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
