effective surgical procedure for initial and recurrent cSDH. Patients with hematological disease or a history of prior shunt surgery are at risk for postoperative acute bleeding; therefore, these patients should be carefully monitored to avoid overdrainage. Surgeons should consider informing patients with diabetes mellitus that this comorbidity is associated with an increased likelihood of recurrence.	\N	\N
25680251	The orbital manifestations of acquired immunodeficiency syndrome(AIDS) are uncommon. To provide a review of orbital manifestations of AIDS, the predisposing factors, investigations, treatment and outcome. Meticulous and systematic literature search of Pubmed to identify manuscripts describing orbital manifestations of AIDS was done and the articles were reviewed.The keywords used in the search were “orbit and AIDS”, “HIV positive and orbit”,“orbit manifestations in AIDS”, “orbital disease and AIDS” and “orbital infections and AIDS”. The orbital involvement in AIDS may present with opportunistic infections from organisms like fungi, viruses, bacteria and protozoa or with malignancies like Kaposi’s sarcoma, squamous cell carcinoma, smooth muscle cell tumors and lymphoma.The predisposing factors for orbital involvement in AIDS are low CD4+ cell count and the immunosuppressive states like diabetes, diabetic ketoacidosis, intravenous drug abuse and neutropenia. A patient may present with fever, headache, nausea, vomiting,decreased vision, ocular pain, and, in cases of mass formation, there is periorbital swelling, axial proptosis, globe displacement and swollen optic disc. Radiologically,mass formation, orbital bony destruction, and spread of disease to contiguous structures including the central nervous system may be seen. The medical management includes therapy for infection and HIV-1 protease inhibitors (highly active antiretroviral therapy)to suppress HIV-1 replication. For tumors, radical surgery including debulking followed by postoperative radiotherapy is generally needed. Orbital involvements with AIDS in any form, infective or malignancy, causes significant morbidity and mortality and should be diagnosed and managed as early as possible.	\N	\N
25682204	The goal of this study is to validate a new, continuous, noninvasive stroke volume (SV) method, known as transbrachial electrical bioimpedance velocimetry (TBEV). TBEV SV was compared to SV obtained by cardiac magnetic resonance imaging (cMRI) in normal humans devoid of clinically apparent heart disease. Thirty-two (32) volunteers were enrolled in the study. Each subject was evaluated by echocardiography to assure that no aortic or mitral valve disease was present. Subsequently, each subject underwent electrical interrogation of the brachial artery by means of a high frequency, low amplitude alternating current. A first TBEV SV estimate was obtained. Immediately after the initial TBEV study, subjects underwent cMRI, using steady-state precession imaging to obtain a volumetric estimate of SV. Following cMRI, the TBEV SV study was repeated. Comparing the cMRI-derived SV to that of TBEV, the two TBEV estimates were averaged and compared to the cMRI standard. CO was computed as the product of SV and heart rate. Statistical methods consisted of Bland-Altman and linear regression analysis. TBEV SV and CO estimates were obtained in 30 of the 32 subjects enrolled. Bland-Altman analysis of pre- and post-cMRI TBEV SV showed a mean bias of 2.87 % (2.05 mL), precision of 13.59% (11.99 mL) and 95% limits of agreement (LOA) of +29.51% (25.55 mL) and -23.77% (-21.45 mL). Regression analysis for pre- and post-cMRI TBEV SV values yielded y = 0.76x + 25.1 and r(2) = 0.71 (r = 0.84). Bland-Altman analysis comparing cMRI SV with averaged TBEV SV showed a mean bias of -1.56% (-1.53 mL), precision of 13.47% (12.84 mL), 95% LOA of +24.85% (+23.64 mL) and -27.97% (-26.7 mL) and percent error = 26.2 %. For correlation analysis, the regression equation was y = 0.82x + 19.1 and correlation coefficient r(2) = 0.61 (r = 0.78). Bland-Altman analysis of averaged pre- and post-cMRI TBEV CO versus cMRI CO yielded a mean bias of 5.01% (0.32 L min(-1)), precision of 12.85% (0.77 L min(-1)), 95% LOA of +30.20 % (+0.1.83 L min(-1)) and -20.7% (-1.19 L min(-1)) and percent error = 24.8%. Regression analysis yielded y = 0.92x + 0.78, correlation coefficient r(2) = 0.74 (r = 0.86). TBEV is a novel, noninvasive method, which provides satisfactory estimates of SV and CO in normal humans.	\N	\N
25713121	Lyme disease is the most important vector-borne disease in the Northern hemisphere and represents a major public health challenge with insufficient means of reliable diagnosis. Skin is rarely investigated in proteomics but constitutes in the case of Lyme disease the key interface where the pathogens can enter, persist, and multiply. Therefore, we investigated proteomics on skin samples to detect Borrelia proteins directly in cutaneous biopsies in a robust and specific way. We first set up a discovery gel prefractionation-LC-MS/MS approach on a murine model infected by Borrelia burgdorferi sensu stricto that allowed the identification of 25 Borrelia proteins among more than 1300 mouse proteins. Then we developed a targeted gel prefractionation-LC-selected reaction monitoring (SRM) assay to detect 9/33 Borrelia proteins/peptides in mouse skin tissue samples using heavy labeled synthetic peptides. We successfully transferred this assay from the mouse model to human skin biopsies (naturally infected by Borrelia), and we were able to detect two Borrelia proteins: OspC and flagellin. Considering the extreme variability of OspC, we developed an extended SRM assay to target a large set of variants. This assay afforded the detection of nine peptides belonging to either OspC or flagellin in human skin biopsies. We further shortened the sample preparation and showed that Borrelia is detectable in mouse and human skin biopsies by directly using a liquid digestion followed by LC-SRM analysis without any prefractionation. This study thus shows that a targeted SRM approach is a promising tool for the early direct diagnosis of Lyme disease with high sensitivity (<10 fmol of OspC/mg of human skin biopsy).	\N	\N
25716730	Allogeneic bone marrow transplantation (allo-BMT) is currently the only way to cure many hematoproliferative disorders. However, allo-BMT use is limited by severe complications, the foremost being graft-versus-host disease (GVHD). Due to the lack of efficiency of the existing methods of GVHD prophylaxis, new methods are being actively explored, including the use of donors' multipotent mesenchymal stromal cells (MMSC). In this work, we analyzed the results of acute GVHD (aGVHD) prophylaxis by means of MMSC injections after allo-BMT in patients with hematological malignancies. The study included 77 patients. They were randomized into two groups - those receiving standard prophylaxis of aGVHD and those who were additionally infused with MMSC derived from the bone marrow of hematopoietic stem cell donors. We found that the infusion of MMSC halves the incidence of aGVHD and increases the overall survival of patients. Four of 39 MMSC samples were ineffective for preventing aGVHD. Analysis of individual donor characteristics (gender, age, body mass index) and the MMSC properties of these donors (growth parameters, level of expression of 30 genes involved in proliferation, differentiation, and immunomodulation) revealed no significant difference between the MMSC that were effective or ineffective for preventing aGVHD. We used multiple logistic regression to establish a combination of features that characterize the most suitable MMSC samples for the prevention of aGVHD. A model predicting MMSC sample success for aGVHD prophylaxis was constructed. Significant model parameters were increased relative expression of the FGFR1 gene in combination with reduced expression levels of the PPARG and IGF1 genes. Depending on the chosen margin for probability of successful application of MMSC, this model correctly predicts the outcome of the use of MMSC in 82-94% of cases. The proposed model of prospective evaluation of the effectiveness of MMSC samples will enable prevention of the development of aGVHD in the maximal number of patients.	\N	\N
25721731	Two recent genome-wide association studies in Asians have reported the association between the PSCA (prostate stem cell antigen) rs2294008C>T gene polymorphism and two Helicobacter pylori infection-related diseases such as gastric cancer (GC) and duodenal ulcer (DU). Since rs2294008 allele frequencies differ notably among ethnicities, we aimed to assess the role of rs2294008 on the susceptibility to GC and DU in a Caucasian population in Spain. Moreover, the relevance of rs2294008 on GC prognosis was evaluated. Genomic DNA from 603 Spanish patients with primary GC, 139 with DU and 675 healthy controls was typed for the PSCA rs2294008C>T polymorphism by PCR-TaqMan assays. H. pylori infection [odds ratio (OR): 8.27; 95% confidence interval (CI): 3.45-15.33] and nonsteroidal anti-inflammatory drugs (OR: 6.54; 95% CI: 3.19-12.43) were identified as independent risk factors for DU whereas the rs2294008T allele was associated with reduced risk of developing the disease (OR: 0.52; 95% CI: 0.33-0.82). Infection with CagA strains (OR: 2.10; 95% CI: 1.63-2.34), smoking (OR: 1.93; 95% CI: 1.54-2.61), family history of GC (OR: 2.83; 95% CI: 2.01-3.83), and the rs2294008T allele (OR: 1.46; 95% CI: 1.07-1.99) were associated with increased risk of GC. Interestingly, the association with the rs2294008T allele was restricted to noncardia GC (OR: 1.43; 95% CI: 1.12-1.82), particularly of the diffuse histotype (OR: 1.59; 95% CI: 1.16-1.92). Finally, Cox regression analysis identified the rs2294008T variant as a prognosis factor associated with worse overall survival in patients with diffuse-type GC (hazard ratio: 1.85; 95% CI: 1.12-3.06). From these results we conclude that the PSCA rs2294008 polymorphism is involved in the susceptibility to GC and DU, as well as in the prognosis of the diffuse-type of GC in Caucasians.	\N	\N
25727171	In this study, we investigated the vasorelaxant and antihypertensive effects of gallic acid (GA), a polyphenol isolated from the green alga Spirogyra sp., to assess its suitability as a therapeutic for cardiovascular diseases (CVDs). We examined the effect of GA on endothelium-dependent vasorelaxation in human umbilical vein endothelial cells (HUVECs). GA increased nitric oxide (NO) levels by increasing phosphorylation of endothelial nitric oxide synthase (eNOS), and its effect on NO production was attenuated by pretreatment with the eNOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME). We also investigated its antihypertensive effect by examining GA-mediated inhibition of angiotensin-I converting enzyme (ACE). GA inhibited ACE with a half-maximal inhibitory concentration (IC50) value of 37.38 ± 0.39 μg/ml. In silico simulations revealed that GA binds to the active site of ACE (PDB: 1O86) with a binding energy of -270.487 kcal/mol. Furthermore, GA clearly reduced blood pressure in spontaneously hypertensive rats (SHR) to an extent comparable to captopril. These results suggest that GA isolated from Spirogyra sp. exerts multiple therapeutic effects and has potential as a CVD treatment.	\N	\N
25728727	The American Heart Association (AHA) established recommendations based on 7 ideal health behaviors and factors with the goal of improving cardiovascular health (CVH) and reducing both morbidity and mortality from cardiovascular disease by 20% by 2020. Few studies have investigated their association with subclinical coronary heart disease. We sought to examine whether the 7 AHA CVH metrics were associated with calcified atherosclerotic plaque in the coronary arteries. In a cross-sectional design, we studied 1,731 predominantly white men and women from the National Heart, Lung, and Blood Institute Family Heart Study without prevalent coronary heart disease. Diet was assessed by a semiquantitative food frequency questionnaire. Coronary artery calcium (CAC) was measured by cardiac computed tomography. We defined prevalent CAC using an Agatston score of 100+ and fitted generalized estimating equations to calculate prevalence odds ratios of CAC. Mean age was 56.8 years, and 41% were male. The median number of ideal CVH metrics was 3, and no participant met all 7. There was a strong inverse relationship between number of ideal CVH metrics and prevalent CAC. Odds ratios (95% CI) for CAC of 100+ were 1.0 (reference), 0.37 (0.29-0.45), 0.35 (0.26-0.44), and 0.27 (0.20-0.36) among subjects with 0 to 1, 2, 3, and 4+ ideal CVH metrics, respectively (P = .0001), adjusting for sex, age, field center, alcohol, income, education, and energy consumption. These data demonstrate a strong and graded inverse relationship between AHA ideal CVH metrics and prevalent CAC in adult men and women.	\N	\N
25738293	Celiac disease (CD) is an autoimmune disease induced by an autoimmune reaction to indigested gluten, which occurs in genetically predisposed population. The etiology of CD is linked to innate and adaptive immunity, mostly mediated by lymphocytes, especially T cells, infiltrating into the small intestinal wall. The subpopulations of T cells that infiltrate inflamed intestinal tissues comprise various CD4+ T cells and CD8+ T cells. The plethora of T cell subtypes activated in CD leads to simultaneous activation of different signaling cascades including GATA1, NF-kB, JAK or STAT5 the activity of which may be modified by diet or drugs. It was recently showed that food allergens may accelerate CD by altering the interaction between IL-15 and CD4+ T cells in the activation of CD8+ T cells. Increased levels of cytokines like IL-15 are considered to play a role in CD development. Furthermore it was showed that some drugs like tofacitinib or ruxolitinib may influence CD by blocking IL-15 signaling and CD8+ T cell activity. This mini-review will summarize the current knowledge on the role of CD4+ T cell and CD8+ T cell in clinical and experimental CD and will describe how T cell-activated signaling pathways and locally released proteins may be influenced by dietary factors and drugs used in CD treatment.	\N	\N
25750286	Herpesvirus entry mediator (HVEM) has been recently suggested to play certain roles in cancer biology. We examined HVEM expression in human colorectal cancer (CRC) to reveal its clinical importance. Immunohistochemical staining was carried-out in normal epithelium, benign and malignant lesions. While intense HVEM expression was not observed in normal epithelium and hyperplastic polyps, 24% of adenoma and more than half of CRCs had high HVEM expression. In 234 CRCs, HVEM expression was significantly associated with tumor status and pathological stage. Patients with high HVEM expression had a significantly poorer prognosis than those with low expression. Importantly, HVEM status had an independent prognostic value in CRC. Furthermore, HVEM status was inversely corrected with the presence of tumor-infiltrating T-cells. HVEM may play a critical role in tumor progression and immune evasion, and may also be a novel prognostic marker and potential therapeutic target in human CRC.	\N	\N
25770253	Although obesity has been viewed traditionally as a disease of excess nutrition, evidence suggests that it may also be a disease of malnutrition. Specifically, thiamin deficiency was found in 15.5-29% of obese patients seeking bariatric surgery. It can present with vague signs and symptoms and is often overlooked in patients without alcohol use disorders. This review explores the relatively new discovery of high rates of thiamin deficiency in certain populations of people with obesity, including the effects of thiamin deficiency and potential underlying mechanisms of deficiency in people with obesity. The 2 observational studies that examined the prevalence in preoperative bariatric surgery patients and gaps in our current knowledge (including the prevalence of thiamin deficiency in the general obese population and whether the current RDA for thiamin meets the metabolic needs of overweight or obese adults) are reviewed. Suggestions for future areas of research are included.	\N	\N
25774918	We sought to determine whether genomic polymorphism in collagen IX genes (COL9A) was associated with Kashin-Beck disease (KBD). Twenty seven single nucleotide polymorphisms (SNPs) in COL9AI, COL9A2 and COL9A3 were genotyped in 274 KBD cases and 248 healthy controls using the Sequenom MassARRAY system. Associations between the COL9A polymorphism and KBD risk were detected using an unconditional logistic regression model. Linkage disequilibrium (LD) and haplotypes analysis were performed with the Haploview software. After Bonferroni correction, the frequency distribution of genotypes in rs6910140 in COL9A1 was significantly different between the KBD and the control groups (X2 = 16.74, df = 2, P = 0.0002). Regression analysis showed that the allele "C" in SNP rs6910140 had a significant protective effect on KBD [odds ratio (OR) = 0.49, 95% confidence interval (CI) = 0.34-0.70, P = 0.0001]. The frequencies of alleles and genotypes in rs6910140 were significantly different among subjects of different KBD stages (allele: X2 = 7.82, df = 2, P = 0.02, genotype: X2 = 14.81, df = 4, P = 0.005). However, haplotype analysis did not detect any significant association between KBD and COL9A1, COL9A2 and COL9A3. We observed a significant association between rs6910140 of COL9A1 and KBD, suggesting a role of COL9A1 in the development of KBD.	\N	\N
25795200	The study aims to compare the efficacy and safety of capecitabine plus oxaliplatin (XELOX) with 5-fluorouracil/leucovorin plus oxaliplatin (FOLFOXs) in patients with advanced gastric cancer. Five databases were searched up to June 2014, without language restrictions. The outcomes included overall response rate (ORR), clinical benefit rate (CBR), and toxicity. Twenty-six eligible trials were selected from 178 studies that initially were identified. All trials were published in Chinese journals between 2005 and 2014 and included 1585 patients (787 in XELOX group and 798 in FOLFOXs group). The pooled results failed to show statistical significance of XELOX regimen on ORR (OR 1.18, 95% CIs 1.00-1.41, P = 0.057) and CBR (OR 1.10, 95% CIs 0.95-1.28, P = 0.191) as compared with FOLFOXs regimen. None of the 26 clinical trials reported progression-free survival, and only one reported overall survival rate. The meta-analysis demonstrated that XELOX regimen was associated with a significant lower risk with nausea, stomatitis, diarrhea and alopecia, and a significant higher risk of hand-foot syndrome. The evidence is limited to suggest that XELOX may share similar efficacy as FOLFOXs and reduce toxicities of chemotherapy in advanced gastric cancer therapy. However, owing to limited data and potential bias of the included studies, further rigorously controlled trials are required.	\N	\N
25801012	Eccentric distribution of atheroma has been associated with plaques likely to rupture and cause an acute coronary syndrome, but the factors responsible for the development of eccentricity remain unknown. Endothelial shear stress (ESS) drives plaque formation. We aimed to investigate the role of the local ESS characteristics in the de novo development and progressive worsening of plaque eccentricity in humans. Vascular profiling (3-vessel 3D coronary reconstruction by angiography/intravascular ultrasound, and blood flow simulation for ESS computation) was performed in 374 patients at baseline & 6-10 months follow-up. At baseline, we identified (i) disease-free segments (n=2157), and (ii) diseased regions of luminal obstructions (n=408). In disease-free regions, baseline low ESS magnitude (p<0.001), marked ESS circumferential heterogeneity (p=0.001), and their interaction (p=0.026) were associated with an increased probability of de novo eccentric plaque formation at follow-up. In diseased regions, baseline low ESS (odds ratio [OR]: 2.33, p=0.003) and large plaque burden (OR: 2.46, p=0.002) were independent predictors of substantially increasing plaque eccentricity index with worsening lumen encroachment. This combined outcome was more frequent in obstructions with both features vs. all others (33 vs. 12%; p<0.001). The incidence of percutaneous coronary intervention in worsening obstructions with increasing plaque eccentricity was higher (13.3 vs. 4.3%, p=0.011). The local hemodynamic environment has a critical effect on the development of eccentric coronary plaques at both an early and advanced stage of atherosclerosis. Local ESS assessment could help in predicting sites prone to plaque disruption and acute coronary syndromes in humans.	\N	\N
25811383	Nephropathic cystinosis is a lysosomal storage disorder caused by mutations in the CTNS gene encoding cystine transporter cystinosin that results in accumulation of amino acid cystine in the lysosomes throughout the body and especially affects kidneys. Early manifestations of the disease include renal Fanconi syndrome, a generalized proximal tubular dysfunction. Current therapy of cystinosis is based on cystine-lowering drug cysteamine that postpones the disease progression but offers no cure for the Fanconi syndrome. We studied the mechanisms of impaired reabsorption in human proximal tubular epithelial cells (PTEC) deficient for cystinosin and investigated the endo-lysosomal compartments of cystinosin-deficient PTEC by means of light and electron microscopy. We demonstrate that cystinosin-deficient cells had abnormal shape and distribution of the endo-lysosomal compartments and impaired endocytosis, with decreased surface expression of multiligand receptors and delayed lysosomal cargo processing. Treatment with cysteamine improved surface expression and lysosomal cargo processing but did not lead to a complete restoration and had no effect on the abnormal morphology of endo-lysosomal compartments. The obtained results improve our understanding of the mechanism of proximal tubular dysfunction in cystinosis and indicate that impaired protein reabsorption can, at least partially, be explained by abnormal trafficking of endosomal vesicles.	\N	\N
25813338	Poor data regarding skin involvement in Myotonic Dystrophy, also named Dystrophia Myotonica type 1, have been reported. This study aimed to investigate the prevalence and types of skin disorders in adult patients with Myotonic Dystrophy type 1. Fifty-five patients and one hundred age- and sex-matched healthy subjects were referred to a trained dermatologist for a complete skin examination to check for potential cutaneous hallmarks of disease. No difference in prevalence of preneoplastic, neoplastic, and cutaneous lesions was detected between the two groups. Among morphofunctional, proliferative and inflammatory lesions, focal hyperhidrosis (p < 0.0001), follicular hyperkeratosis (p = 0.0003), early androgenic alopecia (p = 0.01), nail pitting (p = 0.003), pedunculus fibromas (p = 0. 01), twisted hair (p = 0.01), seborrheic dermatitis (p = 0.02), macules of hyperpigmentation (p = 0.03) were significantly more frequent in patients compared with controls. In patients with Myotonic Dystrophy type 1 significant differences according to sex were found for: early androgenic alopecia, twisted hair and seborrheic dermatitis, whose prevalence was higher in males (p < 0.0001). Our preliminary results seem to rule out an increased prevalence of pre-neoplastic, and neoplastic skin lesions in Myotonic Dystrophy type 1. On the other hand, an increased prevalence of morphofunctional, inflammatory, and proliferative diseases involving adnexal structures seems to characterize adult patients with Myotonic Dystrophy type 1.	\N	\N
25834326	To investigate whether transarterial chemoembolization (TACE) before liver transplantation (LT) improves long-term survival in hepatocellular carcinoma (HCC) patients. A retrospective study was conducted among 204 patients with HCC who received LT from January 2002 to December 2010 in PLA General Hospital. Among them, 88 patients received TACE before LT. Prognostic factors of serum α-fetoprotein (AFP), intraoperative blood loss, intraoperative blood transfusion, disease-free survival time, survival time with tumor, number of tumor nodules, tumor size, tumor number, presence of blood vessels and bile duct invasion, lymph node metastasis, degree of tumor differentiation, and preoperative liver function were determined in accordance with the Child-Turcotte-Pugh (Child) classification and model for end-stage liver disease. We also determined time of TACE before transplant surgery and tumor recurrence and metastasis according to different organs. Cumulative survival rate and disease-free survival rate curves were prepared using the Kaplan-Meier method, and the log-rank and χ(2) tests were used for comparisons. In patients with and without TACE before LT, the 1, 3 and 5-year cumulative survival rate was 70.5% ± 4.9% vs 91.4% ± 2.6%, 53.3% ± 6.0% vs 83.1% ± 3.9%, and 46.2% ± 7.0% vs 80.8% ± 4.5%, respectively. The median survival time of patients with and without TACE was 51.857 ± 5.042 mo vs 80.930 ± 3.308 mo (χ(2) = 22.547, P < 0.001, P < 0.05). The 1, 3 and 5-year disease-free survival rates for patients with and without TACE before LT were 62.3% ± 5.2% vs 98.9% ± 3.0%, 48.7% ± 6.7% vs 82.1% ± 4.1%, and 48.7% ± 6.7% vs 82.1% ± 4.1%, respectively. The median survival time of patients with and without TACE before LT was 50.386 ± 4.901 mo vs 80.281 ± 3.216 mo (χ(2) = 22.063, P < 0.001, P < 0.05). TACE before LT can easily lead to pulmonary or distant metastasis of the primary tumor. Although there was no significant difference between the two groups, the chance of metastasis of the primary tumor in the group with TACE was significantly higher than that of the group without TACE. TACE pre-LT for HCC patients increased the chances of pulmonary or distant metastasis of the primary tumor, thus reducing the long-term survival rate.	\N	\N
25836637	The pathologic correlates of interstitial lung disease (ILD) secondary to connective tissue disease (CTD) comprise a diverse group of histologic patterns. Lung biopsies in patients with CTD-associated ILD tend to demonstrate simultaneous involvement of multiple anatomic compartments of the lung. Certain histologic patterns tend to predominate in each defined CTD, and it is possible in many cases to confirm connective tissue-associated lung disease and guide patient management using surgical lung biopsy. This article will cover the pulmonary pathologies seen in rheumatoid arthritis, systemic sclerosis, myositis, systemic lupus erythematosus, Sjögren syndrome, and mixed CTD.	\N	\N
25857492	Mitochondrial dysfunctions are known to be responsible for a number of heterogenous clinical presentations with multi-systemic involvement. Impaired oxidative phosphorylation leading to a decrease in cellular energy (ATP) production is the most important cause underlying these disorders. Despite significant progress made in the field of mitochondrial medicine during the last two decades, the molecular mechanisms underlying these disorders are not fully understood. Since the identification of first mitochondrial DNA (mtDNA) mutation in 1988, there has been an exponential rise in the identification of mtDNA and nuclear DNA mutations that are responsible for mitochondrial dysfunction and disease. Genetic complexity together with ever widening clinical spectrum associated with mitochondrial dysfunction poses a major challenge in diagnosis and treatment. Effective therapy has remained elusive till date and is mostly efficient in relieving symptoms. In this review, we discuss the important clinical and genetic features of mitochondrials disorders with special emphasis on diagnosis and treatment.	\N	\N
25861414	Chronic kidney disease (CKD) is characterized by increased levels of oxidative stress and inflammation. Oxidative stress and inflammation promote renal injury via damage to molecular components of the kidney. Unfortunately, relationships between inflammation and oxidative stress are cyclical in that the inflammatory processes that exist to repair radical-mediated damage may be a source of additional free radicals, resulting in further damage to renal tissue. Oxidative stress and inflammation also have the ability to become systemic, serving to injure tissues distal to the site of original insult. This review describes select mediators in the exacerbatory relationship between oxidative stress, inflammation, and CKD. This review also discusses oxidative stress, inflammation, and CKD as they pertain to the development and progression of common CKD-associated comorbidities. Lastly, the utility of several widely accessible and cost-effective lifestyle interventions and their ability to reduce oxidative stress and inflammation are discussed and recommendations for future research are provided.	\N	\N
25897458	As of late 2014, interferon beta injection was the standard "disease-modifying" treatment for patients with relapsing-remitting multiple sclerosis, in the absence of a better alternative. Alemtuzumab (Lemtrada degree, Genzyme Therapeutics), an antilymphocyte monoclonal antibody first used in some types of leukaemia, is authorised in the European Union, at a different dosage, for patients with multiple sclerosis. Clinical evaluation in multiple sclerosis is based on three unblinded trials comparing alemtuzumab with interferon beta-1a. These trials were all biased in favour of alemtuzumab and thus fail to establish the potential value of this immunosuppressant. Overall, adverse effects, including the most severe, were more frequent with alemtuzumab than with interferon beta-1a. The adverse effects of alemtuzumab reported in these trials had already been observed in cancer patients. They included potentially severe reactions to the infusion, as well as a risk of infections and cancer due to profound and prolonged immunosuppression. At the dosage authorised in multiple sclerosis, autoimmune disorders such as thyroid disorders and immune thrombocytopenic purpura are particularly frequent and serious. In practice, patients with multiple sclerosis already have difficulty coping with the troublesome consequences of their underlying disease. They should not be subjected to the serious adverse effects of alemtuzumab, especially given the absence of any proven benefit.	\N	\N
25924288	The paper describes the development of alopecia with a patient with echinocccosis alveolaris during treatment with Nemozole (albandazole). To decide to continue or to discontinue Nemozole treatment in the development of alopecia, the patient should be given full information on the risk of alopecia to his life and quality of life as compared to the sequels of recurrent hydatid disease when Nemozole is discontinued.	\N	\N
25924757	Hypercalcaemia is a common biochemical abnormality in the blood that can be caused by malignancy, hyperparathyroidism, medications or underlying medical conditions. Initial signs and symptoms are often vague, however, if someone has severe hypercalcaemia it is treated as an emergency, requiring prompt management to prevent life-threatening complications such as dehydration, cardiac arrhythmias or coma. Understanding the pathophysiology, signs and symptoms of hypercalcaemia enables effective diagnosis and holistic management of the patient with complex health needs.	\N	\N
25925920	Celiac disease (CD) is a chronic small intestinal immune-mediated enteropathy precipitated by exposure to dietary gluten in genetically susceptible individuals. CD-related enteropathy leads to multiple nutritional deficiencies involving macro- and micronutrients. Currently, medical nutrition therapy consisting of the gluten-free diet (GFD) is the only accepted treatment for CD. The GFD is the cornerstone of treatment for CD. Prior published studies have concluded that maintenance of the GFD results in improvement of the majority of nutritional deficiencies. In the past, counseling for CD focused mainly on the elimination of gluten in the diet. However, the GFD is not without its inadequacies; compliance to the GFD may result in certain deficiencies such as fiber, B vitamins, iron, and trace minerals. Paucity of fortified gluten-free foods may be responsible for certain deficiencies which develop on the GFD. Weight gain and obesity have been added to the list of nutritional consequences while on the GFD and have been partially attributed to hypercaloric content of commercially available gluten-free foods. Follow-up of patients diagnosed with CD after starting the GFD has been reported to be irregular and, hence, less than ideal. Monitoring of the nutritional status using blood tests and use of appropriate gluten-free supplementation are integral components in the management of CD. The ideal GFD should be nutrient-dense with naturally gluten-free foods, balanced with macro- and micronutrients, reasonably priced, and easily accessible. Rotation of the pseudo-cereals provides a good source of complex carbohydrates, protein, fiber, fatty acids, vitamins and minerals. Fortification/enrichment of commonly consumed gluten-free commercial grain products should be encouraged. Dietitians specializing in CD play a critical role in the education and maintenance of the GFD for patients with CD.	\N	\N
25934387	C5a plays a central role in antineutrophil cytoplasmic antibody (ANCA)-mediated neutrophil recruitment and activation. A previous study showed that C5a played a crucial role in the regulation of high mobility group box 1 (HMGB1) release from human neutrophils. The current study further investigated the interaction between C5a and HMGB1 in ANCA-induced neutrophil activation. The effects of HMGB1 inhibitors on the translocation of ANCA antigens, ANCA-induced respiratory burst and degranulation of C5a-primed neutrophils were tested. We found that blocking HMGB1 decreased C5a-mediated translocation of ANCA antigens, as well as ANCA-induced respiratory burst and degranulation of C5a-primed neutrophils. Further study showed that supernatant of C5a-primed neutrophils, which contained HMGB1, also caused translocation of ANCA antigens of primary neutrophils, whereas blocking HMGB1 decreased the translocation. In conclusion, blocking HMGB1 may attenuate ANCA-induced activation of C5a-primed neutrophils. The interaction between HMGB1 and C5a might play an important role in ANCA-induced neutrophil activation.	\N	\N
25945002	To compare ultrasound-based acoustic structure quantification (ASQ) with established non-invasive techniques for grading and staging fatty liver disease. Type 2 diabetic patients at risk of non-alcoholic fatty liver disease (n = 50) and healthy volunteers (n = 20) were evaluated using laboratory analysis and anthropometric measurements, transient elastography (TE), controlled attenuation parameter (CAP), proton magnetic resonance spectroscopy ((1)H-MRS; only available for the diabetic cohort), and ASQ. ASQ parameters mode, average and focal disturbance (FD) ratio were compared with: (1) the extent of liver fibrosis estimated from TE and non-alcoholic fatty liver disease (NAFLD) fibrosis scores; and (2) the amount of steatosis, which was classified according to CAP values. Forty-seven diabetic patients (age 67.0 ± 8.6 years; body mass index 29.4 ± 4.5 kg/m²) with reliable CAP measurements and all controls (age 26.5 ± 3.2 years; body mass index 22.0 ± 2.7 kg/m²) were included in the analysis. All ASQ parameters showed differences between healthy controls and diabetic patients (P < 0.001, respectively). The ASQ FD ratio (logarithmic) correlated with the CAP (r = -0.81, P < 0.001) and (1)H-MRS (r = -0.43, P = 0.004) results. The FD ratio [CAP < 250 dB/m: 107 (102-109), CAP between 250 and 300 dB/m: 106 (102-114); CAP between 300 and 350 dB/m: 105 (100-112), CAP ≥ 350 dB/m: 102 (99-108)] as well as mode and average parameters, were reduced in cases with advanced steatosis (ANOVA P < 0.05). However, none of the ASQ parameters showed a significant difference in patients with advanced fibrosis, as determined by TE and the NAFLD fibrosis score (P > 0.08, respectively). ASQ parameters correlate with steatosis, but not with fibrosis in fatty liver disease. Steatosis estimation with ASQ should be further evaluated in biopsy-controlled studies.	\N	\N
25971299	Cancer recurrence and disease-free survival are key outcomes for measuring the burden of illness, assessing the quality of cancer care, and informing decisions about increasingly costly cancer therapies. Yet information about recurrence is not collected in cancer registries or other population-based data sources. To address the lack of population-based recurrence information, researchers are increasingly using algorithms applied to health claims to infer recurrence. However, the validity of these approaches has not been comprehensively evaluated. In this commentary, we review existing studies and discuss options for improving the availability of recurrence data. We found that the validity of claims-based approaches appears promising in small, single institution studies, but larger population-based studies have identified substantial limitations with using claims to identify recurrence. With the increasing availability of health data, there are potential options that can be implemented to enhance information about recurrence. These options include design of software for the electronic medical record that enables rapid and standardized reporting of recurrence, use of electronic pathology reports to facilitate streamlined collection of recurrence by cancer registries, and mandates by insurers to require reporting of recurrence on health claims submitted by physicians. All of these options will require that governmental agencies, health insurers, professional societies, and other groups recognize the importance of population-based recurrence data and determine that this information is a priority for assessing cancer outcomes and costs.	\N	\N
25972525	Relations of the 25 mammalian selenoprotein genes with obesity and the associated inflammation remain unclear. This study explored impacts of high-fat diet-induced obesity on inflammation and expressions of selenoprotein and obesity-related genes in 10 tissues of pigs. Plasma and 10 tissues were collected from pigs (n = 10) fed a corn-soy-based control diet or that diet containing 3-7% lard from weanling to finishing (180 d). Plasma concentrations (n = 8) of cytokines and thyroid hormones and tissue mRNA abundance (n = 4) of 25 selenoprotein genes and 16 obesity-related genes were compared between the pigs fed the control and high-fat diets. Stepwise regression was applied to analyze correlations among all these measures, including the previously reported body physical and plasma biochemical variables. The high-fat diet elevated (P < 0.05) plasma concentrations of tumor necrosis factor α, interleukin-6, leptin, and leptin receptor by 29-42% and affected (P < 0.05-0.1) tissue mRNA levels of the selenoprotein and obesity-related genes in 3 patterns. Specifically, the high-fat diet up-regulated 12 selenoprotein genes in 6 tissues, down-regulated 13 selenoprotein genes in 7 tissues, and exerted no effect on 5 genes in any tissue. Body weights and plasma triglyceride concentrations of pigs showed the strongest regressions to tissue mRNA abundances of selenoprotein and obesity-related genes. Among the selenoprotein genes, selenoprotein V and I were ranked as the strongest independent variables for the regression of phenotypic and plasma measures. Meanwhile, agouti signaling protein, adiponectin, and resistin genes represented the strongest independent variables of the obesity-related genes for the regression of tissue selenoprotein mRNA. The high-fat diet induced inflammation in pigs and affected their gene expression of selenoproteins associated with thioredoxin and oxidoreductase systems, local tissue thyroid hormone activity, endoplasmic reticulum protein degradation, and phosphorylation of lipids. This porcine model may be used to study interactive mechanisms between excess fat intake and selenoprotein function.	\N	\N
25998164	In atopic dermatitis (AD), the inflammatory response between skin-infiltrating T cells and keratinocytes is fundamental to the development of chronic lesional eczema. The aim of this study was to investigate whether skin-derived T cells from AD patients could induce an inflammatory response in mice through keratinocyte activation and consequently cause the development of eczematous lesions. Punch biopsies of the lesional skin from AD patients were used to establish skin-derived T cell cultures, which were transferred to NOD.Cg-Prkd(scid) Il2rg(tm1Sug) /JicTac (NOG) mice. We found that the subcutaneous injection of the human AD skin-derived T cells resulted in the migration of the human T cells from subcutis to the papillary dermis followed by the development of erythema and oedema in the mouse skin. Furthermore, the human T cells induced a transient proliferative response in the mouse keratinocytes shown as increased numbers of Ki-67(+) keratinocytes and increased epidermal thickness. Out of six established AD skin-derived T cell cultures, two were superior at inducing a skin reaction in the mice, and these cultures were found to contain >10% CCR10(+) T cells compared to <2% for the other cultures. In comparison, blood-derived in vitro-differentiated Th2 cells only induced a weak response in a few of the mice. Thus, we conclude that human AD skin-derived T cells can induce a reaction in the mouse skin through the induction of a proliferative response in the mouse keratinocytes.	\N	\N
26026650	The aim of the Activating Schoolyards Study is to develop, implement, document and assess a comprehensive schoolyard intervention to promote physical activity (PA) during school recess for primary school children (grade 4-8). The intervention is designed to implement organizational and structural changes in the physical environment. The study builds on a quasi-experimental study design using a mixed method approach including: 1) an exploratory study aimed at providing input for the developing process; 2) an evaluation of the effect of the interventions using a combination of accelerometer, GPS and GIS; 3) a process evaluation facilitating the intervention development process and identifying barriers and facilitators in the implementation process; 4) a post-intervention end-user evaluation aimed at exploring who uses the schoolyards and how the schoolyards are used. The seven project schools (cases) were selected by means of an open competition and the interventions were developed using a participatory bottom-up approach. The participatory approach and case selection strategy make the study design novel. The use of a mixed methods design including qualitative as well as quantitative methods can be seen as a strength, as the different types of data complement each other and results of one part of the study informed the following parts. A unique aspect of our study is the use of accelerometers in combination with GPS and GIS in the effect evaluation to objectively determine where and how active the students are in the schoolyard, before and after the intervention. This provides a type of data that, to our knowledge, has not been used before in schoolyard interventions. Exploring the change in behavior in relation to specific intervention elements in the schoolyard will lead to recommendations for schools undergoing schoolyard renovations at some point in the future.	\N	\N
26029704	Many common diseases have a complex genetic basis in which large numbers of genetic variations combine with environmental factors to determine risk. However, quantifying such polygenic effects has been challenging. In order to address these difficulties we developed a global measure of the information content of an individual's genome relative to a reference population, which may be used to assess differences in global genome structure between cases and appropriate controls. Informally this measure, which we call relative genome information (RGI), quantifies the relative "disorder" of an individual's genome. In order to test its ability to predict disease risk we used RGI to compare single-nucleotide polymorphism genotypes from two independent samples of women with early-onset breast cancer with three independent sets of controls. We found that RGI was significantly elevated in both sets of breast cancer cases in comparison with all three sets of controls, with disease risk rising sharply with RGI. Furthermore, these differences are not due to associations with common variants at a small number of disease-associated loci, but rather are due to the combined associations of thousands of markers distributed throughout the genome. Our results indicate that the information content of an individual's genome may be used to measure the risk of a complex disease, and suggest that early-onset breast cancer has a strongly polygenic component.	\N	\N
26037125	Vaginal inflammation (vaginitis) is the most common disease caused by the human-pathogenic fungus Candida albicans. Secretory aspartyl proteinases (Sap) are major virulence traits of C. albicans that have been suggested to play a role in vaginitis. To dissect the mechanisms by which Sap play this role, Sap2, a dominantly expressed member of the Sap family and a putative constituent of an anti-Candida vaccine, was used. Injection of full-length Sap2 into the mouse vagina caused local neutrophil influx and accumulation of the inflammasome-dependent interleukin-1β (IL-1β) but not of inflammasome-independent tumor necrosis factor alpha. Sap2 could be replaced by other Sap, while no inflammation was induced by the vaccine antigen, the N-terminal-truncated, enzymatically inactive tSap2. Anti-Sap2 antibodies, in particular Fab from a human combinatorial antibody library, inhibited or abolished the inflammatory response, provided the antibodies were able, like the Sap inhibitor Pepstatin A, to inhibit Sap enzyme activity. The same antibodies and Pepstatin A also inhibited neutrophil influx and cytokine production stimulated by C. albicans intravaginal injection, and a mutant strain lacking SAP1, SAP2, and SAP3 was unable to cause vaginal inflammation. Sap2 induced expression of activated caspase-1 in murine and human vaginal epithelial cells. Caspase-1 inhibition downregulated IL-1β and IL-18 production by vaginal epithelial cells, and blockade of the IL-1β receptor strongly reduced neutrophil influx. Overall, the data suggest that some Sap, particularly Sap2, are proinflammatory proteins in vivo and can mediate the inflammasome-dependent, acute inflammatory response of vaginal epithelial cells to C. albicans. These findings support the notion that vaccine-induced or passively administered anti-Sap antibodies could contribute to control vaginitis. Candidal vaginitis is an acute inflammatory disease that affects many women of fertile age, with no definitive cure and, in its recurrent forms, causing true devastation of quality of life. Unraveling the fungal factors causing inflammation is important to be able to devise novel tools to fight the disease. In an experimental murine model, we have discovered that aspartyl proteinases, particularly Sap2, may cause the same inflammatory signs of vaginitis caused by the fungus and that anti-Sap antibodies and the protease inhibitor Pepstatin A almost equally inhibit Sap- and C. albicans-induced inflammation. Sap-induced vaginitis is an early event during vaginal infection, is uncoupled from fungal growth, and requires Sap and caspase-1 enzymatic activities to occur, suggesting that Sap or products of Sap activity activate an inflammasome sensor of epithelial cells. Our data support the notion that anti-Sap antibodies could help control the essence of candidal vaginitis, i.e., the inflammatory response.	\N	\N
26041263	Several mutations in nuclear genes encoding for mitochondrial components have been associated with an increased cancer risk or are even causative, e.g. succinate dehydrogenase (SDHB, SDHC and SDHD genes) and iso-citrate dehydrogenase (IDH1 and IDH2 genes). Recently, studies have suggested an eminent role for mitochondrial DNA (mtDNA) mutations in the development of a wide variety of cancers. Various studies associated mtDNA abnormalities, including mutations, deletions, inversions and copy number alterations, with mitochondrial dysfunction. This might, explain the hampered cellular bioenergetics in many cancer cell types. Germline (e.g. m.10398A>G; m.6253T>C) and somatic mtDNA mutations as well as differences in mtDNA copy number seem to be associated with cancer risk. It seems that mtDNA can contribute as driver or as complementary gene mutation according to the multiple-hit model. This can enhance the mutagenic/clonogenic potential of the cell as observed for m.8993T>G or influences the metastatic potential in later stages of cancer progression. Alternatively, other mtDNA variations will be innocent passenger mutations in a tumor and therefore do not contribute to the tumorigenic or metastatic potential. In this review, we discuss how reported mtDNA variations interfere with cancer treatment and what implications this has on current successful pharmaceutical interventions. Mutations in MT-ND4 and mtDNA depletion have been reported to be involved in cisplatin resistance. Pharmaceutical impairment of OXPHOS by metformin can increase the efficiency of radiotherapy. To study mitochondrial dysfunction in cancer, different cellular models (like ρ(0) cells or cybrids), in vivo murine models (xenografts and specific mtDNA mouse models in combination with a spontaneous cancer mouse model) and small animal models (e.g. Danio rerio) could be potentially interesting to use. For future research, we foresee that unraveling mtDNA variations can contribute to personalized therapy for specific cancer types and improve the outcome of the disease.	\N	\N
26083239	Dual-isotope simultaneous-acquisition (DISA) rest-stress myocardial perfusion SPECT (MPS) protocols offer a number of advantages over separate acquisition. However, crosstalk contamination due to scatter in the patient and interactions in the collimator degrade image quality. Compensation can reduce the effects of crosstalk, but does not entirely eliminate image degradations. Optimizing acquisition parameters could further reduce the impact of crosstalk. In this paper we investigate the optimization of the rest Tl-201 energy window width and relative injected activities using the ideal observer (IO), a realistic digital phantom population and Monte Carlo (MC) simulated Tc-99m and Tl-201 projections as a means to improve image quality. We compared performance on a perfusion defect detection task for Tl-201 acquisition energy window widths varying from 4 to 40 keV centered at 72 keV for a camera with a 9% energy resolution. We also investigated 7 different relative injected activities, defined as the ratio of Tc-99m and Tl-201 activities, while keeping the total effective dose constant at 13.5 mSv. For each energy window and relative injected activity, we computed the IO test statistics using a Markov chain Monte Carlo (MCMC) method for an ensemble of 1,620 triplets of fixed and reversible defect-present, and defect-absent noisy images modeling realistic background variations. The volume under the 3-class receiver operating characteristic (ROC) surface (VUS) was estimated and served as the figure of merit. For simultaneous acquisition, the IO suggested that relative Tc-to-Tl injected activity ratios of 2.6-5 and acquisition energy window widths of 16-22% were optimal. For separate acquisition, we observed a broad range of optimal relative injected activities from 2.6 to 12.1 and acquisition energy window of widths 16-22%. A negative correlation between Tl-201 injected activity and the width of the Tl-201 energy window was observed in these ranges. The results also suggested that DISA methods could potentially provide image quality as good as that obtained with separate acquisition protocols. We compared observer performance for the optimized protocols and the current clinical protocol using separate acquisition. The current clinical protocols provided better performance at a cost of injecting the patient with approximately double the injected activity of Tc-99m and Tl-201, resulting in substantially increased radiation dose.	\N	\N
26086077	Biological systems consist of multiple organizational levels all densely interacting with each other to ensure function and flexibility of the system. Simultaneous analysis of cross-sectional multi-omics data from large population studies is a powerful tool to comprehensively characterize the underlying molecular mechanisms on a physiological scale. In this study, we systematically analyzed the relationship between fasting serum metabolomics and whole blood transcriptomics data from 712 individuals of the German KORA F4 cohort. Correlation-based analysis identified 1,109 significant associations between 522 transcripts and 114 metabolites summarized in an integrated network, the 'human blood metabolome-transcriptome interface' (BMTI). Bidirectional causality analysis using Mendelian randomization did not yield any statistically significant causal associations between transcripts and metabolites. A knowledge-based interpretation and integration with a genome-scale human metabolic reconstruction revealed systematic signatures of signaling, transport and metabolic processes, i.e. metabolic reactions mainly belonging to lipid, energy and amino acid metabolism. Moreover, the construction of a network based on functional categories illustrated the cross-talk between the biological layers at a pathway level. Using a transcription factor binding site enrichment analysis, this pathway cross-talk was further confirmed at a regulatory level. Finally, we demonstrated how the constructed networks can be used to gain novel insights into molecular mechanisms associated to intermediate clinical traits. Overall, our results demonstrate the utility of a multi-omics integrative approach to understand the molecular mechanisms underlying both normal physiology and disease.	\N	\N
26109487	The aim of this study was to evaluate the long-term outcomes of patients with colorectal cancer liver metastasis (CRCLM) exhibiting disease progression after portal vein embolization (PVE). Patients with CRCLM requiring PVE before hepatectomy between 2003 and 2014 were included. Clinical variables, and liver and tumour volumes determined by three-dimensional CT volumetry were assessed before and after PVE. Overall and disease-free survival data were obtained. Univariable and multivariable logistic regression analyses were performed to identify predictors of tumour progression after PVE. Of 141 patients who underwent PVE, 93 (66.0 per cent) had tumour progression and 17 (12.1 per cent) developed new contralateral lesions. Significantly fewer patients had resectable disease in the group with disease progression than among those with stable disease: 43 (46 per cent) of 93 versus 36 (75 per cent) of 48 respectively (P = 0.001). Median survival was similar in patients with and without tumour growth after PVE: 22.5 versus 26.0 months for patients with unresectable tumours (P = 0.706) and 46.2 versus 52.2 months for those with resectable disease (P = 0.953). However, disease-free survival for patients with tumour progression after PVE was shorter than that for patients with stable disease (6.0 versus 20.2 months; P = 0.045). Response to neoadjuvant chemotherapy was the only significant factor associated with tumour progression in multivariable analysis. Tumour progression after PVE did not affect overall survival, but patients with resected tumours who had tumour growth after embolization experienced earlier recurrence. A borderline response to neoadjuvant chemotherapy seemed to be associated with tumour progression after PVE.	\N	\N
26118068	There has been a significant increase in diabetes morbidity in the past years. Prolonged asymptomatic progression of disease presents a problem and leads to late diagnosis and development of complications. Present study shows efficiency of screening measures to determine actual spread of carbohydrate metabolism disorders among residents of Odessa, frequency of type 2 diabetes mellitus risk factors determination and prevention of complications.	\N	\N
26141335	In the past few years, new biological insights into the myelodysplastic syndromes (MDS) resulting from molecular genetic analysis have improved pathologic understanding, but treatment advances have not kept pace. More than 40 genes are now known to be recurrently mutated in MDS. However, because most of these genes encode spliceosome components, chromatic remodeling factors, epigenetic pattern modulators, or transcription factors rather than more easily inhibited activated tyrosine kinases, there are as of yet few narrowly targeted therapies available for MDS. Three drugs--azacitidine, decitabine, and lenalidomide--were approved by the US Food and Drug Administration for MDS indications a decade ago, and these agents can improve hematopoiesis, delay disease progression, and improve survival and quality of life for a subset of patients. However, only a few patients with MDS respond to these agents, and their benefit is temporary. The only potentially curative therapy for MDS is allogeneic hematopoietic stem cell transplant, but owing to the advanced age of many patients with MDS and the frequency of serious comorbid conditions, less than 10% of patients currently undergo stem cell transplant. This narrative review summarizes the current understanding of MDS and treatment options for these challenging disorders.	\N	\N
26143070	Human T-lymphotropic virus type 1 (HTLV-1), a retrovirus, is the causative agent of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and adult T-cell leukaemia/lymphoma (ATLL). The reported association with pulmonary disease such as bronchiectasis is less certain. A retrospective case review of a HTLV-1 seropositive cohort attending a national referral centre. The cohort was categorised into HTLV-1 symptomatic patients (SPs) (ATLL, HAM/TSP, Strongyloidiasis and HTLV associated inflammatory disease (HAID)) and HTLV-1 asymptomatic carriers (ACs). The cohort was reviewed for diagnosis of bronchiectasis. 34/246 ACs and 30/167 SPs had been investigated for respiratory symptoms by computer tomography (CT) with productive cough +/- recurrent chest infections the predominant indications. Bronchiectasis was diagnosed in one AC (1/246) and 13 SPs (2 HAID, 1 ATLL, 10 HAM/TSP) (13/167, RR 19.2 95 % CI 2.5-14.5, p = 0.004) with high resolution CT. In the multivariate analysis ethnicity (p = 0.02) and disease state (p < 0.001) were independent predictors for bronchiectasis. The relative risk of bronchiectasis in SPs was 19.2 (95 % CI 2.5-14.5, p = 0.004) and in HAM/TSP patients compared with all other categories 8.4 (95 % CI 2.7-26.1, p = 0.0002). Subjects not of African/Afro-Caribbean ethnicity had an increased prevalence of bronchiectasis (RR 3.45 95 % 1.2-9.7, p = 0.02). Bronchiectasis was common in the cohort (3.4 %). Risk factors were a prior diagnosis of HAM/TSP and ethnicity but not HTLV-1 viral load, age and gender. The spectrum of HTLV-associated disease should now include bronchiectasis and HTLV serology should be considered in patients with unexplained bronchiectasis.	\N	\N
26148061	In humans, neurodegenerative disorders such as Huntington's disease (HD) and many spinocerebellar ataxias (SCAs) have been found to be associated with CAG trinucleotide repeat expansion. An important RNA-mediated mechanism that causes these diseases involves the binding of the splicing regulator protein MBNL1 (Muscleblind-like 1 protein) to expanded r(CAG) repeats. Moreover, mutant huntingtin protein translated from expanded r(CAG) also yields toxic effects. To discern the role of mutant RNA in these diseases, it is essential to gather information about its structure. Detailed insight into the different structures and conformations adopted by these mutant transcripts is vital for developing therapeutics targeting them. Here, we report the crystal structure of an RNA model with a r(CAG) motif, which is complemented by an NMR-based solution structure obtained from restrained Molecular Dynamics (rMD) simulation studies. Crystal structure data of the RNA model resolved at 2.3 Å reveals non-canonical pairing of adenine in 5´-CAG/3´-GAC motif samples in different syn and anti conformations. The overall RNA structure has helical parameters intermediate to the A- and B-forms of nucleic acids due to the global widening of major grooves and base-pair preferences near internal AA loops. The comprehension of structural behaviour by studying the spectral features and the dynamics also supports the flexible nature of the r(CAG) motif.	\N	\N
26149802	The importance of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for survival outcomes in patients with acute myeloid leukemia (AML) currently remains unclear. The study aimed to compare measures of clinical treatment for patients with AML in CR1 (the first complete remission) with or without being subjected to allo-HSCT. These consisted of leukemia-free survival (LFS), overall survival (OS), cumulative incidence of relapse (CIR), and non-relapse mortality disease (NRM). Subjects were 622 patients, median age of 44, forming part of the prospective, randomized, and multicenter clinical Polish Adult Leukemia Group trials during 1999-2008. The Mantel-Byar approach was used to assess allo-HSCT on survival endpoints, accounting for a changing transplant status. Undergoing allo-HSCT significantly improved the LFS and OS for the entire group of patients with AML in CR1, along with the DAC induction subgroup and for the group with unfavorable cytogenetics aged 41-60. The CIR demonstrated that allo-HSCT reduced the risk of relapse for patients with AML in CR1 and those with an unfavorable cytogenetic risk. In addition, the NRM analysis showed that allo-HSCT significantly reduced the risk of death unrelated to relapse for the entire group of AML patients in CR1 and aged 41-60. The allo-HSCT treatment particularly benefitted survival for the AML in CR1 group having an unfavorable cytogenetic prognosis.	\N	\N
26160211	The objective of this study was to compare the efficacy and comfort of inelastic bandages (IBs) and adjustable Velcro compression devices (AVCDs) in reducing venous leg edema in the initial treatment phase. Forty legs from 36 patients with untreated venous edema (C3EpsAsdPr) were randomized to two groups. Patients in the first group received IBs (n = 20) and those in the second AVCDs (n = 20). Both compression devices were left on the leg day and night, and were renewed after 1 day. Patients in the AVCD group were asked to re-adjust the device as needed when it felt loose. Leg volume was calculated using the truncated cone formula at baseline (T0), after 1 day (T1) and after 7 days (T7). The interface pressure of the two compression devices was measured by an air filled probe, and the static stiffness index calculated after applying compression at T0 and T1, and just before removal of compression on T1 and T7. Patient comfort with regard to the two compression systems was assessed by grading signs and symptoms using a visual analog scale. At T1, the median percent volume reduction was 13% for the IB group versus 19% for the AVCD group; at T7 it was 19% versus 26%, respectively (p < .001). The pressure of the IBs was significantly higher compared with the AVCDs at T0 (63 vs. 43 mmHg) but dropped by > 50% over time, while it remained unchanged with AVCDs owing to the periodic readjustment by the patient. Comfort was reported to be similar with the two compression devices. Re-adjustable AVCDs with a resting pressure of around 40 mmHg are more effective in reducing chronic venous edema than IBs with a resting pressure of around 60 mmHg. AVCDs are effective and well tolerated, not only during maintenance therapy, but also in the initial decongestive treatment phase of patients with venous leg edema.	\N	\N
26163286	Thymic stromal lymphopoietin (TSLP) is an IL-7-related cytokine that has been studied extensively in atopic diseases and more recently in various rheumatic disorders. It is involved in T cell development in the thymus and promotes homeostatic T cell expansion by classical dendritic cells. However, deregulated TSLP expression in various rheumatic diseases has implicated this cytokine as a strong mediator in immunopathology. Overexpressed TSLP induces strong T cell activation and production of pro-inflammatory cytokines in human cells and animal models for RA, SSc and LN, underscoring the therapeutic potential of targeting the TSLP-TSLP receptor axis.	\N	\N
26174498	The 14(th) -century Black Death was one of the most devastating epidemics in human history, killing tens of millions of people in a short period of time. It is not clear why mortality rates during the epidemic were so high. One possibility is that the affected human populations were particularly stressed in the 14(th) century, perhaps as a result of repeated famines in areas such as England. This project examines survival and mortality in two pre-Black Death time periods, 11-12(th) centuries vs 13(th) century CE, to determine if demographic conditions were deteriorating before the epidemic occurred. This study is done using a sample of individuals from several London cemeteries that have been dated, in whole or in part, either to the 11-12(th) centuries (n = 339) or 13(th) century (n = 258). Temporal trends in survivorship and mortality are assessed via Kaplan-Meier survival analysis and by modeling time period as a covariate affecting the Gompertz hazard of adult mortality. The age-at-death distributions from the two pre-Black Death time periods are significantly different, with fewer older adults in 13(th) century. The results of Kaplan-Meier survival analysis indicate reductions in survival before the Black Death, with significantly lower survival in the 13(th) century (Mantel Cox p < 0.001). Last, hazard analysis reveals increases in mortality rates before the Black Death. Together, these results suggest that health in general was declining in the 13(th) century, and this might have led to high mortality during the Black Death. This highlights the importance of considering human context to understand disease in past and living human populations.	\N	\N
26175069	Dengue hemorrhagic fever (DHF), although predominantly associated with secondary infections, has also been reported in primary infections. An enhanced immune response including antibodies and cytokines is implicated in the pathogenesis of secondary DHF. However, the factors operating in primary DHF are poorly understood. To understand the role of the antibody response, the relative levels of different antibody isotypes during the acute phase of infection in primary and secondary dengue infections were determined. Levels of DENV-specific IgM, IgG, IgA and IgE were measured in the serum samples of 200 dengue patients and 20 dengue-naïve individuals. Samples were collected within 15 days of onset of illness. The DENV-specific IgM levels were significantly higher in DF cases compared to DHF, which was more evident in secondary infections and in post-defervescence samples. The levels of IgG, IgA and IgE were higher in DHF cases, with greater significance in primary infections. A higher level of IgG in DHF cases was evident in pre-defervescence samples, whilst the IgE level was higher in pre- and post-defervescence samples. There was a significant correlation of IgG titres with platelet counts, with higher titres associated with lower platelet counts. It is speculated that IgG, IgA and IgE produced in response to primary infections may contribute to pathogenesis, whilst IgM produced in response to secondary infections may protect against progression to severe disease.	\N	\N
26189088	To determine the statistical correlation between visual acuity (VA) and various quantitative parameters relevant to birdshot retinochoroidopathy (BRC) evaluation. Hospital-based retrospective observational study. setting: Institutional. Consecutive HLA29+ BRC patients were included between May and August 2013 at a single tertiary center (Pitié-Salpétrière Hospital, Paris). Demographic data and quantitative parameters relevant to BRC at baseline were collected: VA, degree of anterior and posterior inflammatory reaction, foveal thickness measured by optical coherence tomography (OCT), Arden ratio, and electrooculography (EOG) light peak. Correlation between VA and the other parameters of the ipsilateral and fellow eye was performed using Spearman rank correlation coefficients. Fifty-five patients were included. Mean VA was 6/9.5 in the right eye (OD) and 6/12 in the left eye (OS). Mean foveal thickness was 240 μm OD (range: 112-606) and 251 μm OS (range: 85-662). Mean Arden ratio was 159% OD and 160% OS. EOG light peak was 714 mV OD (range: 316-1379) and 746 mV OS (range: 272-1652). VA of a given eye was moderately correlated with VA of the contralateral eye (r = 0.4). On the contrary, all other parameters showed a strong correlation between both eyes (all r > 0.7, P < .01). Overall, none of the studied parameters was correlated with its VA (all r < 0.5). In BRC, visual acuity alone does not seem to fully reflect the disease severity in terms of clinical or ancillary quantitative findings at baseline.	\N	\N
26204159	Dividing cells that experience chromosome mis-segregation generate aneuploid daughter cells, which contain an incorrect number of chromosomes. Although aneuploidy interferes with the proliferation of untransformed cells, it is also, paradoxically, a hallmark of cancer, a disease defined by increased proliferative potential. These contradictory effects are also observed in mouse models of chromosome instability (CIN). CIN can inhibit and promote tumorigenesis. Recent work has provided insights into the cellular consequences of CIN and aneuploidy. Chromosome mis-segregation per se can alter the genome in many more ways than just causing the gain or loss of chromosomes. The short- and long-term effects of aneuploidy are caused by gene-specific effects and a stereotypic aneuploidy stress response. Importantly, these recent findings provide insights into the role of aneuploidy in tumorigenesis.	\N	\N
26211602	Small cell carcinoma of head and neck region (SmCCHN) represents a rare entity and its management remains a significant clinical challenge. Complete initial response to primary therapy poses a difficult and controversial scenario for radiation oncologists. Prophylactic cranial irradiation (PCI) has long been established in the management of small cell lung cancer; however, its role in SmCCHN is still called into question. The rationale behind PCI lies in the eradication of possible micro-metastatic brain disease, which is often documented in this type of cancer. No randomized trials on this topic are available. This review, based on 20 retrospective studies, addresses the controversies in the use of PCI in SmCCHN management.	\N	\N
26253469	Under distinct pathological heart conditions, the expression of a single miRNA can display completely opposite patterns. However, the mechanism underlying the bidirectional regulation of a single miRNA and the clinical implications of this regulation remain largely unknown. To address this issue, we examined the regulation of miR-1, one of the most abundant miRNAs in the heart, during cardiac hypertrophy and ischemia/reperfusion (I/R). Our data indicated that different magnitudes and chronicities of ROS levels in cardiomyocytes resulted in differential expression of miR-1, subsequently altering the expression of myocardin. In animal models, the administration of a miR-1 mimic attenuated cardiac hypertrophy by suppressing the transverse aortic constriction-induced increase in myocardin expression, whereas the administration of anti-miR-1 ameliorated I/R-induced cardiac apoptosis and deterioration of heart function. Our findings indicated that a pathologic stimulus such as ROS can bidirectionally alter the expression of miRNA to contribute to the development of pathological conditions exhibiting distinct phenotypes and that the meticulous adjustment of the pathological miRNA levels is required to improve clinical outcomes.	\N	\N
26285805	VEGFs (vascular endothelial growth factors) are a family of conserved disulfide-linked soluble secretory glycoproteins found in higher eukaryotes. VEGFs mediate a wide range of responses in different tissues including metabolic homoeostasis, cell proliferation, migration and tubulogenesis. Such responses are initiated by VEGF binding to soluble and membrane-bound VEGFRs (VEGF receptor tyrosine kinases) and co-receptors. VEGF and receptor splice isoform diversity further enhances complexity of membrane protein assembly and function in signal transduction pathways that control multiple cellular responses. Different signal transduction pathways are simultaneously activated by VEGFR-VEGF complexes with membrane trafficking along the endosome-lysosome network further modulating signal output from multiple enzymatic events associated with such pathways. Balancing VEGFR-VEGF signal transduction with trafficking and proteolysis is essential in controlling the intensity and duration of different intracellular signalling events. Dysfunction in VEGF-regulated signal transduction is important in chronic disease states including cancer, atherosclerosis and blindness. This family of growth factors and receptors is an important model system for understanding human disease pathology and developing new therapeutics for treating such ailments.	\N	\N
26292522	At the death of Cardinal Pietro Basadonna in 1684, his personal physician Romolo Spezioli wrote a report describing the disease, circumstances of death and autopsy findings of the illustrious prelate. This document, kept in the Biblioteca Civica at Jesi, is a significant attestation of the medical terminology and diagnostic and therapeutic procedures of the time. Even with the constraints that interpretation of a clinical account dating back over 300 years inevitably imposes, perusal of this report suggests that Cardinal Basadonna's demise could have been due to septic shock, consequent to a urinary infection caused by a bulky bladder stone.	\N	\N
26293802	Leptin is an adipocytokine produced by adipocytes and controlling body weight. It is unclear whether leptin works as a proinflammatory or an anti-inflammatory cytokine. We investigated the effects of hyperleptinemia on leptin transgenic (LepTg) mice in terms of cartilage destruction, bone destruction, joint synovitis, and serum cytokine levels by using a mouse model of collagen-antibody-induced arthritis (CAIA). CAIA was induced for female age-matched 6- to 8-week-old C57BL/6 J control mice and LepTg mice. Mice were injected intraperitoneally with 5 mg of a combination of monoclonal antibody specific for type II collagen on day 0 and 12.5 mg of lipopolysaccharide (LPS) on day 3. Clinical evaluation of arthritis was monitored for 14 days, and hind paws were examined clinically and histologically. Serum cytokine levels of interleukin (IL)-1β, IL-6, IL-10, and IL-17 and tumor necrosis factor alpha (TNF-α) were also analyzed on days 0 and 5. Moreover, THP-1 cells, which are human monocytic cell line derived from an acute monocytic leukemia patient, were cultured and differentiated into macrophages. The effects of leptin on messenger RNA (mRNA) expression of IL-6 were examined by real-time quantitative polymerase chain reaction (RT-PCR). Serum leptin concentrations were approximately ninefold higher in LepTg mice (62.0 ± 20.7 ng/ml) than in control mice (7.2 ± 0.5 ng/ml). Severity of clinical paw swelling, arthritis score, synovial hyperplasia, and cartilage damage were suppressed in LepTg mice with CAIA. Although serum cytokine levels of IL-1β, IL-17, and IL-10 and TNF-α showed no significant changes in two mice, serum levels of IL-6 in LepTg mice were suppressed at day 5. Moreover, in vitro study showed that IL-6 elevation following LPS exposure in THP-1 cells was suppressed with high leptin concentrations. Our finding suggests that hyperleptinemia suppress IL-6 responses and progression of joint inflammation. Leptin may play an anti-inflammatory role under hyperleptinemia.	\N	\N
26299076	The aim of this study is to observe the association between venous thromboembolism (VTE) and oxidative stress and to see if there is a diagnostic value in the oxidative/antioxidative balance parameters like total oxidant status (TOS), total antioxidant status (TAS), paraoxonase-(PON1), and arylesterase (ARE) enzyme activities in this specific disease. Sixty-nine patients with deep vein thrombosis and/or pulmonary embolism and 40 control subjects were included in the study. Oxidative stress index, total oxidant status, and antioxidant status were examined in addition to the PON1 and ARE enzyme activities in both groups. Serum PON1 and ARE activities were significantly lower in the VTE patients, whereas total oxidant status was higher in patients compared to the controls. This preliminary study showed that oxidative/antioxidative balance shifted towards the oxidative status in venous thromboembolism. ROC analysis results suggested that the parameters used in this study were not good enough to be used in the diagnosis of VTE.	\N	\N
26310351	Google Flu Trends (GFT) was the first application of big data in the public health field. GFT was open online in 2009 and attracted worldwide attention immediately. However, GFT failed catching the 2009 pandemic H1N1 and kept overestimating the intensity of influenza-like illness in the 2012-2014 season in the United States. GFT model has been updated for three times since 2009, making its prediction bias controlled. Here, we summarized the mechanism GFT worked, the strategy GFT used to update, and its influence on public health.	\N	\N
26357715	Anal cancer is a relatively uncommon disease, accounting for only 4% of cancers of the lower gastrointestinal tract. To summarize a single-center experience in the treatment of anal carcinoma using various radiation techniques. We conducted a retrospective chart review of consecutive patients who were treated for anal cancer between the years 2002 and 2011. The data extracted included demographics, type of radiation technique, treatment-associated acute toxicity, and patterns of failure and survival. For statistical analysis purposes, the patients were divided into two groups according to radiotherapy technique: 2D (group A) and 3D (group B). A total of 42 patients--25 (59.5%) females and 17 males (40.5%)--underwent definitive chemo-radiation treatment (CRT) for anal cancer. Group A comprised 26 patients and group B 14 patients. Toxicity did not differ significantly between the groups; only in grade 1-2 skin toxicity which was more common in group B. There were significant differences in the unplanned interruptions in treatment, in both the number of patients who needed a treatment break and the number of days needed (more in group A). There were no differences in treatment response and patterns of failure between these two techniques, or in overall survival between the two groups. Our study results are consistent with reported large randomized trials, indicating that current treatments for anal carcinomas are associated with high grade acute toxicity that may result in significant treatment interruptions. The 2D technique was associated with significantly more treatment interruptions but did not differ from 3D with regard to treatment efficacy.	\N	\N
26375933	There has been considerable effort over the last 25 years to understand the emergence of complexity in motor output and how this relates to properties of the individual (e.g., age, disease state, etc.), environment (e.g., information) and task (e.g., movement, posture, isometric force). This paper addresses the behavioral dimension of motor complexity in movement and posture from a degrees of freedom (DF) perspective together with the change of complexity through aging, disease and fatigue. The dimension of behavior for a given perceptual-motor output is shown to be relatively low, dependent on the interaction between the individual, environmental, and task constraints and varies within a limited adaptive range for a given motor task. The determination of dimension in movement and posture has taken us beyond the traditional motor performance scores of behavior but it is not a sufficient characterization of the adaptive and emergent processes of complexity.	\N	\N
26381985	Assessment of the global burden of disease is based on epidemiological cohort studies that connect premature mortality to a wide range of causes, including the long-term health impacts of ozone and fine particulate matter with a diameter smaller than 2.5 micrometres (PM2.5). It has proved difficult to quantify premature mortality related to air pollution, notably in regions where air quality is not monitored, and also because the toxicity of particles from various sources may vary. Here we use a global atmospheric chemistry model to investigate the link between premature mortality and seven emission source categories in urban and rural environments. In accord with the global burden of disease for 2010 (ref. 5), we calculate that outdoor air pollution, mostly by PM2.5, leads to 3.3 (95 per cent confidence interval 1.61-4.81) million premature deaths per year worldwide, predominantly in Asia. We primarily assume that all particles are equally toxic, but also include a sensitivity study that accounts for differential toxicity. We find that emissions from residential energy use such as heating and cooking, prevalent in India and China, have the largest impact on premature mortality globally, being even more dominant if carbonaceous particles are assumed to be most toxic. Whereas in much of the USA and in a few other countries emissions from traffic and power generation are important, in eastern USA, Europe, Russia and East Asia agricultural emissions make the largest relative contribution to PM2.5, with the estimate of overall health impact depending on assumptions regarding particle toxicity. Model projections based on a business-as-usual emission scenario indicate that the contribution of outdoor air pollution to premature mortality could double by 2050.	\N	\N
26383059	Multiple sclerosis (MS) is a demyelinating disease that affects young adults; in that age group, it represents the second leading cause of disability in our setting. Its precise aetiology has not been elucidated, but it is widely accepted to occur in genetically predisposed patients who are exposed to certain environmental factors. The discovery of the regulatory role played by intestinal microbiota in various autoimmune diseases has opened a new line of research in this field, which is discussed in this review. We reviewed published studies on the role of the microbiota in the development of both MS and its animal model, experimental autoimmune encephalomyelitis (EAE). In mice, it has been shown that intestinal microorganisms regulate the polarisation of T helper cells from Th1-Th17 up to Th2, the function of regulatory T cells, and the activity of B cells; they participate in the pathogenesis of EAE and contribute to its prevention and treatment. In contrast, evidence in humans is still scarce and mainly based on case-control studies that point to the presence of differences in certain bacterial communities. Multiple evidence points to the role of microbiota in EAE. Extrapolation of these results to MS is still in the early stages of research, and studies are needed to define which bacterial populations are associated with MS, the role they play in pathogenesis, and the therapeutic possibilities this knowledge offers us.	\N	\N
26402460	Perforin-2 (MPEG1) is a pore-forming, antibacterial protein with broad-spectrum activity. Perforin-2 is expressed constitutively in phagocytes and inducibly in parenchymal, tissue-forming cells. In vitro, Perforin-2 prevents the intracellular replication and proliferation of bacterial pathogens in these cells. Perforin-2 knockout mice are unable to control the systemic dissemination of methicillin-resistant Staphylococcus aureus (MRSA) or Salmonella typhimurium and perish shortly after epicutaneous or orogastric infection respectively. In contrast, Perforin-2-sufficient littermates clear the infection. Perforin-2 is a transmembrane protein of cytosolic vesicles -derived from multiple organelles- that translocate to and fuse with bacterium containing vesicles. Subsequently, Perforin-2 polymerizes and forms large clusters of 100 Å pores in the bacterial surface with Perforin-2 cleavage products present in bacteria. Perforin-2 is also required for the bactericidal activity of reactive oxygen and nitrogen species and hydrolytic enzymes. Perforin-2 constitutes a novel and apparently essential bactericidal effector molecule of the innate immune system.	\N	\N
26427384	The ubiquitin-proteasome pathway (UPP) is the primary degradation system of short-lived regulatory proteins. Cellular processes such as the cell cycle, signal transduction, gene expression, DNA repair and apoptosis are regulated by this UPP and dysfunctions inthis system have important implications in the development of cancer, neurodegenerative, cardiac and other human pathologies. UPP seems also to be very important in the function of eukaryote cells of the human parasites like Plasmodium falciparum, thecausal agent of the neglected disease Malaria. Hence, the UPP could be considered as an attractive target for the development of compounds with Anti-Malarial or Anti-cancer properties. Recent online databases like ChEMBL contains a larger quantity of information in terms of pharmacological assay protocols and compounds tested as UPP inhibitors under many different conditions. This large amount of data give new openings for the computer-aided identification of UPP inhibitors, but the intrinsic data diversity is an obstacle for the development of successful classifiers. To solve this problem here we used the Bob-Jenkins moving average operators and the atom-based quadratic molecular indices calculated with the software TOMOCOMD-CARDD (TC) to develop a quantitative model for the prediction of the multiple outputs in this complex dataset. Our multi-target model can predict results for drugs against 22 molecular or cellular targets of different organisms with accuracies above 70% in both training and validation sets.	\N	\N
26432016	The continuous search for drugs targeting type 2 diabetes mellitus (T2DM) has led to the identification of small molecules that disrupt the binding between glucokinase and glucokinase regulatory protein (GKRP). Although mice studies are encouraging, it will take years before these disruptors can be introduced to T2DM patients. Recently, genome-wide association studies (GWASs) have shown that variants in the gene encoding GKRP protect against T2DM and kidney disease but predispose to gout, nonalcoholic fatty liver disease, and dyslipidemia. These genetic data, together with previous experience with systemic and hepatospecific glucokinase activators, provide insight into the anticipated efficacy and safety of small-molecule disruptors in humans. Interestingly, they suggest that the opposite--enhanced GKRP-glucokinase binding--could be beneficial in selected patients.	\N	\N
26470622	Hidradenitis suppurativa (HS) is a chronic inflammatory disease that commonly develops painful, deep dermal abscesses and chronic, draining sinus tracts. Classically, pharmacologic and surgical therapies have been effective for reducing lesion activity and inflammation, but provide only modest success in the prevention of future recurrences and disease progression. Adjunctive therapies, such as laser and light-based therapies, have become more commonly used in the management of HS. These therapies work to reduce the occurrence of painful HS flare-ups by decreasing the number of hair follicles, sebaceous glands, and bacteria in affected areas, and by ablatively debulking chronic lesions. The best results are seen when treatment is individualized, taking disease severity into consideration when selecting specific energy-based approaches. This article will discuss various light-based therapies and the evidence supporting their use in the management of HS.	\N	\N
26525918	Micrographia is a common symptom in Parkinson's disease, which manifests as either a consistent or progressive reduction in the size of handwriting or both. Neural correlates underlying micrographia remain unclear. We used functional magnetic resonance imaging to investigate micrographia-related neural activity and connectivity modulations. In addition, the effect of attention and dopaminergic administration on micrographia was examined. We found that consistent micrographia was associated with decreased activity and connectivity in the basal ganglia motor circuit; while progressive micrographia was related to the dysfunction of basal ganglia motor circuit together with disconnections between the rostral supplementary motor area, rostral cingulate motor area and cerebellum. Attention significantly improved both consistent and progressive micrographia, accompanied by recruitment of anterior putamen and dorsolateral prefrontal cortex. Levodopa improved consistent micrographia accompanied by increased activity and connectivity in the basal ganglia motor circuit, but had no effect on progressive micrographia. Our findings suggest that consistent micrographia is related to dysfunction of the basal ganglia motor circuit; while dysfunction of the basal ganglia motor circuit and disconnection between the rostral supplementary motor area, rostral cingulate motor area and cerebellum likely contributes to progressive micrographia. Attention improves both types of micrographia by recruiting additional brain networks. Levodopa improves consistent micrographia by restoring the function of the basal ganglia motor circuit, but does not improve progressive micrographia, probably because of failure to repair the disconnected networks.	\N	\N
26527069	Cancer, more than any other human disease, now has a surfeit of potential molecular targets poised for therapeutic exploitation. Currently, a number of attractive and validated cancer targets remain outside of the reach of pharmacological regulation. Some have been described as undruggable, at least by traditional strategies. In this article, we outline the basis for the undruggable moniker, propose a reclassification of these targets as undrugged, and highlight three general classes of this imposing group as exemplars with some attendant strategies currently being explored to reclassify them. Expanding the spectrum of disease-relevant targets to pharmacological manipulation is central to reducing cancer morbidity and mortality.	\N	\N
26574670	The neurodegenerative synucleinopathies, which include Parkinson disease, multiple-system atrophy, and Lewy body disease, are characterized by the presence of abundant neuronal inclusions called Lewy bodies and Lewy neurites. These disorders remain incurable, and a greater understanding of the pathologic processes is needed for effective treatment strategies to be developed. Recent data suggest that pathogenic misfolding of the presynaptic protein, α-synuclein (α-syn), and subsequent aggregation and accumulation are fundamental to the disease process. It is hypothesized that the misfolded isoform is able to induce misfolding of normal endogenous α-syn, much like what occurs in the prion diseases. Recent work highlighting the seeding effect of pathogenic α-syn has largely focused on the detergent-insoluble species of the protein. In this study, we performed intracerebral inoculations of the sarkosyl-insoluble or sarkosyl-soluble fractions of human Lewy body disease brain homogenate and show that both fractions induce CNS pathology in mice at 4 months after injection. Disease-associated deposits accumulated both near and distal to the site of the injection, suggesting a cell-to-cell spread via recruitment of α-syn. These results provide further insight into the prion-like mechanisms of α-syn and suggest that disease-associated α-syn is not homogeneous within a single patient but might exist in both soluble and insoluble isoforms.	\N	\N
26622256	Endometriosis is a frequent gynecologic disease with a severe impact on the quality of life in the affected women; its pathogenesis is yet to be fully understood, with an altered immunity as a possible key factor. The present study aimed to investigate the serum anti-inflammatory cytokine profile in the patients with endometriosis compared with the healthy controls. One hundred and sixty women were included, divided into two study groups (Group I - endometriosis; Group 2 - healthy women). We evaluated the serum levels of interleukin-1 receptor antagonist (IL-1Ra), IL-2, IL-2R, IL-4, IL-10, IL-13, and IL-15 with the use of Human multiplex cytokine panels. Statistical analyses (normality distribution analysis, independent t-test, Mann-Whitney U-test) were performed using IBM SPSS software (version 22.0) and GraphPad Prism (version 5.00); receiver operating characteristic curve were used to demonstrate the diagnostic performance of the studied markers. The mean serum level of IL-1Ra, IL-4, and IL-10 were significantly higher in women with endometriosis compared to women free of disease from the control group (30.155, 138.459, and 1.489, respectively, compared to 14.109, 84.710, and 0.688, respectively; P < 0.001, P < 0.001, and P = 0.002, respectively.). No significant differences in the mean serum levels of IL-2, IL-13, and IL-15 were observed between the studied groups and IL-2R had a very low detection rate. Endometriosis is associated with elevated levels of anti-inflammatory cytokines, IL-1Ra, IL-4, and IL-10, markers that have a potential role as a prognostic factor for endometriosis.	\N	\N
26628350	Adult tissue-derived mesenchymal stromal cells (MSCs) are showing promise in clinical trials for systemic lupus erythematosus (SLE). However, the inability to manufacture large quantities of functional cells from a single donor as well as donor-dependent variability in quality limits their clinical utility. Human embryonic stem cell (hESC)-derived MSCs are an alternative to adult MSCs that can circumvent issues regarding scalability and consistent quality due to their derivation from a renewable starting material. Here, we show that hESC-MSCs prevent the progression of fatal lupus nephritis (LN) in NZB/W F1 (BWF1) mice. Treatment led to statistically significant reductions in proteinuria and serum creatinine and preserved renal architecture. Specifically, hESC-MSC treatment prevented disease-associated interstitial inflammation, protein cast deposition, and infiltration of CD3(+) lymphocytes in the kidneys. This therapy also led to significant reductions in serum levels of tumor necrosis factor alpha (TNFα) and interleukin 6 (IL-6), two inflammatory cytokines associated with SLE. Mechanistically, in vitro data support these findings, as co-culture of hESC-MSCs with lipopolysaccharide (LPS)-stimulated BWF1 lymphocytes decreased lymphocyte secretion of TNFα and IL-6, and enhanced the percentage of putative regulatory T cells. This study represents an important step in the development of a commercially scalable and efficacious cell therapy for SLE/LN.	\N	\N
26633764	Ebola emerged in West Africa around December 2013 and swept through Guinea, Sierra Leone and Liberia, giving rise to 27,748 confirmed, probable and suspected cases reported by 29 July 2015. Case diagnoses during the epidemic have relied on polymerase chain reaction-based tests. Owing to limited laboratory capacity and local transport infrastructure, the delays from sample collection to test results being available have often been 2 days or more. Point-of-care rapid diagnostic tests offer the potential to substantially reduce these delays. We review Ebola rapid diagnostic tests approved by the World Health Organization and those currently in development. Such rapid diagnostic tests could allow early triaging of patients, thereby reducing the potential for nosocomial transmission. In addition, despite the lower test accuracy, rapid diagnostic test-based diagnosis may be beneficial in some contexts because of the reduced time spent by uninfected individuals in health-care settings where they may be at increased risk of infection; this also frees up hospital beds. We use mathematical modelling to explore the potential benefits of diagnostic testing strategies involving rapid diagnostic tests alone and in combination with polymerase chain reaction testing. Our analysis indicates that the use of rapid diagnostic tests with sensitivity and specificity comparable with those currently under development always enhances control, whether evaluated at a health-care-unit or population level. If such tests had been available throughout the recent epidemic, we estimate, for Sierra Leone, that their use in combination with confirmatory polymerase chain-reaction testing might have reduced the scale of the epidemic by over a third.	\N	\N
26646939	Non-alcoholic fatty liver disease (NAFLD) is a consequence of sedentary life style and high fat diets with an estimated prevalence of about 30% in western countries. It is associated with insulin resistance, obesity, glucose intolerance and drug toxicity. Additionally, polymorphisms within, e.g., APOC3, PNPLA3, NCAN, TM6SF2 and PPP1R3B, correlate with NAFLD. Several studies have already investigated later stages of the disease. This study explores the early steatosis stage of NAFLD with the aim of identifying molecular mechanisms underlying the etiology of NAFLD. We analyzed liver biopsies and serum samples from patients with high- and low-grade steatosis (also pre-disease states) employing transcriptomics, ELISA-based serum protein analyses and metabolomics. Here, we provide a detailed description of the various related datasets produced in the course of this study. These datasets may help other researchers find new clues for the etiology of NAFLD and the mechanisms underlying its progression to more severe disease states.	\N	\N
26666493	Studies have addressed the immunomodulatory effects of helminths and their protective effects upon asthma. However, anti-Ascaris IgE has been reported to be associated with an increased risk of asthma symptoms. We examined the association between serum levels of anti-Ascaris IgE and bronchial hyper-responsiveness (BHR) in children living in rural Bangladesh. Serum anti-Ascaris IgE level was measured and the BHR test done in 158 children aged 9 years selected randomly from a general population of 1705 in the Matlab Health and Demographic Surveillance Area of the International Centre for Diarrhoeal Disease Research, Bangladesh. We investigated wheezing symptoms using a questionnaire from the International Study of Asthma and Allergies in Childhood. BHR tests were successfully done on 152 children (108 'current wheezers'; 44 'never-wheezers'). We examined the association between anti-Ascaris IgE level and wheezing and BHR using multiple logistic regression analyses. Of 108 current-wheezers, 59 were BHR-positive; of 44 never-wheezers, 32 were BHR-negative. Mean anti-Ascaris IgE levels were significantly higher (12.51 UA/ml; 95% confidence interval (CI), 9.21-17.00) in children with current wheezing with BHR-positive than in those of never-wheezers with BHR-negative (3.89; 2.65-5.70; t test, p < 0.001). A BHR-positive test was independently associated with anti-Ascaris IgE levels with an odds ratio (OR) = 7.30 [95% CI, 2.28-23.33], p = 0.001 when adjusted for total IgE, anti-Dermatophagoides pteronyssinus IgE, pneumonia history, parental asthma, Trichuris infection, forced expiratory volume in one second, eosinophilic leukocyte count, and sex. Anti-Ascaris IgE level is associated with an increased risk of BHR among 9-year-old rural Bangladeshi children.	\N	\N
26685524	In the first century B.C.E., a group of Greek physicians called the Methodists denied that medicine could be based on such "hidden causes" as humors, atoms, or elements. They argued that the inner workings of the body were ultimately unknowable, existing beyond the limits of human knowledge and inference. Yet they insisted that medical certainty was still possible, claiming that every disease shared one of three directly apprehensible "manifest commonalities"--stricture, laxity, or some mixture of the two. Medicine could therefore be a science; it was simply noncausal in structure. This essay examines these medical theories in light of Herbert Simon's concept of "bounded rationality," suggesting that the Methodists were proposing a type of medical "heuristic" in response to the limitations of human knowledge and processing power. At the same time, the essay suggests that such an epistemology had its consequences, setting up an ontological crunch whereby the demands formerly placed on diseases and their causes transferred to "affections" and the commonalities, with successive generations of Methodists disagreeing about the status of symptoms, signs, and diseased states. Borrowing vocabulary from the Methodists themselves, the essay calls the consequent ontological slippage between causes and effects "metalepsis".	\N	\N
26700806	Colorectal cancer remains a major unmet medical need, prompting large-scale genomics efforts in the field to identify molecular drivers for which targeted therapies might be developed. We previously reported the identification of recurrent translocations in R-spondin genes present in a subset of colorectal tumours. Here we show that targeting RSPO3 in PTPRK-RSPO3-fusion-positive human tumour xenografts inhibits tumour growth and promotes differentiation. Notably, genes expressed in the stem-cell compartment of the intestine were among those most sensitive to anti-RSPO3 treatment. This observation, combined with functional assays, suggests that a stem-cell compartment drives PTPRK-RSPO3 colorectal tumour growth and indicates that the therapeutic targeting of stem-cell properties within tumours may be a clinically relevant approach for the treatment of colorectal tumours.	\N	\N
26722363	Matrix metalloproteinases (MMPs) play intricate roles in cancer progression; some promote invasion and angiogenesis while others suppress tumor growth. For example, human MMP-26/endometase/matrilysin-2 was reported to be either protective or pro-tumorigenic. Our previous reports suggested pro-invasion and anti-inflammation properties in prostate cancer. Here, we provide evidence for a protective role of MMP-26 in the prostate. MMP-26 expression levels in androgen-repressed human prostate cancer (ARCaP) cells, transfected with sense or anti-sense MMP-26 cDNA, are directly correlated with those of the pro-apoptotic marker Bax. Immunohistochemical staining of prostate cancer tissue samples shows similar protein expression patterns, correlating the expression levels of MMP-26 and Bax in benign, neoplastic, and invasive prostate cancer tissues. The MMP-26 protein levels were upregulated in high grade prostate intraepithelial neoplasia (HGPIN) and decreased during the course of disease progression. Further analysis using an indirect terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay showed that many tumor cells expressing MMP-26 were undergoing apoptosis. This study showed that the high level of MMP-26 expression is positively correlated with the presence of apoptotic cells. This pro-apoptotic role of MMP-26 in human prostate cancer cells and tissues may enhance our understanding of the paradoxical roles of MMP-26 in tumor invasion and progression.	\N	\N
26749833	Twenty bromotyrosine alkaloids, including a new compound, 13-oxosubereamolline D (5), were isolated from the Thai sponge Acanthodendrilla sp. Their structures were determined by analyses of 1D- and 2D-NMR, high-resolution mass, and circular dichroism data. The complete 1H and 13C NMR assignments of 5,7β-dichlorocavernicolin (19) and 5,7α-dichlorocavernicolin (20) are described herein for the first time. The acetylcholinesterase (AChE) inhibitory activity of all isolated compounds was evaluated. Only homoaerothionin (7) and fistularin 1 (10) exhibited inhibitory activity against human recombinant AChE (hrAChE) with IC50s of 4.5 and 47.5 µM, respectively. The hrAChE inhibition kinetics of 7, the most potent alkaloid, showed increased Km and unchanged Vmaxvalues, suggesting its competitive mode of inhibition. The spirocyclohexadienylisoxazole and the length of the alkyl diamine linkage were proposed as the crucial parts for its strong inhibitory activity. This finding indicates a therapeutic potential for 7 in acetylcholine-related diseases, most importantly Alzheimer's disease.	\N	\N
26769066	Genetic ancestry, sex, and individual alleles have been associated with multiple sclerosis (MS) susceptibility. To determine whether established risk factors for disease onset are associated with relapse rate in pediatric MS. Whole-genome genotyping was performed for 181 MS or high-risk clinically isolated syndrome patients from two pediatric MS centers. Relapses and disease-modifying therapies were recorded as part of continued follow-up. Participants were characterized for 25-hydroxyvitamin D serum status. Ancestral estimates (STRUCTURE v2.3.1), human leukocyte antigen (HLA)-DRB1*15 carrier status (direct sequencing), sex, and a genetic risk score (GRS) of 110 non-HLA susceptibility single-nucleotide polymorphisms (SNPs) were evaluated for association with relapse rate with Cox and negative binomial regression models. Over 622 patient-years, 408 relapses were captured. Girls had greater relapse rate than boys (incident rate ratio (IRR) = 1.40, 95% confidence interval (CI) = 1.04-1.87, p = 0.026). Participants were genetically diverse; ~40% (N = 75) had <50% European ancestry. HLA-DRB1*15 status modified the association of vitamin D status (pixn = 0.022) with relapse rate (per 10 ng/mL, in DRB1*15+ hazard ratio (HR) = 0.72, 95% CI = 0.58-0.88, p = 0.002; in DRB1*15- HR = 0.96, 95% CI = 0.83-1.12, p = 0.64). Neither European ancestry nor GRS was associated with relapse rate. We demonstrate that HLA-DRB1*15 modifies the association of vitamin D status with relapse rate. Our findings emphasize the need to pursue disease-modifying effects of MS genes in the context of environmental factors.	\N	\N
26789921	Viruses are obligate parasites and thus require the machinery of the host cell to replicate. Inhibition of host factors co-opted during active infection is a strategy hosts use to suppress viral replication and a potential pan-antiviral therapy. To define the cellular proteins and processes required for a virus during infection is thus crucial to understanding the mechanisms of virally induced disease. In this report, we generated fully infectious tagged influenza viruses and used infection-based proteomics to identify pivotal arms of cellular signaling required for influenza virus growth and infectivity. Using mathematical modeling and genetic and pharmacologic approaches, we revealed that modulation of Sec61-mediated cotranslational translocation selectively impaired glycoprotein proteostasis of influenza as well as HIV and dengue viruses and led to inhibition of viral growth and infectivity. Thus, by studying virus-human protein-protein interactions in the context of active replication, we have identified targetable host factors for broad-spectrum antiviral therapies.	\N	\N
22511225	The proteasome was first identified as a high MW protease complex that gets resolved into a series of low MW protein species upon denaturation. As the dominant protease dedicated to protein turnover, the proteasome shapes the cellular protein repertoire. Our knowledge of proteasome regulation and activity has improved considerably over the past decade. Novel inhibitors, in particular, have helped to advance our understanding of proteasome biology. They range from small peptide-based structures that can be modified to vary target specificity to large macromolecular inhibitors that include proteins. Although these reagents have an important role in establishing our current knowledge of the proteasome's catalytic mechanism, many questions remain. The future lies in designing compounds that can function as drugs to target processes involved in disease progression. Our focus in this chapter is to highlight the use of various classes of inhibitors to probe the mechanism of the proteasome and to identify its physiological significance in the cell, so that the mechanism of inhibition of proteasome will work as a definite source for design of protocols for newer therapeutic agents for the treatment of inflammation and in cancer therapy.	\N	\N
